Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1cccc2ccccc12
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc2ccccc12

Procedure:
Example 31 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanatonaphthalene (19.6 μl) to give the title compound (0.0304 g). LC-MS (System A): Rt 2.43 mins, Mass Spectrum m/z 444 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[CH2:25]([OH:27])[CH3:26].[O-]CC.[Na+]>O>[CH2:25]([O:27][C:17]1[C:16]([CH3:22])=[N:15][N:14]([CH3:23])[C:13](=[O:24])[C:12]=1[C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:26]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC
Temperature: 70 °C
Reaction time: 4 h
Yield: 177.5 %

Procedure:
To a test tube (outside diameter: 21 mm φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (52.2 mg), ethanol (674.3 mg), and sodium ethoxide (121.8 mg) were added under a nitrogen atmosphere at room temperature and stirred for 4 hours at 70° C. To the reaction mixture was added water (4 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 83.6 mg of 5-ethoxy-4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-6)-(1)-39).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:19][CH3:20])=[N:11][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:14]=1
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1nc(C(F)(F)F)cnc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.8 %

Procedure:
First, 23.3 g of 3-(2,4-difluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1004) was dissolved in 150 ml of acetone, to which 17.5 g of potassium carbonate and 14.3 g of methyl iodide were added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, most of the acetone was distilled out under reduced pressure, and the residue was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=19:1), which afforded 16.1 g of 3-(2,4-difluorophenyl)-2-methoxy-6-trifluoromethylpyrazine (m.p., 55.3° C.) as the earlier eluted O-methylated compound and 7.13 g (yield, 29%) of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-10; m.p., 73.0° C.) as the later eluted desired compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>>[C:13]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([OH:12])=[O:11])[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C1CCCC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccccc2c1C1=CCCC1

Procedure:
Condensation of the indole carboxylic acid with cyclopentanone in the presence of aqueous sodium hydroxide gave the 3-cyclopenteneyl indole carboxylic acid, which was subjected to hydrogenation in the presence of catalytic amount of palladium on carbon to afford the corresponding cyclopentyl carboxylic acid in 80% overall yield. Double methylation of the carboxylic acid and the nitrogen with methyl carbonate in NMP at 130° C. provided the N-methyl indole carboxylate methyl ester in 90% yield. Bromination of the indole carboxylate with bromine in acetonitrile furnished the 2-bromo-3-cyclopentyl indole carboxylate in 90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:20](C=O)C>ClCCl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH2:20])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.00 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was added 2 M oxalyl choride in methylene chloride (5 mL, 10 mmol). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. Ammonium hydroxide (15 mL) was added dropwise via additional funnel. After addition, the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried and concentrated in vacuo to give 2-(4-bromophenoxy)acetamide (350 mg, 70% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.37-7.35 (m, 2 H), 6.81-6.79 (m, 2 H), 4.59 (s, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[CH:15]=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1.[OH-].[K+].[I:18]I>CN(C=O)C>[I:18][C:15]1[C:9]2[C:10](=[CH:11][N:12]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)[NH:13][N:14]=1
Reactant: II
Reactant: c1cncc(-c2cc3cn[nH]c3cn2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-(Pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine (196 g, 1 mol) was dissolved in 1000 mL DMF. KOH (112 g, 2 mol) was added. After stirring for 30 min, I2 (303 g, 1.2 mol) was added. The mixture was stirred for 1 h at room temperature. After reaction, the reaction was quenched with saturated aq. Na2S2O5 solution followed by the addition water (5 L). The solid was filtered and washed with water to give 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (290 g, 90%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[CH2:12]1[NH:19][CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][N:19]2[CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]2)=[C:6]([F:8])[CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Fc1cc(Br)cc(F)c1CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2c(F)cc(Br)cc2F)CC1

Procedure:
A solution of 3.8 g (11.3 mmol) 5-bromo-2-bromomethyl-1,3-difluoro-benzene, 1.83 g (13.6 mmol) thiomorpholine dioxide and 1.88 ml (13.6 mmol) triethylamine in 40 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is taken up in diethylether, vigorously stirred, and the title compound is obtained after filtration as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(OCC3CC3)c2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (300 mg, 1.36 mmol, 1 eq) under nitrogen was added potassium carbonate (377 mg, 2.73 mmol, 2 eq), 5 mL of DMF and bromomethylcyclopropane (145 uL, 1.50 mmol, 1.1 eq) and the reaction was stirred at room temperature for 16 h. After work-up and flash column chromatography, 4-cyclopropylmethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 94% yield (350 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.4 (m, 2 H) 0.6 (m, 2 H) 1.3 (m, 1 H) 1.3 (d, J=14.4 Hz, 3 H) 2.7 (d, 3 H) 4.0 (d, J=6.8 Hz, 2 H) 4.3 (q, J=7.1 Hz, 2 H) 6.8 (dd, J=8.1, 0.5 Hz, 1 H) 7.2 (dd, J=8.3, 0.5 Hz, 1 H) 7.4 (t, J=8.2 Hz, 1 H).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[CH2:7][CH2:6]1)=O.[Li+].[BH4-].Cl>C1COCC1.CCOCC>[C:16]([O:15][C:13](=[O:14])[N:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]1)[CH3:12])([CH3:17])([CH3:19])[CH3:18]
Reactant: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CO)CC1

Procedure:
17.1 g (62.95 mmol) of trans-4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic acid methyl ester, dissolved in 150 ml of THF, were treated with 2.74 g (126 mmol) LiBH4. The reaction-mixture was stirred under reflux for 6 h and then 200 ml of 1N HCl were dropped to the solution under ice-cooling. The mixture was dissolved in ether and washed with water. The solvent was evaporated under reduced pressure yielding 16.2 g trans-(4-Hydroxymethyl-cyclo-hexyl)-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Yield: 41.8 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (1.49 g, 3.95 mmol) was treated with boron tribromide (1M in dichloromethane, 20 ml, 20 mmol) with dichloromethane (10 ml) as a solvent according to the method described in Example 23. The resulting crude was purified by flash chromatography using SP1® Purification System (0% to 30%, dichloromethane-ethyl acetate) to obtain 0.6 g (42% yield) of the title compound. Purity: 100%
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl.Cl.[C:17]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:44])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:35])[CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)CCC>[C:17]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:2]2[S:3][C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)[CH2:28][CH2:27]1)=[O:44]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Reactant: Cc1nc(Br)sc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)OC(C)(C)C
Yield: 28.6 %

Procedure:
tert-Butyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (247 mg, 0.739 mmol), the compound (199 mg, 0.369 mmol) obtained in Example 11c, triethylamine (180 μL) and 4.0 mL of n-butanol were used to give the title compound (70 mg; yield, 29%) as a colorless oily substance according to the same procedure as in Example 104b.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].O>C(O)C>[C:15]([N:19]1[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NN
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnn(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
8.51 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt of was suspended in 80 ml of ethanol, and 8.09 g of t-butylhydrazine hydrochloride was then added. The mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 5.26 g of methyl 1-t-butyl-pyrazole-4-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][N:7]1[S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:23])=[O:22].[OH-].[Na+].Cl>CCO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][S:11][C@H:9]2[CH2:8][N:7]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[C@H:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])[CH2:10]2)=[CH:18][CH:17]=1
Reactant: COC(=O)CC[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)O)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Yield: 94.6 %

Procedure:
185 mg (0.37 mmol, 1eq) (2R,4R)-3-[4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester in 5 ml EtOH were treated with 1.85 ml 1M NaOH (1.85 mmol, 5 eq) for 2 h at RT, the pH was adjusted to 7 by the addition of 1M HCl, the solvent was evaporated and the crude product redissolved in EtOH and filtered from solids and evaporated, yielding 170 mg (94%) (2R,4R)-3-[4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-propionic acid as brown gum, MS: 486 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:17])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (10.0 g, 41 mmol), EDCI (23.64 g, 123 mmol) and HOBt (18.88 g, 123 mmol) in 1-methyl-2-pyrrolidinone (150 mL) was stirred at RT for 3 hours. Morpholine (10.75 mL, 123 mmol) was then added, and the resulting mixture was stirred at RT for 78 hours. The reaction was quenched by adding water and the resulting mixture was extracted with EtOAc. The organic layer was separated and washed twice with K2CO3 (sat'd aq) and an HCl (aq, 10%), again with once with a saturated K2CO3 (sat'd aq) and with brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was triturated with Et2O and filtered to give 5.9 g of [4-(morpholine-4-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white powder.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH:18][CH3:19]>CCO>[CH3:17][N:18]([CH3:19])[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CN(C)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-methylmethanamine (2.0 M in MeOH, 0.50 ml, 1.0 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 271 (M+, 1), 77 (4), 59 (4), 58 (bp), 51 (3).
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19].[NH4+].[Cl-]>C1COCC1>[CH3:11][N:12]1[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][C:17]1([CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:18]
Reactant: BrC=Cc1ccccc1
Reactant: CN1C(=O)CCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(O)C=Cc1ccccc1

Procedure:
The Grignard reagent prepared in 300 ml of THF from 24 g (1.0 mole) of magnesium and 42 g (0.30 mole) of β-bromostyrene is decanted from excess metal and added dropwise under nitrogen to a solution of 27 g (0.21 moles) of N-methyl glutarimide at 3°- 5°. After 11/2 hrs. at room temperature, the mixture is treated with 250 ml of saturated NH4Cl solution with cooling. The separated aqueous layer is reextracted and the combined THF extracts washed with salt, dried over MgSO4 and freed of solvent. Product is extracted into hot ether and crystallized on cooling to yield white crystals, mp 108°- 112° C.
Reaction SMILES: [OH-].[K+].[C:3]([OH:19])(=[O:18])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:3]([OH:19])(=[O:18])/[CH:4]=[CH:5]/[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCC/C=C/C=C/C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCC=C/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
To the trans-2-tridecenal (1.7 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenyl phosphorane (4.0 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). Potassium hydroxide (2.0 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans, trans-2,4-pentadecadienoic acid (1.9 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml ), and para-nitrophenol (1.2 g) and N,N'-dicyclohexylcarbodiimide (1.7 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-pentadecadienoic acid (1.3 g). To the active ester (600 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (750 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK285 in the yield of 530 mg.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19]([C:20](O)=[O:21])[C:18]=1[SH:26]>N1C=CC=CC=1>[CH3:16][C:17]1[C:18]2[S:26][C:1]([C:3]3[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=3)=[N:2][C:20](=[O:21])[C:19]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1cccc(C#N)n1
Reactant: Cc1cccc(C(=O)O)c1S
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3cccc(C(=O)OC(C)(C)C)n3)sc12
Yield: 58.3 %

Procedure:
tert-Butyl 6-cyano-2-pyridinecarboxylate (3.2 g, 15 mmol) and 3-methylthiosalicylic acid (4.7 g, 28 mmol) were dissolved in pyridine (40 ml), and the mixture was refluxed for 16 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-tetrahydrofuran (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (3.1 g, 56%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCCN1CCCCC1
Product: O=C(NCCCN1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 3-(piperidine-1-yl)propylamine (46 mg, 0.32 mmol). The title compound was obtained as a solid (50 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.37 (1H, m), 9.03 (2H, s), 8.46 (1H, s), 7.32 (2H, dd), 7.20 (2H, dd), 4.43 (2H, m). MS m/z: 475.09, 477.08 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH3:24])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[N:14]1)C1C=CC=CC=1>CO.[Pd]>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[CH2:12][CH:11]([NH2:10])[CH3:24])=[CH:17][CH:18]=1
Reactant: COc1ccc2cnn(CC(C)NC(=O)OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2cnn(CC(C)N)c2c1
Reaction time: 20 h
Yield: 97.4 %

Procedure:
To a solution of the product from Step B (0.68 g, 2.0 mmol) in methanol was added Pd/C (10%, 0.10 g) under a nitrogen atmosphere at room temperature. The mixture was stirred for 20 h under a hydrogen atmosphere and filtered through a filter aid. The filtrate was evaporated to a residue which was purified by chromatography (silica, 5% methanol in dichloromethane to 10% methanol in dichloromethane) to give a syrup (0.40 g, 97%). Treatment of the syrup with fumaric acid gave a residue that was recrystallized from methanol/ether to provide a colorless solid: mp 151–152° C.; MS (ES) m/z 206 (M+). Analysis. Calculated for C11H15N3O.1.0 C4H4O4. 1.0H2O: C, 53.09; H, 6.24; N, 12.38. Found: C, 52.88; H, 6.31; N, 12.14.