Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:28])[C:24](=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:1])=[CH:11][C:10]2=[O:12])[C:25](=[O:27])[CH3:26]
Reactant: COc1ccccc1C(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccccc1C(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
250 mg (1.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 280.9 mg (1.46 mmol) of 1-(2-methoxyphenyl)butane-1,3-dione, 99.7 mg (1.66 mmol) of acetic acid and 11.3 mg (0.13 mmol) of piperidine in 5 ml of dichloromethane and, after addition of molecular sieves, heated under reflux under argon for 4 h. The solvent is removed after filtration in vacuo. 480 mg (99% of theory) of the title compound are obtained and are employed without further purification in the next stage.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[N:12]=[C:11]([CH2:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)(Cl)Cl.O1CCOCC1>[Br:1][CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[N:12]=1)[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Cc1ccnc(C(C)(C)C)n1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(Br)c1ccnc(C(C)(C)C)n1
Temperature: 12.5 °C

Procedure:
Bromine (3.25 g, 20.7 mmol) in chloroform (20 ml) is added dropwise over 5 hours to a stirred solution of 1-(2-tert-butyl-pyrimidin-4-yl)-propan-2-one (4.0 g, 20.7 mmol) in dioxane (300 ml) maintained at 10-15° C. When the addition is complete the solvent is removed in vacuo to give the titled compound as a hydrobromide salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:3]=1[C:28]#[N:29].C(N(CC)CC)C.Br[CH2:38][CH2:39][C:40](Cl)=[O:41]>CS(C)=O.C(Cl)(Cl)Cl>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:3]([C:28]#[N:29])=[C:2]([NH2:1])[N:7]=[C:6]([S:8][CH2:9][C:10]3[N:11]=[C:12]([CH2:16][NH:17][C:40](=[O:41])[CH:39]=[CH2:38])[CH:13]=[CH:14][CH:15]=3)[N:5]=2)=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: O=C(Cl)CCBr
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN)n3)nc(N)c2C#N)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NCc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(NC(C)=O)cc3)n2)n1
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
The compound of Example 32 (0.5 g) and triethylamine (0.3 mL) was dissolved in 5 mL of DMSO, to the solution at ice temperature added 0.17 g of 3-bromopropionyl chloride, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with chloroform, washed with water (twice) and brine (once), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the resulting crude crystal was washed with diethyl ether to give 0.12 g of N-{6-[4-(4-acetylaminophenyl)-6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl]pyridin-2-ylmethyl}acryl-amide as a white powder.
Reaction SMILES: [C:1]([C:3](=[C:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][C:13]=2[F:29])[CH2:8][CH2:7]1)[C:4]#[N:5])#[N:2].[I-].[CH3:31][S+](C)(C)=O.CC(C)([O-])C.[K+]>CS(C)=O>[C:1]([C:3]1([C:4]#[N:5])[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:14][C:13]=3[F:29])[CH2:8][CH2:7]2)[CH2:31]1)#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)C(=O)O1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CC4(C#N)C#N)c(F)c2)C(=O)O1
Yield: 57 %

Procedure:
The title compound was prepared by reacting (S)-N-[3-{4-[4-dicyanomethylidenepiperidin-1-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]-acetamide (1.0 mmol, Example C), trimethyloxosulphonium iodide (1.3 mmol), potassium tert-butoxide (1.3 mmol) in dimethylsulfoxide (10 ml) at a temperature 25° C. for 14 hours in 57% yield.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].C1(=O)OCC1.C([NH-])C=C>>[CH2:16]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCCCCCCBr
Reactant: O=C1CCCCO1
Agent: C=CC[NH-]
Agent: O=C1CCO1
Product: C=CCCCCCCC1CCCOC1=O
Yield: 63 %

Procedure:
13.25 g of tetrahydro-3-(7-octenyl)-2H-pyrane-2-one of interest was prepared in the same manner as in Example 1 except that 10.01 g (100.0 mmol) of δ-valerolactone and 22.93 g (110.0 mmol) of 8-bromo-1-octene were used instead of β-propiolactone and allyl amide described in Preparation Example 1.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12][CH2:13][C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2

Procedure:
A suspension of bicyclic olefin imidazole (0.1 mmol, the title compound of Example 1434) and 20 mg (0,019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1436.
Reaction SMILES: [Na].[CH3:2][SH:3].Cl[CH2:5][CH2:6][CH2:7][N:8]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:22][CH3:23])[CH2:13]1)[CH2:9][CH2:10][CH3:11]>C(O)C>[CH3:23][O:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][CH:12]([N:8]([CH2:7][CH2:6][CH2:5][S:3][CH3:2])[CH2:9][CH2:10][CH3:11])[CH2:13]2
Reactant: CCCN(CCCCl)C1CCc2c(cccc2OC)C1
Reactant: CS
Agent: [Na]
Solvent: CCO
Product: CCCN(CCCSC)C1CCc2c(cccc2OC)C1
Reaction time: 1 h

Procedure:
2.35 g sodium are dissolved in 50 ml absolute ethanol and immediately 4.8 g methylmercaptan in 60 ml ethanol are added dropwise. The mixture is warmed to 45° and at this temperature a solution of 19.7 g 2-[N-(3-chloropropyl)-N-propylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene in 120 ml absolute ethanol are added. The mixture is stirred at 50° for 1 hour. The residue is partitioned between ether and water. The ether phase is dried over potassium carbonate, filtered and concentrated. The resultant oil containing the heading compound is used further as such.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11](OC)=O)[CH:9]=[CH:10][C:4]=2[NH:3]1.P(Cl)(Cl)(Cl)=O>O>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[NH:3][C:2](=[O:1])[NH:6][C:5]=2[CH:7]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-6-carboxylate (43 g, 0.22 mol) was charged into phosphorus oxychloride (286 ml). Dry hydrogen chloride was bubbled through the boiling reaction mass for 12 hours. After cooling reaction mass was poured in mixture of ice and water (2 kg). Precipitate was filtered out. Filtrate was diluted with water (1.25 litres) and ammonia solution (˜800 ml). After that pH was adjusted to 5.6 with ammonia solution. Precipitate was filtered and rinsed with water. Yield 39.5 g (84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)=[O:4]>CO.C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-Nitro-1H-indole-2-carboxylic acid methyl ester 108 200 mg (0.91 mmole) in a mixture of methanol/ethylacetate (1:1) 10% Pd/C (40 mg) was added. The flask was rinsed 3 times with hydrogen and filled with hydrogen at 30 to 35 psi. The suspension was stirred vigorously at room temperature for 30 minutes. The catalyst was filtered off, the filtrate was evaporated in vacuo to dryness. The resulted 6-amino-1H-indole-2-carboxylic acid methyl ester gave a single spot on TLC (Silica, toluene-ethylacetate 7:3, Rf: 0.31) and was used for the next step without purification
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:44])[C:13]2=[N:14][N:15]([CH2:17][C:18]3[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=3)[N:16]=[C:11]3[C:12]2=[C:6]([CH2:7][S:8][N:9]=[C:10]3[N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:5]1=[O:43].CO>O>[NH2:28][C:10]1[C:11]2[C:12]3[C:13](=[N:14][N:15]([CH2:17][C:18]4[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=4)[N:16]=2)[C:4]([F:44])([F:3])[CH:5]([OH:43])[C:6]=3[CH2:7][S:8][N:9]=1
Reactant: COc1c(C)cnc(CN2N=C3C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC4=C3C(=N2)C(F)(F)C4=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3C(N)=NSCC4=C3C(=N2)C(F)(F)C4O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
Sodium borohydride (6 mg) was added to a mixture composed of the above di-tert-butyl {9,9-difluoro-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (41 mg) and methanol (2 ml) under ice-cooling, and the mixture was stirred at 0° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (8.7 mg, 42% in total from Example 110) as a solid.
Reaction SMILES: BrCC[C@H]1CC[C@H](CCCCC)CC1.[Mg].P(OCC)(OCC)(OCC)=O.Cl[SiH]1CCC([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[C:44]([F:46])[C:43]([O:47][C:48]([F:51])([F:50])[F:49])=[C:42]([F:52])[CH:41]=3)=[CH:36][CH:35]=2)CC1>[Cu]I.C1COCC1>[F:46][C:44]1[CH:45]=[C:40]([C:37]2[CH:36]=[CH:35][CH:34]=[CH:39][CH:38]=2)[CH:41]=[C:42]([F:52])[C:43]=1[O:47][C:48]([F:49])([F:50])[F:51]
Reactant: Fc1cc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc(F)c1OC(F)(F)F
Agent: [Cu]I
Agent: CCCCC[C@H]1CC[C@H](CCBr)CC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: Fc1cc(-c2ccccc2)cc(F)c1OC(F)(F)F
Yield: 90.1 %

Procedure:
26.1 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-pentylcyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 40.7 g (0.1 mol) of 4-(4-chloro-4-silacyclohexyl)3',5'-difluoro-4'-trifluoromethoxybiphenyl. After a conventional after treatment, 4-(2-(trans-4-n-pentylcyclohexyl)ethyl)-4-silacyclohexyl)-3',5'-difluoro-4'-trifluoromethoxybiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 44.3 g (yield 90.1%) of the trans isomer.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:15][C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=1[OH:23].[C:24](O)(=O)/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>CS(O)(=O)=O>[Br:22][C:20]1[CH:19]=[CH:18][C:17]2[O:23][C:24](/[CH:25]=[CH:26]/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][C:16]=2[CH:21]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: Brc1ccc2oc(/C=C/c3ccccc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
Phosphorus pentaoxide (2.84 g) was added to methanesulfonic acid (10 ml) and the mixture was stirred at 100° C. for 1 hour to give a solution. To the solution were added 2-amino-4-bromophenol (1.88 g) and trans-cinnamic acid (1.48 g), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was poured onto ice, neutralized with an 8 N sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:3, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 5-bromo-2-[(E)-2-phenylethenyl]benzoxazole (966 mg, 32%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:8]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:7][C:5]=2[N:6]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:26]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:8]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:7][C:5]=2[N:6]=1)(=[O:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc3sc(N)nc3cc2C(C)(C)C)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cc(C(C)(C)C)c(SS(=O)(=O)c3ccc(C)cc3)cc2s1

Procedure:
The title compound was prepared as described in Example BB-15 using toluene-4-thiosulfonic acid S-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in Example BB-1; 1.75 g, 4.47 mmol), acetyl chloride (4 mL), pyridine (5 mL), DMAP (0.3 g) and CH2Cl2 (20 mL). The crude product was purified by flash silica gel chromatography (20%-70% EtOAc in hexanes as eluents). MS(APCI): 435 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:18][CH3:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:18][CH3:19])=[N:22][CH:23]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCC1C(=O)N(CC)CCc2c1ccc(N)c2OC
Product: CCC1C(=O)N(CC)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3C(=O)NC)n1)c2OC

Procedure:
Prepared in the same manner as Example 151 from 7-amino-1,3-diethyl-6-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (85 mg, 0.32 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.36 mmol) to yield 2-[5-Chloro-2-(1,3-diethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow powder. MP: 157-158° C.; 1H-NMR (CDCl3) δ 11.01 (s, 1H), 8.65 (d, J=8.6 Hz, 1H), 8.09 (d, J=17.3 Hz, 2H), 7.50-7.35 (m, 3H), 7.08 (t, J=7.8 Hz, 1H), 6.69 (s, 1H), 6.28 (br s, 1H), 3.96-3.80 (m, 5H), 3.60-3.40 (m, 4H), 3.12-2.91 (m, 5H), 2.21 (p, J=7 Hz, 1H), 1.90 (p, J=7 Hz, 1H), 1.09 (m, 6H); LC/MS (ESI+): 523 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:17])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCOc1ccccc1Cl
Product: O=C(Cl)CCCOc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 4-(2-chloro-phenoxy)-butyric acid (250 mg, 1.165 mmol) was added portion wise thionyl chloride (1.69 mL), and the reaction mixture was stirred for 3 hours at 90° C. After such time the excess of thionyl chloride was removed in vacuo to yield the crude title compound which was used in the next step without any further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([O:26]C)=[O:25])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.2 %

Procedure:
To a solution of example 53 (0.190 g, 0.480 mmol) in methanol (2.7 ml), lithium hydroxide (0.201 g, 4.80 mmol) in water (0.75 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as brown solid (0.070 g, 38%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.39 (s, 1H), 8.87 (d, J=2.6 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.07 (m, 3H), 7.85 (dd, J=8.7, 1.5 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.52 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10]SC.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([S:10][CH3:9])=[CH:7][N:6]=1
Reactant: CSSC
Reactant: Clc1ncc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cnc(Cl)nc1
Reaction time: 2 h
Yield: 17.9 %

Procedure:
A solution of 1.00 g (5.17 mmol) of 5-bromo-2-chloropyrimidine and 551 μl (6.20 mmol) of dimethyl disulfide in 26 ml of tetrahydrofuran was cooled to −78° C. and 1.89 ml (5.17 mmol) of 2.73 N n-butyl lithium/n-hexane solution was added thereto, and the reaction solution was stirred for 2 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 149 mg of the title compound as a white solid (yield: 18%).
Reaction SMILES: C(O[C@H:9]([CH3:31])[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:28])=[N:22][C:23]=3[Cl:27])[C@H:15]([OH:29])[C@@H:14]1[OH:30])=[O:11])C1C=CC=CC=1.[C:32]([O:36]CCC(O)=O)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][CH2:31][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:28])=[N:22][C:23]=3[Cl:27])[C@H:15]([OH:29])[C@@H:14]1[OH:30])=[O:11])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OCCC(=O)O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CC(C)(C)OCCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared as described for (R)-2-benzyloxy-N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (Example 181, Step 1), by replacing (R)-2-benzyloxy-propionic acid with 3-tert-butoxypropionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1.Cl.Br[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[N:8]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:4]=2[C:3]=1[O:13][CH2:14][CH:15]1[CH2:18][CH2:17][CH2:16]1
Reactant: Cn1c(=O)[nH]c2c(OCC3CCC3)c(Br)ccc21
Reactant: BrCCN1CCOCC1
Agent: Cl
Product: Cn1c(=O)n(CCN2CCOCC2)c2c(OCC3CCC3)c(Br)ccc21

Procedure:
This compound was synthesized according to the procedure of Example 44, Step 2, using 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 4-(2-bromoethyl)morpholine hydrochloride as the starting materials. LCMS calculated for C19H27BrN3O3 (M+H)+: m/z=424.1, 426.1. found: 424.3, 426.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH3:17][C:18]([CH3:26])([CH3:25])[C:19]#[C:20]/[CH:21]=[CH:22]/[CH2:23]Br.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[CH2:23]/[CH:22]=[CH:21]/[C:20]#[C:19][C:18]([CH3:26])([CH3:25])[CH3:17])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)C#C/C=C/CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C/C=C/C#CC(C)(C)C)P(=O)(OCC)OCC
Yield: 66.8 %

Procedure:
3.34 g of diethylphosphonoacetic acid ethyl ester is dissolved in 40 ml of ethanol, 594 mg of 60% oily sodium hydride is added under ice cooling and stirring, and ethanol solution (10 ml) of 600 mg of (E)-6,6-dimethyl-2-hepten-4-ynyl bromide is added dropwise, and the mixture is stirred for 5 hours. The reaction solution is neutralized with 1N hydrochloric acid and then concentrated under reduced pressure, the residue is dissolved in a mixture of water with ethyl acetate, the organic layer is taken and post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 140 g; hexane/ethyl acetate=3/1→1/1] to obtain 686 mg of (E)-diethylphosphono-(6,6-dimethyl-2-hepten-4-ynyl)acetic acid ethyl ester as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][C:16]#[N:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.N.CO>O1CCCC1.CO.[Co]>[F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(F)cc2n1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc2c3c(c(F)cc2n1)CCC3=CCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (5-fluoro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)acetonitrile (156 mg, 0.686 mmol) in tetrahydrofuran/methanol (5 mL/5 mL) were added Raney cobalt (1.5 g) and 2M ammonia/methanol solution (2 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (157 mg, yield 99%).