Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.[CH2:47]([Si:49]([C:54]#[CH:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:48]>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.CN(C)C=O>[Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:48]#[C:47][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51]
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC[Si](C#Cc1c(Cl)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12)(CC)CC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To 61 mg (0.14 mmol) of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 30-(b) were added 5 mg of bis(triphenylphosphine)palladium dichloride, 4 mg of cuprous iodide, 8 mg of triphenylphosphine, 1 ml of diisopropylamine, 0.04 ml of triethylsilylacetylene and 0.4 ml of N,N-dimethylformamide, the mixture was degassed under reduced pressure and replaced with argon, and the mixture was stirred at 80° C. for 1.5 hours. After completion of the reaction, toluene was added to the reaction mixture, and the mixture was washed successively with 5% aqueous sodium hydrogen sulfite solution, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 47 mg of the title compound as a yellowish solid. (Yield: 75%)
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:74])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:72])[C:57]4[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:73])[C:36]([O:38]C)=[O:37]>>[CH3:74][CH:34]([CH3:33])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:72])[C:57]4[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:73])[C:36]([OH:38])=[O:37]
Reactant: CCCCCCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 75 %

Procedure:
The compound of example 186 was prepared analogous to compound of example 98 by hydrolysis of compound of example 185.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[O:7][CH2:8][C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(P(N(C)C)(N(C)C)=O)C>[CH2:44]([C@@H:8]([O:7][C@H:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH3:28])[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[O:7][CH2:8][C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: BrCc1ccccc1
Agent: CCCCC(OCC(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCC[C@H](O[C@H](Cc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)c1ccco1

Procedure:
Using the procedure in example 90 and (4S) benzhydryl 4-(2-furyl)-3-oxaoctanoate (5.0 g, 13.2 mmol), THF (50 mL), sodium bis(trimethylsilyl)amide (1.0M in THF, 14 mL, 14 mmol), and benzyl bromide (1.7 mL, 14 mmol) in 10 mL HMPA gave (2R,4S) benzhydryl 2-Benzyl-4-(2-furyl)-3-oxaoctanoate, 646.6 mg (10%) and 723 mg (12%) of the (2S 4S) diastereomer which was identical to the sample prepared in example 90. (2R,4S) diastereomer: [α]25D -34.8° (c 1.12, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.78 (t, 3H, J=7 Hz), 1.12 (m, 4H), 1.69 (m, 1H), 1.83 (m, 1H), 2.98 (m, 2H), 4.11 (t, 1H, J=7 Hz), 4.21 (dd, 1H, J=8 Hz), 6.07 (m, 2H), 6.72 (s, 1H), 7.26 (m, 16H); mass spectrum (FAB): 486 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Yield: 17.2 %

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (710 mg) in dioxane (10 mL) was added CDI (42.6 mg, 2.63 mmol). The resulting mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (130 mg, 17% over 2 steps). ESI-MS m/z [M+H]+ 431.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1>CN(C=O)C>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)cc1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.1 %

Procedure:
A solution of 5-bromo-2,4-dihydroxy-benzoic acid (520 mg, 2.33 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (471 mg, 2.45 mmol) then HOBt (362 mg, 2.68 mmol). After 25 min, 2,3-dihydro-1H-isoindole (0.5 mL, 2.63 mmol) was added then the mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo then the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine then dried (MgSO4) and concentrated. The residue was triturated with methanol to afford the title compound as a grey solid (328 mg, 44%). 1H NMR (DMSO-d6) 10.45 (1H, s), 10.32 (1H, s), 7.36 (1H, br.s), 7.35 (1H, s), 7.28 (3H, br.s), 6.59 (1H, s), 4.77 (2H, br.s), 4.71 (2H, br.s). MS: [M+H]+332/334.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.O>N1CCCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[CH:1][C:2]2[N:3]=[C:4]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:7]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1nc(N2CCOCC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(C=Cc2nc(N3CCOCC3)c([N+](=O)[O-])c(N3CCOCC3)n2)cc1
Yield: 34.3 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A solution of 2-methyl-4,6-dimorpholino-5-nitropyrimidine (1.13 g, 3.65 mmol) and p-anisaldehyde (3.50 ml, 29.3 mmol) in piperidine (5 ml) was agitated under heating for 4 hours at 130 degrees Celsius. Water was added, and extraction was carried out 2 times using ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=1:1), and 535 mg of 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine (yield 58%) was obtained. The NMR data for the obtained 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine is shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])=[N:6][CH:7]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>CC(N(C)C)=O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[N:6]=[CH:7][C:2]=1[NH:1][C:25](=[O:28])[CH2:26][CH3:27]
Reactant: Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reactant: CCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
A mixture of 4-{[(5-Amino-4-hydroxy-pyridin-2-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione (332 mg, 0.761 mmole), 6 mL of dimethylacetamide is stirred, then propionyl chloride (705 mg, 7.61 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, and then stirred overnight with a saturated aqueous sodium bicarbonate solution, the solid is filtered, washed well with water and dried to give a yellow solid, 46 mg, (11%); m.p. 210-18° C. dec; MS (ES+): m/z 492.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:27]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:27][CH:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The bromination of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-(4-chlorophenylsulfonyl)-pentan-3-one was carried out in the same manner as that of Example 3 but using 25 g of 1-(2,4-dichlorophenyl)-1-(4-chlorophenylsulfonyl)-4,4-dimethylpentan-3-one, 8.9 g of bromine, 200 ml of acetic acid and 300 ml of chloroform, and 24.4 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-(4-chlorophenylsulfonyl)pentan-3-one was obtained. m.p. 184°-185° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:20][C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][O:13][C:14]=2[CH:19]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCO2
Yield: 64.5 %

Procedure:
9.3 g (66 mmol) of 2-fluoro-nitrobenzene and 10 g (73 mmol) of benzo[d][1,3]dioxol-5-ylamine were dissolved in N,N-dimethylformamide (60 mL) and 10.9 g (79 mmol) of potassium carbonate was added thereto. Mixed solution was heated to reflux for 10 hours while stirring. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:3), to obtain 11 g (yield: 65%) of N-(2-nitrophenyl)benzo[d][1,3]dioxol-5-ylamine as red-purple crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ccnc3[nH]2)CC1

Procedure:
A mixture of Example 14A (6.500 g, 13.32 mmol) and 20% sodium hydroxide (6 mL) in dioxane (80 mL) was heated at 90° C. for 7 hours. The mixture was concentrated and the residue was treated with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The precipitate was filtered, washed with ethyl acetate/ether and dried under vacuum to give of the title compound. The filtrate was concentrated and purified by flash chromatography on silica (ISCO Companion), eluting with a gradient of 3:7 to 2:8 heptanes/ethyl acetate to give an additional quantity of the title compound. MS (ESI+) m/z 333.9 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=1)=O.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][CH:2]([F:19])[C:3]1[N:22]2[N:23]=[CH:24][C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=2)[CH:4]=1
Reactant: Cc1cc(C(=O)CC(=O)C(F)F)ccc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 69.2 %

Procedure:
Reaction of 4,4-difluoro-1-(3-methyl-4-trifluoromethyl-phenyl)-butane-1,3-dione (140 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg, 69%). MS (ISP) 405.4 [(M+H)+]; mp 236° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].CCN(CC)CC.Cl>[Cu]Cl.O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.1 %

Procedure:
To a stirred mixture of 1-tert-butyloxycarbonylpiperazine (1.10 g, 5.91 mmol), 3-chloro-3-methyl-1-butyne (0.88 ml, 7.81 mmol), THF (10 ml), and NEt3 (1.10 ml, 7.91 mmol) under nitrogen was added copper(I) chloride (45 mg, 0.46 mmol). An exothermic reaction ensued and a precipitate formed. After stirring for 0.5 hours at room temperature water (20 ml) and 1 N aqueous hydrochloric acid (8 ml) were added and the mixture was concentrated under reduced pressure to ⅔ of its original volume. The mixture was washed with ethyl acetate (2×20 ml) and made basic by addition of potassium carbonate (approx. 4 g). Extraction with ethyl acetate (3×20 ml), washing of the combined extracts (30 ml brine), drying with magnesium sulphate, and concentration under reduced pressure yielded 1.15 g (77%) of the title compound as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([NH:10][C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)[N:3]=1.[CH3:18][C:19](C)(C)C([O-])([O-])[O-].C(S(O)(=O)=O)C>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:9]=[C:18]([CH3:19])[N:10]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: Nc1nc(Cl)c(N)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: CCS(=O)(=O)O
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)nc(N)nc2n1[C@H]1C=C[C@@H](CO)C1
Reaction time: 24 h

Procedure:
(±)-cis-4-[(2,5-Diamino-4-chloro-6-pyrimidinyl)amino]-2-cyclopentene-1-methanol prepared as in Example 3 (1.12 g, 4.38 mmol) was stirred in N,N-dimethylformamide (5 mL) with trimethylorthoacetate (30 mL) and ethane sulfonic acid (0.66 g, 5.7 mmol) at 70° C. for 3 days. The resulting solution was evaporated to a yellow syrup. Acetic anhydride (20 mL) was added and this solution was refluxed for 2.5 hours. The resulting dark solution was evaporated to a syrup, which was dissolved in 1N hydrochloric acid (50 mL). After 24 hours, the pH was adjusted to 6 with sodium hydroxide and most of the water evaporated. Crude product was extracted into 20% isopropyl alcohol-chloroform. This solution was dried (MgSO4) and solvent evaporated to leave (±)-cis-4-(2-amino-6-chloro-8-methyl- 9H-purin-9-yl)-2-cyclopentene-1-methanol as a pale yellow glass (0.30 g); structure confirmed by 1H-NMR. This sample was dissolved in methanol (10 mL) and stirred in a Parr bomb with cyclopropylamine (1 mL) at 70° C. for 12 hours. Evaporation and chromatography on silica gel gave title compound, eluted as a cream-colored solid foam (136 mg) with 5% methanol-chloroform.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([NH:22][CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH3:21])=O.[ClH:26].[OH-].[Na+]>>[ClH:26].[ClH:26].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]([NH:22][CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH3:21]
Reactant: CCc1ccccc1C(Cc1ccccc1NC(=O)C(C)(C)C)NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccccc1C(Cc1ccccc1N)NC
Temperature: 0 °C

Procedure:
A solution of 14.0 g of 2,2-dimethyl-N-[2-[2-methylamino-2-(2-ethylphenyl)ethyl]phenyl]propanamide and 100 ml of 6N hydrochloric acid was refluxed for 8 hr, cooled and poured into 250 ml of ice. The mixture was basified with 50% sodium hydroxide solution and extracted with dichloromethane. The extracts were combined, dried over anhydrous sodium sulfate and concentrated. The oil was dissolved in 50 ml methanol and the solution was treated with ethereal hydrogen chloride and diluted with 700 ml anhydrous ether. The solid was recrystallized from methanol/ether to give 2-amino-α-(2-ethylphenyl)-N-methylphenethylamine dihydrochloride, mp 251°-253° C. (dec).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:12]1[C@@H:22]2[C@H:13]1[CH2:14][C:15](=[CH2:28])[CH:16]=[CH:17][C@H:18]([CH:25]([CH3:27])[CH3:26])[CH2:19][CH:20]([OH:24])[C:21]2=[O:23].CCOCC>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[O:12]1[C@@H:22]2[C@H:13]1[CH2:14][C:15](=[CH2:28])[CH:16]=[CH:17][C@H:18]([CH:25]([CH3:26])[CH3:27])[CH2:19][C:20](=[O:24])[C:21]2=[O:23]
Reactant: C=C1C=C[C@H](C(C)C)CC(O)C(=O)[C@@H]2O[C@@H]2C1
Agent: O=[Cr](=O)([O-])Cl
Agent: C=C1/C=C/[C@H](C(C)C)CC(=O)C(=O)[C@@H]2O[C@@H]2C1
Agent: C=C1/C=C/[C@H](C(C)C)CC(O)C(=O)[C@@H]2O[C@@H]2C1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C1C=C[C@H](C(C)C)CC(=O)C(=O)[C@@H]2O[C@@H]2C1

Procedure:
100 mg of pyridinium chlorochromate and 200 mg of Molecular Sieves 3A were suspended in 6 ml of dry methylene chloride. While the suspension was cooled with ice and stirred, a solution of 50 mg of the product obtained in step 5, in a small amount of methylene chloride, was added. The temperature was elevated to room temperature, and the reaction mixture was allowed to react for 6 hours under vigorous agitation. After 10 ml of ether were added to the reaction mixture, the mixture was filtered using 15 g of "Florisil", and the precipitate and the "Florisil" were washed well with ether. The filtrate and the washing solution were combined and were evaporated to dryness to provide a crude product. Using n-hexane-ethyl acetate as an eluent, the crude product was subjected to column chromatography using 3 g of alumina (activity: II). The fraction which eluted with n-hexane-ethyl acetate (99:1) was recovered and was evaporated to dryness to provide 42 mg of purified (3S,4E,8R,9R)-8-epoxy-3-isopropyl-6-methylene-10-oxo-4-cyclodecen-1-one (the compound of formula 8). The yield was 85%.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:16][CH3:17].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1
Reactant: CCCc1ccc(O)cc1
Reactant: OCCCCCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(OCCCCCCBr)cc1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A solution of diisopropylazodicarboxylate (2.12 g, 10.5 mmol) in THF (25 mL) was added via syringe pump over 1.5 h to a mixture of 4-propylphenol (purchased from Aldrich Chemical Co.) (1.36 g, 10.0 mmol), 6-bromo-1-hexanol (purchased from Aldrich Chemical Co.) (1.81 g, 10.0 mmol), and triphenylphosphine (2.75 g, 10.5 mmol) in THF (25 mL) at 0° C. under argon. The slightly yellow reaction was stirred at 0° C. for 30 min, whereupon additional triphenylphosphine (262 mg, 1.00 mmol) was added, followed by addition of diisopropyl-, azodicarboxylate (200 mL, 1.0 mmol) over 30 min. The reaction was allowed to warm to RT, at which time silica gel (15 g) was added. The mixture was concentrated in vacuo and the white powder obtained was purified by flash chromatography on silica gel (150 g) eluted with a step gradient of hexane to 2:98 EtOAc/hexane. The slightly impure product obtained was rechromatographed on silica gel (150 g) eluted with 1:99 EtOAc/hexane to give title compound (2.00 g, 67%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:31][CH2:32]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: COc1ccc(CSC)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CSC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(methylthiomethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.