Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10]Cl)=[C:5]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:4]=1.[CH3:18][NH:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][N:19]([CH3:18])[C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:5]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:4]=1
Reactant: Cc1nc(Cl)cc(OC2CCCC2)c1CCl
Reactant: CN[C@H]1CCCc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(Cl)cc(OC2CCCC2)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-3-chloromethyl-4-cyclopentyloxy-2-methyl-pyridine hydrochloride salt, (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (3.0 g, 18.6 mmol), N,N-diisopropylethylamine (4.0 mL, 22.9 mmol), and anhydrous acetonitrile (50 mL) is stirred for 5 hours at 80° C. The reaction is cooled to ambient temperature and concentrated in vacuo. The obtained residue is dissolved in a mixture of hexane and ethyl:acetate (4:1, 100 mL) and filtered over a small pad of silica gel (35 g), which is subsequently rinsed with additional 100 mL of the same mixture of hexane and ethyl acetate. The filtered solution is concentrated in vacuo and the resultant residue is chromatographed on silica gel (hexane/ethyl Acetate 4:1) to afford (S)-(6-chloro-4-cyclopentyloxy-2-methyl-pyridin-3-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR: (CDCl3) 7.53 (m, 1H), 7.09 (m, 2H), 7.02 (m, 1H), 6.63 (s, 1H), 4.77 (m, 1H), 3.83 (d, 1H), 3.73 (dd, 1H), 3.56 (d, 1H), 2.73 (m, 2H), 2.63 (s, 3H), 2.07 (m, 2H), 2.04 (s, 3H), 1.98 (m, 2H), 1.82 (m, 4H), 1.68 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[N+:14]([C:7]1[CH:6]=[C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C(C)c1ccc(O)cc1
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a mixture of 18ml of nitric acid and 30ml of acetic acid 2.76g of methyl 2-(4-hydroxyphenyl)propionate was stirred at -10° to -20° C for 4 hours. The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with a sodium hydrogen carbonate solution and water and dried over magnesium sulfate. The chloroform was distilled off to give the desired compound in a yield of 2.35g (69%). The physical data of this compound coincided with those of the compound as described above.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 2-(chloromethyl)quinoline hydrochloride (15 g), 4-hydroxybenzaldehyde (8.56 g) and anhydrous potassium carbonate (29 g) was heated under reflux in acetone (300 mL) for 86 h. After cooling to room temperature, ether (400 mL) was added and the mixture was filtered on celite. The filtrate was evaporated to dryness under reduced pressure and purified by flash chromatography using 15% ethyl acetate/hexane. The title compound was obtained after recrystallization from ethyl acetate/hexane m.p. 89°-90°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:19](=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[C:20](=O)[NH:21][C:22]=2[CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:19](=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[C:20]([Cl:3])=[N:21][C:22]=2[CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1cc2c(n1)c(=O)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc2c(n1)c(Cl)nc1cc(OCc3ccccc3)ccc12
Temperature: 100 °C

Procedure:
Phosphorous oxychloride (15 mL) was added to 7-benzyloxy-2-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (1.20 g, 3.76 mmol) and heated at 100° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the poured onto crushed ice while stirring. 6 N Sodium hydroxide solution was added to the suspension at 4° C. and the solid was harvested by filtration and dried to afford 1.23 g of 7-benzyloxy-4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline as a yellow solid, mp 155-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18]C)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.NC1N=C(C2C=C(Br)C=CC=2O)C=C(Cl)N=1.[N:36]1(CCO)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: OCCN1CCOCC1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Agent: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Product: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCCN2CCOCC2)n1
Yield: 41 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 2-morpholin-4-yl-ethanol provided 4-[5-bromo-2-(2-morpholin-4-yl-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine (41% yield).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]2[C:14]([NH:15][C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]3)=S)=[CH:13][N:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>[Hg]=O.CO>[C:1]1([CH2:7][N:8]2[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][CH:13]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cncnc2NCc2ccccc2)CC1
Agent: N
Agent: O=[Hg]
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2nc3cncnc3n2Cc2ccccc2)CC1
Yield: 92.1 %

Procedure:
A mixture of 24 parts of ethyl 4-[[[[4-[(phenylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate, 24 parts of mercury(II) oxide and 240 parts of methanol, saturated with ammonia was stirred overnight at reflux temperature. The reaction mixture was filtered while hot and the filtrate was evaporated. The residue was taken up in a mixture of trichloromethane and ethanol. After washing with water, the organic layer was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 20.3 parts (92.1%) of ethyl 4-[[9-(phenylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate; mp. 156.9° C. (compound 9).
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[C:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:4]2[C:5](=[O:17])[C:6](=[O:16])[C:7]=2[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccccc2O)c(Nc2ccccc2-c2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-aminobiphenyl (36.3 mg, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 357.2 (M+).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C@@H:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][OH:19]>>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:16][C@@H:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][OH:19])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1-c1ccccc1
Yield: 64 %

Procedure:
2 g (10 mmol) of 2-phenylbenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3a, affording 2.1 g (64%) of the product.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH3:39])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:40])=[O:2])(=[O:10])=[O:11])=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[O:38][CH3:39]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Cl)c(OC)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Cl)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.5 %

Procedure:
To 100 mg of (S)-2-{4′-[(5-chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester was added 2 mL of THF and 2 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O) was added. The mixture was stirred at room temperature for 3 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 60 mg (62% yield) of (S)-2-{4′-[(5-chloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (dd, J=13.1, 6.6 Hz, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 3.9 (s, 3 H) 7.5 (d, J=8.6 Hz, 1 H) 7.6 (m, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][N:21]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CN1CCN2C(Cc3cc(OC)c(OC)cc3C2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added potassium carbonate (0.8 g) and methyl bromoacetate (0.5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=9:1) to give 8,9-dimethoxy-2-methoxycarbonylmethyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (940 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:10]1[C:20]([O:22]CC)=[O:21])C>C(O)C>[C:6]([CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[C:10]1[C:20]([OH:22])=[O:21])([OH:25])=[O:5]
Reactant: CCOC(=O)CCn1cc(-c2ccccc2)cc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCn1cc(-c2ccccc2)cc1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
10% Aqueous sodium hydroxide solution (20 mL) was added to a stirred solution of ethyl 1-(3-ethoxy-3-oxo-propyl)-4-phenyl-pyrrole-2-carboxylate (2.0 g, 6.35 mmol) in ethanol (20 mL). The reaction mixture was stirred for 2 h at 50-60° C. The ethanol was evaporated in vacuo and then water added to the residue and acidified with 5N HCl to pH 4-5. The precipitated solid was filtered, washed with water and dried in vacuo to afford 1-(2-carboxyethyl)-4-phenyl-pyrrole-2-carboxylic acid (900 mg, 56%) as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:14](=[O:26])[N:13]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:12]2=[O:38])C1C=CC=CC=1.C([O-])=O.[NH4+].C(Cl)Cl>CCO.[Pd]>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[CH2:27][N:13]1[C:12](=[O:38])[C:11]2[C:16](=[CH:17][C:18]([F:19])=[C:9]([OH:8])[CH:10]=2)[N:15]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:14]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(O)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Yield: 66.5 %

Procedure:
A mixture of 0.2 g of the compound obtained in Step 4.6, 0.036 g of ammonium formate and 0.041 g of Pd/C (10%) in 4 ml of EtOH is irradiated in a microwave field for 5 minutes at 60° C. DCM is added, the mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (95/5, v/v) to (0/100, v/v) to give 0.11 g of the expected product.
Reaction SMILES: S.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)=[O:20])=[O:11])=[N:7][CH:8]=1.[NH2:35][C@H](C(O)=O)CCSC>N1C=CC=CC=1.CCN(CC)CC.CC(C)=O.C(O)(=O)C.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([NH2:35])=[NH:34])=[CH:23][CH:22]=2)=[O:20])=[O:11])=[N:7][CH:8]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CSCC[C@H](N)C(=O)O
Agent: S
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.5 %

Procedure:
A stream of H2S (g) was bubbled through a 0° C. solution of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide (100 mg. 0.22 mmol, 1.0 equiv.) in 9 mL pyridine and 1 mL NEt3 until saturation. The mixture was stirred at rt for 1 day and evaporated. The resulting residue was treated with Met (94 mg, 0.663 mmol, 3.0 equiv.) in 10 mL acetone at reflux temperature for 1 hr and concentrated to dryness. The resulting residue was treated with a mixture of NH4OAc (340 mg, 4.42 mmol, 20 equiv.) in 0.5 mL acetic acid and 2 mL methanol at 50° C. for 2 days. The solvent was removed at reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN to give 2-[4-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]phenyl }carbamoyl)phenyl]benzenecarboxamidine (15 mg, 15%). MS found for C26H20ClN5O, (M+H)+: 470.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:8])[CH:3]([CH2:4]2)[CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[C:9]1([C:7]2([OH:8])[CH2:6][CH:5]3[CH2:4][CH:3]2[CH2:2][CH2:1]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CC2CCC1C2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccccc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of norcamphor (60.0 g, 0.54 mole) in THF (1 L) at −65° C. was added phenyl magnesium bromide (200 mL of a 3 M solution in ether, 0.60 mole). The temperature was kept between −65° C. and −20° C. during the addition. After completion of addition, the mixture was slowly warmed to room temperature and stirred overnight. The mixture was cooled to 0° C. and saturated aqueous ammonium chloride (200 mL) was added carefully. A solution of 1 N hydrochloric acid was added until the residual salts were dissolved. The mixture was then extracted twice with ether and the combined organic phases were washed successively with water and brine. The organic layer was dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc 9:1) provided I-2a as a white solid (95.0 g).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]#[N:15]>C1COCC1>[NH2:15][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[CH:2][C:1]#[N:3]
Reactant: CC#N
Reactant: N#Cc1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccco1
Reaction time: 0.25 h

Procedure:
Following the method of Gupta et al. (Tetrahedron 1990, 46, 3703) and Bullock and Gregory (Can. J. Chem. 1965, 43, 332), to a stirred solution of 0.53 ml (10.0 mmol) acetonitrile in 25 ml dry THF under argon at −78° C. was added 6.25 ml (10.0 mmol) n-butyllithium solution (1.6M in hexane) and stirring continued for 15 minutes. 0.87 ml (10.0 mmol) 2-furonitrile was then added dropwise and stirring continued for 45 minutes at −78° C. The reaction mixture was quenched at 0° C. with 3 ml water and then partitioned between ether and water. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 1.10 g (82%) (E or Z)-3-amino-3-furan-2-yl-acrylonitrile as a yellow crystalline solid which was stored in the refrigerator. EI-MS m/e (%): 134 (M+, 100).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(I)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 620.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[C:5]([Cl:28])=[CH:4][N:3]=1.CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[Fe].CCOC(C)=O.O>[NH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6]2[C:5]([Cl:28])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:11]=1)=[O:27]
Reactant: O=C(Nc1cccc(CNc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc(C(=O)Nc2cccc(CNc3nc(Cl)ncc3Cl)c2)c1
Temperature: 70 °C
Yield: 96.6 %

Procedure:
Into a reaction flask were added N-(3-{[(2,5-dichloropyrimidin-4-yl)amino]methyl}phenyl)-3-nitrobenzamide (0.30 g, 0.72 mmol), methanol (20 mL), acetic acid (2.0 mL), and water (1 mL). Then iron (0.50 g, 9.0 mmol) powder was added. The reaction mixture was heated at 70° C. overnight. After cooling, the mixture was filtered and washed with EtOAc. The filtrate was concentrated under vacuum to give a residue, which was treated with NaHCO3 (saturated aqueous solution) and EtOAc. The organic layer was dried and concentrated under vacuum to provide the desired product (0.27 g, 97%). LCMS for C18H16Cl2N5O (M+H)+: m/z=388.0, 390.0.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:17])[O:15][C:14](=[O:16])[CH2:13][CH2:12]2)=[C:7]1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.C(Cl)Cl.O.[CH2:27](O)[CH3:28]>>[CH3:17][C:11]1([CH2:12][CH2:13][C:14]([O:15][CH2:27][CH3:28])=[O:16])[C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2
Reactant: CCO
Reactant: CC1(c2ccsc2-c2cccs2)CCC(=O)O1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCC1(C)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (0.30 mL) was added dropwise to a solution of 5-([2,2′-bithiophen]-3-yl)-5-methyldihydrofuran-2(3H)-one (0.030 g, 0.11 mmol) in ethanol (2 mL) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent dichloromethane) to afford a pure dark yellow oil (IIv) (0.0106 g, 31.9%). 1H-NMR (CDCl3): δ=7.15 (d, J=4.9 Hz, 2H), 6.93 (d, J=4.7 Hz, 2H), 3.96 (q, J=7.1 Hz, 2H), 2.28-2.21 (m, 2H), 1.80-1.74 (m, 2H), 1.45 (s, 3H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O:20]CC)=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+:27].[Na+]>C(O)C.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[Na+:27]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@H](COCC(C)C)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 148.1 %

Procedure:
Crude ethyl (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (15.29 g) synthesized according to the process (acid chloride method) similar to that described in Patent reference 1 was dissolved in ethanol (24 mL). While the solution was stirred at room temperature, sodium carbonate (2.44 g) dissolved in water (24 mL) was dropped. After the solution was stirred at room temperature for 1 hour, it was further stirred at 90° C. to 95° C. for 2 hours. The solvent was distilled off under reduced pressure, and water (50 mL) was added to the residue. The obtained solution was washed with two portions of ethyl acetate (50 mL), and water was distilled off under reduced pressure. Acetone (400 mL) was dropped to the residue, and the obtained solution was stirred overnight at room temperature. The precipitated crystalline product was collected by filtration, washed with a mixture of 3% water-acetone (30 mL), washed again with acetone (30 mL), and dried in air to obtain white solid sodium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (10.55 g, 70.3%). The NMR data of the solid product were the same as those in Example 9.