Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][N:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[S:14]>>[Br:1][CH2:2][CH2:3][CH2:4][N:9]1[C:10](=[O:13])[C:11](=[O:12])[N:7]([CH3:6])[C:8]1=[S:14]
Reactant: CN1C(=O)C(=O)NC1=S
Reactant: BrCCCBr
Product: CN1C(=O)C(=O)N(CCCBr)C1=S

Procedure:
By the procedure of Example 1(i), 1,3-dibromopropane was reacted with 1-methyl-2-thioxo-4,5-imidazolidinedione to yield 1-(3-bromopropyl)-3-methyl-2-thioxo-4,5-imidazolidinedione which, on reaction with thiourea by the procedure of Example 1(ii) gave S-[6-(1-(3-methyl-4,5-dioxo-2-thioxoimidazolidinyl))propyl]isothiourea hydrobromide. Hydrolysis of the latter compound by the procedure of Example 1(iii) and recrystallisation of the product from water gave the title compound, m.p. 141°-143°.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45](=[NH:47])[NH2:46])[CH:41]=2)[CH:36]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:14][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:45](=[NH:46])[NH2:47])[CH:41]=2)[CH:36]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
To a solution of 3.6 g of lauric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with ether, then with acetone, dissolved in methanol, freed from the insolubles by filtration, concentrated under reduced pressure, and recrystallized from ethanol to yield 1.2 g of white crystals of 6-amidino-2-naphthyl laurate methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](I)=[C:4]([CH3:10])[CH:3]=1.C([Mg]Cl)(C)C.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:18]2[CH:19]=[CH:20][O:16][C:17]=2[CH2:21][OH:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1I
Reactant: O=Cc1ccco1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1-c1ccoc1CO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
4-Bromo-2,6-dimethyl-1-iodobenzene (5 g, 16 mmol) is dissolved in dry tetrahydrofuran (20 ml) and cooled to −78° C. under an atmosphere of dry nitrogen. Isopropylmagnesium chloride (2M solution in tetrahydrofuran, 10 ml, 20 mmol) is added dropwise with vigorous stirring over 30 minutes. When the addition is complete, the reaction is allowed to warm to room temperature and is stirred for 30 minutes at room temperature. The reaction mixture is cooled to −78° C. and a solution of 2-furaldehyde (2.4 g, 25 mmol) in dry tetrahydrofuran (10 ml) is added dropwise over 30 minutes. Once the addition is complete, the mixture is allowed to warm to room temperature and stirring continued for 2 hours. A solution of saturated aqueous ammonium chloride (30 ml). is added, and the mixture is extracted with dichloromethane (3×25 ml). The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give ([4-bromo-2,6-dimethylphenyl]furan-2-yl)methanol (3.71 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:16])[F:14])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2[nH]c(=O)ccc12)C(F)(F)F
Yield: 60.6 %

Procedure:
Analogously to Example 20, 226 mg (0.73 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 140 mg (0.87 mmol) of 5-amino-2-quinolone are reacted to form 200 mg of the product.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[O:28]C>>[CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][N:22]=[C:21]4[OH:28])[C:6]=2[CH:5]2[CH2:4][CH2:3][N:2]1[CH2:16][CH2:15]2
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: COc1ncnc2ccc(Br)cc12
Product: Oc1ncnc2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc12

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (127 mg, 0.6 mmol; Example 187A) and 6-bromo-4-methoxyquinazoline (215 mg, 0.9 mmol; ChemBridge) was performed as described in Example 68 to afford the title compound as the major product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.96-2.20 (m, 4H) 2.90-2.97 (m, 1H) 3.08-3.29 (m, 4H) 4.36 (s, 2H) 7.07-7.13 (m, 3H) 7.39-7.46 (m, 1H) 7.75-7.82 (m, 1H) 7.87-7.94 (m, 1H) 8.13 (d, J=2 Hz, 1H) 8.18 (s, 1H); MS (DCI/NH3) m/z 357 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Yield: 69.8 %

Procedure:
A mixture of p-bromonitrobenzene (2.02 g, 10 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.3 mmol), and copper(I) iodide (0.05 g, 0.3 mmol) in 40 ml of N,N-diisopropylamine was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.2 g, 12 mmol) was added and the mixture was refluxed for 12 hours. After removal of amine by rotary evaporation, the residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered, and rotary evaporated. The residue was purified by column chromatography (EtOAc/hexanes, 1:10) to afford 4-(trimethylsilylethynyl)nitrobenzene (1.53 g, 70%). (Procedure adapted from Takahashi, S; Kuroyama, Y; Sonogashira, K; Hagihara, N. Synthesis, 1980, 627.)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26]O)[O:23][C:22]3=[O:28])=[CH:16][C:15]=2[F:29])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:30]1[CH:34]=[N:33][NH:32][C:31]1=[O:35]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:32]4[N:33]=[CH:34][S:30][C:31]4=[O:35])[O:23][C:22]3=[O:28])=[CH:16][C:15]=2[F:29])=[CH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncs1
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Product: O=C1O[C@@H](Cn2ncsc2=O)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Yield: 30.1 %

Procedure:
Essentially the procedure of Example 35 was used, but starting with (5R)-3-(4-(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-hydroxymethyloxazolidin-2-one (800 mg, 2 mM), and 3H-1,3,4-thiadiazol-2-one (214 mg, 2.2 mM, Helv. Chim. Acta, 1982, 65, 2606), and stirring the reaction for 18 hours. After elution from the SCX column, the gum after evaporation was triturated with diethyl ether to give the desired product (291 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([O:44][CH:45]([CH3:47])[CH3:46])[C:30]([F:43])=[C:31]([CH:42]=1)/[CH:32]=[N:33]/[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[CH3:25]>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:33]([CH2:32][C:31]1[CH:42]=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=[C:29]([O:44][CH:45]([CH3:47])[CH3:46])[C:30]=1[F:43])[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2cnc3ccccc32)cc1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc3ccccc3n2COCc2ccccc2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
To a solution of Intermediate 10.1 (50.0 mg, 0.210 mmol) in 2 mL THF at −78° C. was added 1.6 M solution of BuLi in THF (144 μL, 0.231 mmol). The mixture was stirred at −78° C. for 15 min, then a solution of Intermediate 7.3 (69 mg, 0.210 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at −78° C. for 30 min, was allowed to warm to rt over 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 95 mg of Intermediate 10.2 as a pale yellow oil.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[OH:34])[CH:29]=O>C1(C)C=CC=CC=1.O>[F:25][C:26]1[CH:27]=[C:28](/[CH:29]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C=C/c1ccc(O)c(F)c1
Temperature: 80 °C
Yield: 77.3 %

Procedure:
13.1 g (0.039 mol, 2.2 eq) of methyl (triphenylphosphoranylidene)acetate are added to a solution of 2.5 g (0.0178 mol, 1 eq) of 3-fluoro-4-hydroxybenzaldehyde in 30 ml of toluene. The reaction mixture is heated at 80° C. for 2 hours. The reaction medium is hydrolyzed in water and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (70/30 heptane/ethyl acetate). 2.7 g of methyl (E)-3-(3-fluoro-4-hydroxyphenyl)acrylate are obtained in solid form. Yield=78%
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[N:10]=[C:6]([CH2:5][O:4][CH3:3])[O:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: COCc1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(methoxymethyl)oxazol-4-yl)methanol (76 mg, 0.53 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.10 mL, 0.69 mmol) followed by DMAP (6.6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.67 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (5 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 118 mg of crude (2-(methoxymethyl)oxazol-4-yl)methyl methanesulfonate as a brown oil. LC-MS-conditions 07: tR=0.51 min, [M+H]+=222.02. A solution of this crude material (118 mg) in DMF (1.3 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (635 mg of a 9.6% solution in DMF, 0.53 mmol) in DMF (1.3 mL) pre-treated for 30 min with DIPEA (0.18 mL, 1.07 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.31. LC-MS-conditions 07: tR=0.62 min, [M+H]+=240.10.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.Cl.Cl.[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.O1CCCC1>[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([C:13]([CH:5]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2](=[O:1])[CH2:3][CH2:4]2)=[O:15])[CH2:36][CH2:35]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCC(=O)N2c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To an ice-cold stirred solution of 5-oxo-1-phenylproline (Reference Example 12, 0.22 g, 1.08 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (10 mL) was added oxalyl chloride (0.14 g, 1.10 mmol). The mixture was stirred at 0° C. for 30 min, and then allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in pyridine (10 mL). To this mixture was added 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% NaHCO3 solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to give an orange solid. This solid was recrystallized from hexane-ethyl acetate to give the title compound (0.26 g, 59%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C@@H:4]([C:5]#[C:6][C:7](C(O)=O)=[O:8])[C@H:3]1[C:12]([O:14][C@H:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13].[C:32]([OH:37])([CH2:35][CH3:36])([CH3:34])[CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[C@@H:4]([C:5]#[C:6][C:7]([O:37][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:8])[C@H:3]1[C:12]([O:14][C@H:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)C(=O)O
Reactant: CCC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
82 mg of 4-dimethylamino-pyridine were added with stirring at 5° C. to a mixture of 2.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-carboxycarbonyl-ethynyl]-cyclopropane-carboxylate, 12.5 ml of methylene chloride and 2.5 ml of tert.-amyl alcohol followed by the addition of 1.55 g of dicyclohexylcarbodiimide. The mixture was stirred at 20° C. for 41/2 hours and was cooled to 0° C. and filtered. The filtrate was evaporated to dryness under reduced pressure and was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.35 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-tert.-amyloxycarbonyl-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[CH3:9][C:6]1[C:7]([O:8][C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[C:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCC(CNc1nc(C)c(O)c(C)n1)c1ccccc1
Product: CCCCC(CNc1nc(C)c(OC(=O)Oc2ccccc2)c(C)n1)c1ccccc1

Procedure:
In a manner similar to that of the method of Example 2, the title compound was prepared from 0.76 g (2.6 mmol) of 4,6-dimethyl-5-hydroxy-2-phenylhexylaminopyrimidine and phenyl chloroformate (0.40 g, 2.6 mmol) to afford 0.74 g of product, mp: 76°-77° C. Mass spectrum m/e=419. NMR (CDCl3) delta: 7.4-6.9 (m, 10H); 4.99 (bs, 1H): 3.3 (q, 7, 4 Hz, 2H); 2.5 (t, 4 Hz, 2H); 2.3 (s, 6H): 1.8-1.1 (m, 8H). IR (CHCl3): 1780, 1583 cm-1. Anal. Calc'd for C25H29N3O3 : C, 71.57; H, 6.97: N, 10.02. Found: C, 71.51; H, 6.95; N, 10.09.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>CCOCC>[CH3:7][O:6][C:1](=[O:5])[CH2:2][CH:3]([S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:4]
Reactant: C/C=C/C(=O)OC
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CC(C)Sc1ccccc1
Reaction time: 12 h

Procedure:
Methyl crotonate (150 g, 1.5 mole) is added over a period of 15 min. to a solution at 5° C of benzenethiol (165 g, 1.5 mole) and triethylamine (10 ml) in ether (500 ml). After standing for 12 hours at room temperature the reaction mixture is distilled to give β-(phenylthio)butyric acid methyl ester as an oil, b.p. 96°-98° C/<1 mm, νmaxCHCl3 1730 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[CH:16]1([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCO>[CH3:1][O:2][C:3](=[O:15])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:23][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCCCC1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
Methyl(4-fluoro-3-nitrophenyl)carbamate (1.00 g, 4.67 mmol) and cyclohexylmethyl amine (0.730 mL, 5.60 mmol) were stirred in EtOH (20 mL) containing TEA (1.0 mL, 7.00 mmol) at 75° C. for 24 h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with 5% KHSO4 aqueous solution, saturated NaHCO3 aqueous solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 4:1/hexanes:EtOAc on silica gel. Yield: 1.05 g (73%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.04 (m, 2H), 1.25 (m, 3H), 1.69 (m, 2H), 1.77 (m, 2H), 1.83 (m, 1H), 1.86 (m, 1H), 3.14 (m, 2H), 3.78 (s, 3H), 6.46 (m, 1H), 6.84 (d, J=9.37, 1H), 7.63 (m, 1H), 8.05 (d, J=2.54 Hz, 1H), 8.09 (m, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CN2CCC(CN)CC2)CCCC1
Yield: 99.9 %

Procedure:
A solution of methyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidine-1-yl)methyl]cyclopentanecarboxylate (1.16 g, 3.27 mmol, Step 2) in CH2Cl2 (25 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was then concentrated and basified with sat. NaHCO3 aq. (100 mL), extracted with CHCl3 (100 mL) for five times. The combined extract was dried and concentrated to give 0.831 g (100%) of title compound as yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:29](I)[CH3:30]>O>[NH2:1][C:2]1[N:3]([CH2:29][CH3:30])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: CCI
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(N)nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c1=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (88 mg, 0.31 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 16 mg, 0.40 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of ethyl iodide (62 mg, 0.40 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 3 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 53 mg (55%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH:19]4[CH2:27][CH2:26][CH:22]3[CH2:21][CH2:20]4)[C:17]2=[O:28])=[C:11]([CH3:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:29])[C:12]([C:16]2[C:17](=[O:28])[CH:18]3[CH:23]([CH:22]4[CH2:26][CH2:27][CH:19]3[CH2:20][CH2:21]4)[C:24]=2[O:25][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(CC3)C2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-benzyloxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1,3-dione (2.9 g, 0.008 mol), pivaloyl chloride (1.5 ml, 0.012 mol), triethylamine (2 ml, 0.0014 mol) and dichloromethane (100 ml) is stirred at room temperature for 3 hours. The reaction mixture is next evaporated and the crude product is dissolved in dichloromethane, absorbed on to silica then purified by flash column chromatography (20% ethyl acetate in hexanes as eluant) to afford 2,2-dimethylpropionic acid 2-(4-benzyloxy-2,6-dimethylphenyl)-3-oxo-3a,4,5,6,7,7a-hexahydro-3H-4,7-ethanoinden-1-yl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Reaction time: 20 h
Yield: 30 %

Procedure:
A solution of 2-amino-6-chlorobenzoic acid (10.0 g, 0.06 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in 300 mL 3-necked flask fitted with a magnetic stirring bar and constant additional funnel. Bromoacetyl bromide was added dropwise over a 20-25 min period, while maintaining the internal temperature between 0° C. to 1° C. After the addition was completed, the ice-bath was removed and stirring was continued for 20 h. The reaction mixture was cooled in an ice-bath, water (150 mL) was added, and then the yellow crystalline product which formed was filtered and washed sequentially with 5% HBr solution (50 mL) and water (50 mL). After drying in a vacuum oven (20 h, 40°-45° C.), 5.0 g (30%) of the title compound was obtained: mp 133°-135° C. (dec.); 1H NMR (CD3OD) δ7.70 (d, 1H, J=8), 7.43 (t, 1H, J=8.4), 7.35 (d, 1H, J=8), 4.05 (s, 2H); 13C NMR (CD3OD) δ168.19, 167.84, 137.24, 133.31, 132.85, 132.08, 128.78, 128.21, 124.20, 29.21; MS (EI, m/z) 293 (M+)