Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:8][C:9]=1[NH2:10])=[O:4]
Reactant: CNC(=O)c1nc(-c2ccccn2)sc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1nc(-c2ccccn2)sc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-pyridin-2-yl-thiazole-4-carboxylic acid methylamide (34 mg, 0.10 mmol) in dichloromethane (0.5 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred at ambient temperature for 3 h. After solvent evaporation, the residue was dissolved in ethyl acetate and washed with NaOH (1N aqueous solution), water and brine. The organic layer was dried and the solvent was evaporated. The remaining residue was suspended in diethylether, sucked off, and the remaining material was dried to yield the product as yellow solid (10 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[CH:30]=[CH:29][S:28][C:27]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:27]2[S:28][CH:29]=[CH:30][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:25])=[O:24])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-benzenesulfonylthiophene-2-carbaldehyde.
Reaction SMILES: [H-].[Na+].I[CH3:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[CH:20]=3)[N:15]=[C:14]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([O:27][CH3:4])([CH3:25])[CH3:26])[CH:20]=3)[N:15]=[C:14]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:10][CH:11]=1
Reactant: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(C)(C)OC)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.186 g of 60% sodium hydride and 2.90 ml of iodomethane in THF at room temperature is added 1.00 g of 3-[(4-bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone. The reaction mixture is stirred overnight at room temperature and then quenched with ammonium chloride solution and diluted with water. The aqueous layer is extracted with ether and the combined organics are dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash chrmoatography eluting with ethyl acetate/hexanes (1:3) to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]#[N:17])[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18]C#N.O>CO>[NH2:17][CH2:16][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12][C:11]([CH3:18])([OH:15])[CH2:10]1
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC(=O)C1
Reactant: CC#N
Solvent: O
Solvent: CO
Product: CC1(O)CCCC(CN)(c2ccc(Cl)c(Cl)c2)C1
Yield: 81 %

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-3-oxo-cyclohexanecarbonitrile (1.0 g, 3.7 mmol) according to General Procedure Y, followed by General Procedure E (Scheme 31). The crude product was dissolved in MeOH (4 ML) and subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give (±) 3-aminomethyl-3-(3,4-dichloro-phenyl)-1-methyl-cyclohexanol (0.57 g, 81%).
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[F:9][C:10]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH4+].[Cl-].Cl>O1CCCC1>[F:9][C:10]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=1[C:12](=[O:13])[CH2:1][C:2]#[N:3]
Reactant: COc1ccc(C(=O)Cl)c(F)c1
Reactant: CC#N
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of MeCN (4.35 g, 106.0 mmol) in THF (200 mL) at −78° C. was added n-BuLi, 2.5 M in hexanes (32.5 mL, 79.5 mmol). The resulting solution was stirred for 20 minutes and then a solution of 2-fluoro-4-methoxybenzoyl chloride (5.00 g, 26.5 mmol) in tetrahydrofuran (THF) (50 mL) was added slowly. The reaction mixture was allowed to proceed for 1 hour at −78° C. and then saturated aqueous NH4Cl (250 mL) was added. As the reaction warmed to room temperature, it was acidified with 1 N HCl (250 mL). Then, the resulting mixture was extracted with 1:1 EtOAc:hexanes (500 mL), and the organic extract was washed with brine, dried over MgSO4, and evaporated in vacuo to provide 3.5 g (68% crude yield) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[S:22][CH:23]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[S:22][CH:23]=[C:19]([CH3:18])[N:20]=2)[CH2:25][CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: Cc1csc(N2CCNCC2)n1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: Cc1csc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)n1
Yield: 87 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-methyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an amorphous yellow solid (yield 87%). MS (m/e): 424.1 (M+H+, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[N:15]=[C:16]([NH:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[N:17]=[C:18]([NH2:19])[C:13]=3[S:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[N:15]=[C:16]([NH:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[N:17]=[C:18]([NH2:19])[C:13]=3[S:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(Nc2nc(N)c3scc(-c4cccc([N+](=O)[O-])c4)c3n2)cc(OC)c1OC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc(Nc2nc(N)c3scc(-c4cccc(N)c4)c3n2)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
7-(3-Nitrophenyl)-N2-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,4-diamine (400 mg, 0.88 mmol) was dissolved in ethanol (3.0 mL) and tin(II) chloride dihydrate (996 mg, 4.41 mmol) was added. The reaction mixture was stirred at 80° C. for 2 hours. After removing ethanol by distillation under reduced pressure, ammonia water was slowly added to make pH 5. Sodium carbonate was added to thus prepared yellow precipitate until the pH reached 7. The precipitate was filtered and washed several times with ethyl acetate. Concentration of the filtrate yielded the target compound of Example 11 (320 mg, 85% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: CC(C)(O)CN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(C)(C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (300 mg, 0.673 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and 1-amino-2-methyl-2-propanol (150 mg, 1.68 mmol), WSCI•HCl (185 mg, 0.965 mmol) and 4-dimethylaminopyridine (165 mg, 1.35 mmol) were added, followed by stirring at room temperature for 17 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (307 mg, yield 88%) as a white solid.
Reaction SMILES: [NH2:1][C@:2]1([C:41]([OH:43])=[O:42])[C@@H:6]([CH2:7][CH2:8][CH2:9][B:10]2[O:14]C(C)(C)C(C)(C)[O:11]2)[CH2:5][N:4]([C:19](=[O:40])[C@H:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[NH:21]C(OC(C)(C)C)=O)[CH2:3]1.[ClH:44]>C1COCC1.O1CCOCC1.O>[ClH:44].[ClH:44].[NH2:1][C@:2]1([C:41]([OH:43])=[O:42])[C@@H:6]([CH2:7][CH2:8][CH2:9][B:10]([OH:14])[OH:11])[CH2:5][N:4]([C:19](=[O:40])[C@H:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=2)[NH2:21])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N)(C(=O)O)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the crude (3R,4S)-3-amino-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylic acid (Step 2, 242 mg) in anhydrous THF (6 mL) under nitrogen was treated with 4 N HCl in 1,4-dioxane (6 mL). After stirring for 2 h at room temperature, 1M aqueous HCl (6 mL) was added and stirring was continued for an additional 1.5 h. The reaction mixture was diluted with water (15 mL) and washed successively with ethyl acetate (25 mL) and methylene chloride (25 mL). The aqueous phase was concentrated and the residue was purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[4-(trifluoromethyl)phenylalanyl]-pyrrolidine-3-carboxylic acid dihydrochloride (mixture of two diastereomers, each a racemate) (43 mg, 12% overall for 3 steps) as a pale yellow amorphous solid. MS (ESI+) m/z 414 (M−H2O+H+), 396 (M−2 H2O+H+); MS (ESI−) m/z 412 (M−H2O−H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:14][C:2]1([CH3:1])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: Nc1ccncc1
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Product: CC1(C)[C@@H](C(=O)Nc2ccncc2)[C@@H]1c1ccccc1
Yield: 93.4 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250 mg, 1.31 mmol) and 4-aminopyridine (123 mg, 1.31 mmol) were reacted as described under General Procedure D to furnish the title compound (326 mg, 93%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 8.48-8.45 (m, 2H), 8.35 (br s, 1H), 7.63-7.60 (m, 2H), 7.31-7.16 (m, 5H), 2.87 (d, J=5.7 Hz, 1H), 1.96 (d, J=5.7 Hz, 1H), 1.40 (s, 3H), 0.97 (s, 3H). ESIMS m/z [M+H]+ 267.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:14][OH:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:14][OH:15])[CH2:8][CH2:7]1
Reactant: COCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: COCCCN1CCC(=NO)CC1

Procedure:
1-(3-Methoxypropyl)-4-piperidone oxime is prepared from l-(3-methoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][CH2:17][C@H:18]([OH:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11][C:10]=2[CH:28]=1)=[O:5].[OH-].[Na+:30]>CO>[OH:27][C@H:18]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:17][NH:16][CH:12]1[CH2:11][C:10]2[CH:28]=[C:6]([C:4]([O-:5])=[O:3])[CH:7]=[CH:8][C:9]=2[CH2:15][CH2:14][CH2:13]1.[Na+:30]
Reactant: COC(=O)c1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2

Procedure:
8-[(2S)-2-Hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester hydrochloride was converted to the corresponding free base in a usual manner. A solution of the base (91 mg) in methanol (1 ml) and 1N sodium hydroxide aqueous solution (0.246 ml) was stirred at 70° C. for 6 hours and evaporated in vacuo. The residue was triturated in diisopropyl ether, and the precipitated powder was collected by filtration to afford sodium 8-[(2S)-2-hydroxy-3-phenoxypropyl]amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylate (74 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([OH:26])=O)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32](=[O:48])[NH:33][CH2:34][CH2:35][CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][NH2:39])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C@H:12]([C:24]([NH:39][CH2:38][C@@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:48])=[O:26])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 120 mg (0.33 mmol) of N5-(tert-butoxycarbonyl)-N2-[(benzyloxy)carbonyl]-L-ornithine and 136 mg (0.43 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 82 mg (0.43 mmol) of EDC and 13 mg (0.1 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[Cl:23])(=O)C1C=CC=CC=1.[CH:24]1([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)CCC.Cl>C(OCC)(=O)C>[ClH:23].[CH:24]1([N:29]([C:19]2[N:18]=[CH:17][N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(C)c(CNC2CCCC2)c1
Reactant: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(CN(c2ncnc3c2ncn3COCCO)C2CCCC2)c1
Yield: 75 %

Procedure:
A mixture of 9.0 g. (27 mmole) 9-[(2-benzoyloxyethoxy)-methyl]-6-chloropurine, 16.5 g. (81 mmole) N-cyclopentyl-(2,5-dimethylbenzyl)-amine and 130 ml. butanol is heated under reflux for 16 hours. The reaction mixture is evaporated, the residue is taken up in dichloromethane, washed with dilute acetic acid and subsequently with water, dried over anhydrous sodium sulphate, evaporated, mixed with a solution of 3.3 g. sodium in 200 ml. methanol, heated under reflux for 3 hours, evaporated and the residue taken up in water, extracted with dichloromethane, dried over anhydrous sodium sulphate and evaporated. After chromatography on silica gel with an elution mixture of 95% dichloromethane and 5% methanol, there are obtained 8.0 g. of the title compound (75% of theory) in the form of an oily base, the hydrochloride of which, prepared in ethyl acetate, melts at 132°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=1)=[O:12]
Reactant: O=C(Cl)Cl
Reactant: OCc1cc(F)cc(F)c1
Product: O=C(Cl)OCc1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 3,5-difluorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][C:5](F)([F:7])[C:4]([F:10])([F:9])[C:3]1([F:12])[F:11].[H][H]>[C].[Pd]>[F:1][C:2]1([F:13])[CH2:6][CH:5]([F:7])[C:4]([F:9])([F:10])[C:3]1([F:11])[F:12]
Reactant: [H][H]
Reactant: FC1(F)CC(F)(F)C(F)(F)C1(F)F
Agent: [Pd]
Product: FC1CC(F)(F)C(F)(F)C1(F)F
Temperature: 30 °C
Reaction time: 10 h

Procedure:
Octafluorocyclopentane (at a purity of 99.9%, 42.4 g, 200 mmol) and 5% palladium carbon (2.12 g) were charged in a 70 ml-autoclave fitted with an agitator, for hydrogenation a hydrogen pressure of 6 kg/cm2 at 50° C. Fifteen hours later when hydrogen consumption was completely ceased, heating was terminated to stop the reaction. After sufficient neutralization with saturated sodium bicarbonate solution, the organic layer was separated, followed by addition of 200 ml of an aqueous sodium carbonate solution at a concentration of 1 mol. The resulting mixture was agitated at 30° C. for 10 hours. The reaction solution was separated into two layers; the resulting organic layer was again charged, together with 5% palladium carbon (1.78 g) and 1 g of tridecane, in a 70 ml-autoclave, for hydrogenation at 50° C. under a hydrogen pressure of 6 kg/cm2. When hydrogen absorption was ceased 15 hours later, the reaction was terminated in the same manner as described above; then, the resulting solution was neutralized with saturated sodium bicarbonate solution, followed by distillation, to recover 1,1,2,2,3,3,3,4-heptafluorocyclopentane (at a purity of 99.0%; 34.0 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22].[CH3:23][OH:24]>>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH2:12][NH:11][C:10]1[C:5]2[N:6]([C:21]([CH3:22])=[C:3]([CH2:2][O:24][CH3:23])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Reactant: CO
Product: COCc1nc2c(NCc3c(C)cccc3C)cccn2c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
2-chloromethyl-8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine (0.3 g, 0.96 mmol) was solved in methanol (20 ml) and stirred for 20 h. at room temperature and refluxed for 20 min. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed with a bicarbonate solution. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether:petroleum ether (2:1) as eluent and crystallization from diethyl ether:petroleum ether (2:1) gave 0.13 g (44%) of the desired product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)OCC1.Cl.O1CCC[CH2:42]1>C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([OH:1])[CH2:10][CH2:9]2)[C:12]2[N:13]([N:37]=[C:38]([CH3:42])[N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (14 g), 3N hydrochloric acid (50 mL) and tetrahydrofuran (50 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (40 mL) and methanol (40 mL), sodium borohydride (1.5 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (12 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-(3-hydroxyphenyl)acetamide (5.5 g, 0.019 mol) in DMF (25 ml) was added potassium carbonate powder (3.93 g, 0.028 mol). To the flask was added benzyl bromide (2.37 ml, 0.021 mol). The reaction was allowed to stir overnight. Solvent was removed and the reaction was diluted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, filtered and concentrated. The crude product was triturated with ether and hexanes to provide the title compound (4.65 g, 64% yield): ES-MS (m/z) 386 [M+H]+.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.O1CCC[CH2:22]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21

Procedure:
In 100 ml of tetrahydrofuran is suspended 25 g of methyltriphenylphosphonium bromide and 40 ml of 1.6 N-n-butyl lithium helium hexane solution is dropwise added thereto under a nitrogen atmosphere and ice-cooling. After stirring the mixture under ice-cooling for 30 minutes, a solution obtained by dissolving 15 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 250 ml of tetrahydrofuran is dropwise added thereto and the mixture is stirred at room temperature for two hours. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=3:1) to obtain 3.7 g of the desired product as a colorless oily matter.