Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:19][CH2:18]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(C4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=[O:18].O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:18])[CH3:12])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1ccc2nc(C)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(C)=O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methyl-1,3-benzoxazol-6-yl acetate (5.05 g, 28.8 mmol) in THF (100 mL) a mixture of trifluoroacetic acid/water (4 mL/10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, saturated aqueous NaHCO3 (150 mL) was added. The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo to give sub-title compound (4.0 g) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH:19]=[CH2:20]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([OH:15])[CH2:20][CH:19]=[CH2:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Solvent: C1CCOC1
Product: C=CCC(O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 2 h

Procedure:
(S)-2,2-Dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid t-butyl ester (2.29 g, 9.44 mmol) was dissolved in dry tetrahydrofuran (25 mL). Then at −78° C., allyl magnesium bromide (1.0M in diethyl ether, 9.9 mL) was added. The mixture was warmed to −15° C. and stirred for 2 h. The mixture was extracted with diethyl ether and aqueous citric acid solution. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and solvents were evaporated to afford (S)-4-(2-hydroxy-pent-4-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.54 g) as an oil.
Reaction SMILES: [O:1]=[O+][O-].[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=C)[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)(=O)C>[C:11]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:24]2=[O:49])=[C:20](\[OH:1])/[CH3:21])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[O+][O-]
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Solvent: CCOC(C)=O
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 equivalent of ozone (diluted with oxygen) is passed into a solution, cooled to -70° C., of 681 mg (1.0 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 30 ml of ethyl acetate. The reaction solution is allowed to warm up, concentrated to 10 ml in vacuo, mixed with 1.0 ml of dimethyl sulphide and stirred for 15 hours at room temperature. Solvent and excess reagent are removed in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel, using toluene/ethyl acetate, 4:1 (15 ml fractions). 2-[4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin- 1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester is obtained as a solid amorphous substance. [α]D = 130° ± 1° (CHCl3 ; c= 0.8) IR spectrum (CH2Cl2): 2.95, 5.60, 5.92, 6.04 and 8.10 μ.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([CH3:16])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:8]([OH:15])[CH2:7]1.N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:15][CH:8]1[CH:9]([CH:12]([CH3:13])[CH3:14])[CH2:10][CH2:11][CH:6]([CH3:16])[CH2:7]1)=[O:4]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1CCC(C(C)C)C(OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of chloroacetyl chloride (6.4 mL, 80 mmol) in 40 mL anhydrous diethyl ether was added dropwise within 2 h to a solution of (−)-menthol (3a) (12.5 g, 80 mmol) and pyridine (6.5 mL, 80 mmol) in anhydrous diethyl ether (160 mL) at 0° C. After warming to RT, the white suspension was stirred for 2 h and the resulting mixture was then filtered. The filtrate was washed with HCl (60 mL, 2 N), saturated. NaHCO3 (60 mL), brine and dried with Na2SO4. Removal of the solvent and drying under vacuum afford (−)-menthyl chloroacetate (4a) (17.64 g, 94%), which was used without further purification. U.S. Pat. No. 4,456,611; Helv. Chim. Acta 1988, 71, 1553.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:18][CH2:17][CH2:15][OH:16])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c1

Procedure:
0.35 mol (76 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, in the course of 10 minutes, whilst stirring, to 150 ml of ethanolamine, the reaction medium being cooled as necessary so as not to exceed 75° C. When the addition has ended, the stirring is maintained for 5 minutes and the reaction medium is then poured into 600 g of iced water. The expected product precipitates. It is filtered off, washed with water and then recrystallised from ethanol. After drying in vacuo, it melts at 131° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:23][C:20]([F:22])([F:21])[C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[C:7]([OH:27])[C:8]2=[CH:26][CH:25]=[CH:24][N:9]12
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2cccc(C(F)(F)F)c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(3-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.O[C:20]1[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([C:21]1[C:20]([O:5][CH2:6][C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:25][CH:24]=[CH:23][N:22]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Reactant: N#Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C#N
Temperature: 100 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213.), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C:6]1=[O:25])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[CH:15][C:14]=1[CH2:13][CH2:12]3)C.[C:26]1(C)C=CC=CC=1.C[Li].Cl>CCOCC.O>[CH:4](=[C:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C:6]1=[O:25])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[CH:15][C:14]=1[CH2:13][CH2:12]3)[CH3:26]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C(=CN(C)C)C[C@@H]12
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC=C1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)C1=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 5 g. of 16-dimethylaminomethylene-3-methoxy-1,3,5(10)-estratrien-17-one in 150 ml. of toluene is combined dropwise at -10° C. with 28.5 ml. of a 5% solution of methyllithium in ether. After this dropwise addition, the mixture is agitated for 15 minutes at -10° C.; then about 10 ml. of water is gently added in drops, and the reaction solution is poured into about 200 ml. of 0.5 N hydrochloric acid. The organic phase is separated, dried over sodium sulfate, and concentrated under vacuum. After crystallization of the residue from ethyl acetate/ether, 3.9 g. of 16-ethylidene-3-methoxy-1,3,5(10)-estratrien-17-one is obtained, m.p. 139°-140° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[H-].[Na+].CS([C:31]1[N:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][N:32]=1)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[N:32][C:31]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:13])=[O:14])[C:6]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:36][CH:35]=1
Reactant: COc1cnc(S(C)(=O)=O)nc1
Reactant: CCCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ncnc(OCCOc2ncc(OC)cn2)c1-c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (115.5 mg) was dissolved in THF (10 ml) and sodium hydride (60 mg) was added followed by stirring for 15 min at 50° C. Then 2-methanesulfonyl-5-methoxy-pyrimidine (138 mg) was added and stirring was continued for 8 h at 75° C. The reaction mixture was poured onto ice water, acidified with solid citric acid and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated. The crude material was purified by plate chromatography with diethyl ether to give propane-1-sulfonic acid {6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (61 mg) as a white powder. LC-MS: tR: 4.51, [M+H]+: 460.27.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCNCC1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C=C(N2CCCCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.90 g, 2.4 mmol) and piperidine (4 ml) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1c(O)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2sc1=O

Procedure:
7-(3,5-Dichloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 3,5-dichlorophenylboronic acid under conditions analogous to Example 7(a). The crude product was purified by silica gel chromatography (eluting with 5%-60% EtOAc in CH2Cl2) to provide 7-(3,5-dichloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester. MS ESI(−) m/e: 378.98 (M−1).
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C@H:3]1[OH:23])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([OH:21])[CH2:14][CH2:15]1)=[CH:10][C@@H:9]3[OH:22].[OH-:24].[Na+]>CN(C)C=O>[OH:21][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11](=[CH:10][C@H:9]([OH:22])[C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][C@@H:2]([OH:24])[C@@H:3]2[OH:23])[CH2:12]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1C[C@@H](Br)[C@@H]2O
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1C[C@@H](O)[C@@H]2O

Procedure:
16α-bromo-3β,7β,17β-trihydroxyandrost-5-ene (CLIII, X=Br) is reacted with sodium hydroxide in dimethylformamide to form 3β,7β,16α,17β-tetrahydroxyandrost-5-ene (CLXI)
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:27])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[F:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CCOCC>[CH:28]1([NH:31][CH:4]=[C:5]([C:11](=[O:27])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:14][C:13]=2[F:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Solvent: CCOCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCN(C)CC2)cc1F
Reaction time: 8 h

Procedure:
A solution of 3.81 g (10 mmoles) of ethyl α-(ethoxymethylene)-2,5-difluoro-4-(1-methyl-4-piperidinyl)β-oxobenzenepropanoate in 50 ml of ether was treated with 0.60 g (10 mmoles) of cyclopropylamine. After standing overnight the mixture was evaporated to dryness to afford the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[N:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[CH2:28]([O:31][C:32]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH3:47])[CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35])[CH2:29][CH3:30]>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:34]([C:33]2[CH:40]=[CH:41][C:42]([O:44][CH2:45][CH2:46][CH3:47])=[CH:43][C:32]=2[O:31][CH2:28][CH2:29][CH3:30])=[O:35])=[CH:23][CH:22]=1
Reactant: Cc1ccncc1
Reactant: CCCOc1ccc(C(=O)N(C)OC)c(OCCC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCOc1ccc(C(=O)Cc2ccncc2)c(OCCC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a cooled solution of lithium diisopropylamide (generated from diisopropylamine (109 mg, 1.07 mmol) and a solution of n-butyllithium in hexanes (0.49 mL of a 2.5M solution, 1.22 mmol)) in THF (0.5 mL) at -78° C. was added 4-picoline (95 μL, 0.98 mmol). Stirred -78° to 0° C. for 1 h. The reaction mixture was cooled to -78° C. and a solution of 2,4-di-n-propyloxy-N-methoxy-N-methyl-benzamide from Step B (274 mg, 0.98 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred <0° C. for 4 h and then quenched by the addition of a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvents removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-50% ethyl acetate in hexanes to yield the title compound (147 mg, 48% yield), mass spectrum (CI) m/e=314 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12]O)=[O:9])[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:18]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][Cl:18])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NC(=O)c1cccc(N)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(CCl)NC(=O)c1cccc(N)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 6-amino-N-(1-hydroxy-2-methylpropan-2-yl)picolinamide (0.35 mmol, 74 mg) in CHCl3 was cooled to 0° C. and SOCl2 (2.8 mmol, 200 μL) was added. The mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with 1 M NaOH. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried with MgSO4. The crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=2:1 as eluent). White solid, 76 mg, 95% yield. 1H NMR (500 MHz, CDCl3): 7.93 (br, 1H), 7.57-7.54 (m, 1H), 7.52-7.51 (m, 1H), 6.62 (d, 1H, J=8.0 Hz), 4.51 (br, 2H), 3.94 (s, 2H), 1.52 (s, 6H). 13C NMR (125 MHz, CDCl3): 163.97, 156.83, 148.37, 138.88, 112.33, 111.63, 53.72, 51.19, 25.08. MS (ESI, MeOH): 228 (100%, (M+1)+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:6][C:5]([C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)=[N:7][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N=C(N)c1cc(F)cc(F)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cc(F)cc(F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=380.9 (M+H+), was prepared from 3,5-difluorobenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(C)CCCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(CCCc1ccc(Cl)cc1)c1ccc(C(=O)O)cc1

Procedure:
A 1.80 g. portion of 4-[[3-(p-chlorophenyl)propyl]methylamino]benzoic acid, ethyl ester is dissolved in 15 ml. of 95% ethanol. A 1 g. portion of potassium hydroxide is added, and the mixture is refluxed overnight. The solution is poured into 30 ml. of water, the pH is adjusted to 6 using 37% hydrochloric acid, and the solid is collected and dried. This solid is dissolved in benzene, filtered, and evaporated, giving 750 mg. of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([SH:22])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COc1cccc(S)c1
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Sc2cccc(OC)c2)c([N+](=O)[O-])s1
Temperature: 50 °C
Yield: 91.6 %

Procedure:
To a cooled (ice bath) solution of 4-bromo-5-nitrothiophene-2-carboxylic acid methyl ester (0.5 g, 1.88 mmol) from above step c, in dimethylformamide (DMF) was added 3-methoxybenzenethiol (0.29 g, 2.1 mmol) and Cs2CO3 (0.67 g, 2.1 mmol). The resulting mixture was heated at 50° C. for 3 h. DMF was removed under vacuum and the residue was partitioned between EtOAc and 10% HCl. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography (EtOAc:hexane) to give 0.56 g (91%) of 4-(3-Methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. This ester was dissolved in CH2Cl2 (6 mL) and treated with m-chloroperoxybenzoic acid (MCPBA, 1.1 g) and heated at reflux for 6 h. The resulting mixture was diluted with CH2Cl2 (10 mL) and washed with sat. sodium thiosulfate, 1N NaOH and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane) to give an oil. This oil was dissolved in DMF (5 mL) and cooled in an ice bath. To this solution sodium thiomethoxide (126 mg, Aldrich Chemical Company) was added and the mixture was stirred for 5 h. The reaction was quenched with 10% HCl and the solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin-layer chromatography to give 171 mg of 4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester, which was directly used in the next step.
Reaction SMILES: [N:1]([CH2:18][CH2:19][OH:20])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[Na+]>C(#N)C.O>[N:1]([CH2:18][CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCN(CCO)CCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCN(CCCCCCCC)CCOS(C)(=O)=O
Temperature: 10 °C
Yield: 74.3 %

Procedure:
In 200 ml of acetonitrile was dissolved 28.5 g (0.1 mol) of (C8H17)2NCH2CH2OH and then 11.5 g (0.1 mol) of methanesulfonyl chloride was added dropwise to the solution with stirring at 10° C. Then, after stirring the mixture for 3 hours at temperatures below 20° C., the reaction mixture was neutralized carefully with a solution of 4 g (0.1 mol) of sodium hydroxide in 40 ml of water. After concentrating the reaction mixture under reduced pressure, the residue was dispersed in 1 liter of water and the product was extracted with 500 ml of ether. The organic layer obtained was dried by anhydrous magnesium sulfate and then ether was distilled away to provide 27.0 g of (C8H17)2NCH2CH2OSO2CH3.