Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=2)[S:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:19]([O:21][C:22](=[O:38])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:19][O:21][C:22](=[O:38])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH2:34][CH2:35][CH2:36][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:7]4[S:8][CH:9]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:6]=4)=[CH:11][C:12]=3[O:17][CH3:18])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: COc1cc(-c2nc(OC(C)C)cs2)ccc1O
Reactant: CCOC(=O)Cn1ccc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OCCCOc3ccc(-c4nc(OC(C)C)cs4)cc3OC)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a mixture of 4-(4-isopropoxy-1,3-thiazol-2-yl)-2-methoxy-phenol (Example 37, 269 mg, 1.01 mmol) and ethyl[5-(3-bromopropoxy)-1H-indol-1-yl]acetate (Example 47, 331 mg, 1.01 mmol) in 8 mL DMF (containing 1 v/v % of water), was added cesium carbonate (661 mg, 2.03 mmol). After stirring the reaction mixture for 16 h at rt, DMF was evaporated under reduced pressure. The residue was suspended in ethyl acetate and filtered through a silica gel plug to give 204 mg (39%) of a white solid, which was used in the next step with no further purification.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH:12]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.O1CCCC1>[CH2:1]=[C:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:24]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: [Li]CCCC
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A suspension of methyl triphenylphosphonium bromide (31.22 g; 87.3 mmol) in 500 mL of ether was added at -30° C. 10M n-butyllithium in hexane (8.73 mL; 87.3 mmol) and the mixture was allowed to stir at room temperature for 1/2 h. To the above mixture was added 15 g (83.2 mmol) of 9-fluorenone in 50 mL of tetrahydrofuran and the mixture was refluxed for 1 h. The above mixture was cooled to 0° C., filtered, and concentrated to yield 11.3 g (76.3%) of 9-methylene-fluorene (Formula III: R3 =R4 =H; R5 =R6 together form a 9-fluorene ring).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])=[C:16]4[CH2:26][CH2:27][CH2:28][CH2:29][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(O[N:42]1N=[N:49][C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.NCC#N>C(Cl)Cl.O>[C:43]([CH2:44][NH:49][C:23](=[O:25])[CH2:22][NH:21][C:19]([C:17]1[S:18][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=2)=[C:15]2[CH2:29][CH2:28][CH2:27][CH2:26][C:16]=12)=[O:20])#[N:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCNC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 44.7 %

Procedure:
Stir a mixture of 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic acid (230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and NEt3 (133 mg, 1.32 mmol) in DCM (5 mL) at room temperature for 15 min, followed by addition of 2-aminoacetonitrile hydrochloride (61 mg, 0.65 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (110 mg, 44.7%). MS (m/z): 559.1 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (t, J=5.6 Hz, 1H), 8.22 (t, J=5.6 Hz, 1H), 7.81-7.80 (m 1H), 7.68 (s, 2H), 4.35-4.22 (m, 2H), 4.16-4.15 (m, 2H), 3.88-3.86 (m, 2H), 2.94-2.86 (m, 4H), 1.70-1.69 (m, 4H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[CH:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[CH:17](=O)[CH3:18].C([BH3-])#N.[Na+]>>[CH2:17]([NH:7][CH:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:5]([O:4][CH2:2][CH3:3])=[O:16])[CH3:18]
Reactant: CC=O
Reactant: CCOC(=O)C(N)Cc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCNC(Cc1ccc(O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 9, a reaction was carried out using DL-tyrosine ethyl ester hydrochloride (983 mg), acetaldehyde (0.26 ml) and sodium cyanoborohydride (100 mg) and the reaction mixture was treated to afford the desired compound (515 mg) as a syrup which was allowed to stand to give crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH:7]([CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8]([OH:10])=[O:9]
Reactant: BrCCCc1ccccc1
Reactant: Cc1c(CC(=O)O)sc2ccccc12
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(CCCc2ccccc2)C(=O)O)sc2ccccc12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a stirred solution of 3-methylbenzo[b]thiophene-2-acetic acid (1.00 g) in THF at −78° C. under nitrogen was added a solution of n-butyllithium in hexanes (2.5M; 3.98 ml). Stirring was continued for 15 mins at this temperature before 1-bromo-3-phenylpropane (965 mg) was added. The mixture was stirred for 30 mins before allowing to warm up to RT and then stirred at RT for a further 1 h. The reaction mixture was poured on to a mixture of water (50 ml) and 1 N sodium hydroxide solution (10 ml). The organic layer was separated and washed with water (2×10 ml), brine (10 ml) and dried (MgSO4). Filtration and evaporation of solvents under reduced pressure gaven the crude product, which was purificatied by silica gel column chromatography, eluting with 2:1 hexane/ethyl acetate, to give the title compound (579 mg, 37%) as a pale green oil. Rf 0.45 (2:1 hexane/ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:20])([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CS([O-])(=O)=O.[CH3:21][NH2:22]>O1CCCC1>[F:1][C:2]([F:20])([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:22][CH3:21]
Reactant: CN
Reactant: O=S(=O)([O-])CCCCCCC(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: CNCCCCCC(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
In a solution of 44.7 g of 6,6,7,7,8,8,8-heptafluoro-octylmethanesulfonate in 134 ml of tetrahydrofuran, 41.5 g of methylamine is condensed at −78° C. and stirred for 24 hours at room temperature in a pressurized reactor. Then, it is evaporated to the dry state in a vacuum, washed with water as well as common salt solution, dried on sodium sulfate and evaporated to the dry state in a vacuum. 34.9 g of crude 6,6,7,7,8,8,8-heptafluoro-octyl-methylamine is obtained, and after distillation, 21 g of pure 6,6,7,7,8,8,8-heptafluoro-octyl-methylamine with a boiling point of 89-93° C. at 69 mbar is obtained.
Reaction SMILES: CS(OCCC[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:21][CH3:22])[C:15]=2[O:19][CH3:20])[CH:10]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:20][O:19][C:15]1[C:14]([O:21][CH3:22])=[C:13]([O:23][CH3:24])[CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([CH2:10][CH2:9][CH2:18][N:25]1[CH2:30][CH2:29][N:28]([CH2:12][CH2:11][CH2:16][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:21][CH3:22])[C:15]=4[O:19][CH3:20])[CH:10]=3)[CH2:27][CH2:26]1)=[CH:10]2
Reactant: COc1cc2cc(CCCOS(C)(=O)=O)ccc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2cc(CCCN3CCN(CCCc4ccc5c(OC)c(OC)c(OC)cc5c4)CC3)ccc2c(OC)c1OC

Procedure:
2-(3-Methanesulfonyloxypropyl)-5,6,7-trimethoxynaphthalene (213 mg) and piperazine (26 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][C@@H:2]([S:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)(=[O:7])=[O:6])[CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[NH:38][C:39]([NH2:42])=[N:40][N:41]=2)=[CH:33][CH:32]=1>CN(C=O)C.C(Cl)Cl.C1COCC1>[CH3:1][C@@H:2]([S:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:42][C:39]1[NH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[N:41][N:40]=1)=[O:11])(=[O:6])=[O:7])[CH2:3][CH3:4]
Reactant: COc1ccc(-c2nnc(N)[nH]2)cc1
Reactant: CC[C@@H](C)S(=O)(=O)C(C)(C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@@H](C)S(=O)(=O)C(C)(C)C(=O)Nc1nnc(-c2ccc(OC)cc2)[nH]1
Temperature: 80 °C
Yield: 19.8 %

Procedure:
Activation of 0.5 g (2.40 mmol) of 2-[(2R)-butane-2-sulfonyl]-2-methyl-propionic acid as the corresponding acid chloride is achieved by treatment with oxalyl chloride (0.41 mL, 4.80 mmol), DMF (1 drop) in DCM (10 mL) at room temperature for 18 h. The reaction is concentrated under reduced pressure and excess oxalyl chloride is removed by azeotrope distillation with toluene (3×5 mL) under reduced pressure. The crude acid chloride is dissolved in THF (5 mL) and added to a solution of N,N-diisopropylethylamine (0.84 mL, 4.80 mmol) and 0.3 g (1.58 mmol) of 5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylamine in THF (5 mL). After complete addition the reaction is heated to 80° C. for 48 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3 solution (20 mL). The aqueous layer is back-extracted with DCM (2×20 mL). The combined organic layers are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: heptanes, 0-50% ethyl acetate) to yield 0.119 g of 2-[(2R)-butane-2-sulfonyl]-N-[5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl]-2-methylpropanamide. Yield: 13%; ES-MS: m/z 381 [M+H]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:13]>CO.[Cu]Br>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([NH2:13])[CH:7]=[N:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: [NH4+]
Reactant: CC(C)Oc1cncc(Br)c1
Agent: [Cu]Br
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cncc(N)c1
Temperature: 170 °C
Yield: 72 %

Procedure:
Crude 5-bromo-3-isopropoxypyridine (3.71 g, 17.18 mmol) was dissolved in methanol (46 mL) and added to concentrated ammonium hydroxide (29.7%, 14.8 M, 50 mL) and copper(I) bromide (2.46 g, 17.18 mmol) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 170° C. (oil bath temperature) for 24 h. After cooling, the solution was concentrated by rotary evaporation. Sodium carbonate solution (17.6%, 200 mL) was added, and the mixture was extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to give 1.88 g (72.0%) of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:16]3[CH2:17][CH2:18][O:19][CH:15]3[O:14][N:13]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]([C:12]2[CH:16]3[CH2:17][CH2:18][O:19][CH:15]3[O:14][N:13]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC3OCCC23)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC2OCCC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
60.0 g (168.8 mmol) of methyl 2-chloro-4-methylsulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazol-3-yl)benzoate are dissolved in 600 ml of tetrahydrofuran/300 ml of water, and 7.34 g (183.4 mmol) of sodium hydroxide are added. After the reaction mixture has been stirred for 18 hours at room temperature, it is concentrated, brought to pH 2 with 2 N hydrochloric acid and extracted with dichloromethane. This gives 63.6 g of crude 2-chloro-4-methylsulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazol-3yl)benzoic acid as a foam.
Reaction SMILES: Cl[CH:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>>[CH2:24]([N:27]([CH2:28][CH2:29][CH3:30])[CH:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:25][CH3:26]
Reactant: CC(Cl)CCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: CCCNCCC
Product: CCCN(CCC)C(C)CCOc1ccccc1/C=C/c1nc2ccccc2o1

Procedure:
The title compound was prepared as described in Example 1 starting with (B) of this Example (3.0 g, 9.2 mmol) and using dipropylamine in place of dibutylamine to produce 0.61 g (17% yield) of the free base of the title compound which was converted to the HCl salt, mp 152°-153° C. IR(KBr): 1600 cm-1. MS: 393(MH+). 1H NMR (CDCl3): δ 8.24-6.97 (m, 10H), 4.08 (t, J=5.2 Hz, 2H), 3.18 (m, 6H), 1.98 (m, 8H), 0.99 (m, 6H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C1(C)C=CC=CC=1.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[S:22])=[CH:17][CH:16]=1.Cl>C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[S:22])=[CH:23][CH:24]=1
Reactant: S=C=NCc1ccc(Cl)cc1
Reactant: O=C(O)CCS
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To a solution of 1.06 g. of 3-mercaptopropionic acid in 5 ml. of toluene and 2.0 g. of triethylamine, there was added with cooling 1.83 g. of p-chlorobenzylisothiocyanate. Two phases formed. The mixture was acidified with 1-N hydrochloric acid and extracted with chloroform. The chloroform phases were washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile, and 2.1 g. of 3-{[(p-chlorobenzyl)thiocarbamoyl]thio}-propionic acid having a melting point of 126°-127° C. were obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:17][O:18][C:19]1[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22]>>[C:1]1([NH:7][C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[Se:8][S:17][O:18][C:19]2[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1OS
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Product: O=C(O)c1ccccc1OS[Se]c1ccccc1C(=O)Nc1ccccc1

Procedure:
Prepared similar to example 1 from 5 g (18,2 mmol) of 2-phenyl-1,2-benzisoselenazole-3(2H)-one and 2,8 g (18,2 mmol) of mercaptosalicylic acid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([CH2:13][NH:14][OH:15])=[CH:10][CH:9]=1.C[Si]([N:22]=[C:23]=[O:24])(C)C.Cl>O1CCOCC1>[OH:15][N:14]([CH2:13][C:11]1[S:12][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[CH:9][CH:10]=1)[C:23]([NH2:22])=[O:24]
Reactant: ONCc1ccc(CCCCCC(F)(F)F)s1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(CCCCCC(F)(F)F)s1
Reaction time: 1 h

Procedure:
To a solution of N-[5-(6,6,6-trifluorohexyl)thien-2-ylmethyl]hydroxylamine (1.4 g) in dioxan (50 ml) under nitrogen with stirring, was added trimethylsilyl isocyanate (1.42 ml) and the reaction mixture stirred for 1 hour, poured onto 2N hydrochloric acid (100 ml), extracted with ether (2×100 ml), dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 4:1 hexane/ethyl acetate to give a white solid. Recrystallised from ether/petroleum ether (40°-60° C.) to give a white crystlline solid m.p. 94° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].[CH2:12]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)[CH3:13]>>[C:1]([C:3]1[N:4]=[CH:5][C:6]([C:7]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=2[N+:22]([O-:24])=[O:23])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: N#Cc1ccc(C(=O)O)cn1
Product: CCOc1ccc(NC(=O)c2ccc(C#N)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-cyanonicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.22 (s, 1H), 9.31-9.30 (m, 1H), 8.81 (d, J=9.3, 1H), 8.42-8.38 (m, 1H), 7.90-7.87 (m, 1H), 7.76 (d, J=3.0, 1H), 7.34-7.30 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:25])([C:20]1[O:21][CH:22]=[N:23][N:24]=1)[CH3:19]>>[CH3:17][C:18]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[O:21][CH:22]=[N:23][N:24]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nnco1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1nnco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-[1,3,4]oxadiazol-2-yl-ethylamine as starting materials, MS (LC/MS): 343.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])/[C:4](/[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[N:20]2)=[C:15]([Cl:25])[CH:14]=1)=[CH:5]/[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:25][C:15]1[CH:14]=[C:13](/[C:4](=[CH:5]\[CH:6]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)/[C:3]([OH:26])=[O:2])[CH:18]=[CH:17][C:16]=1[N:19]1[C:23]([CH3:24])=[N:22][N:21]=[N:20]1
Reactant: COC(=O)/C(=C/C1CCCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1Cl
Temperature: 47.5 °C
Yield: 87.5 %

Procedure:
A solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylic acid methyl ester (1.20 g, 3.2 mmol) in ethanol (15 mL) was treated with a 1N aqueous sodium hydroxide solution (6.5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (50 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×70 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-acrylic acid (1.01 g, 87%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:22]C(=O)C)[S:5][C:6]=1[C:7]1[CH:11]=[C:10]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[S:9][CH:8]=1.CCO>Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH2:22])[S:5][C:6]=1[C:7]1[CH:11]=[C:10]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[S:9][CH:8]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCN(C)CC3)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 124 %

Procedure:
N-(4-methyl-5-{5-[(4-methylpiperazin-1-yl)sulfonyl]-3-thienyl}-1,3-thiazol-2-yl)acetamide (34) (978.5 mg; 2.44 mmol; 1 eq) is dissolved in hydrochloric acid 1.25 M in EtOH (39.09 ml; 1.25 M; 48.9 mmol; 20 eq). The mixture is stirred overnight at 90° C. It is cooled down to RT, filtrated, affording Compound (43) as a white solid (1084.3 mg; 91%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]([OH:14])=[O:13])=[O:5])[CH3:18]
Reactant: CCOC(=O)c1c(C)noc1C(=O)N(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1onc(C)c1C(=O)O
Yield: 67.4 %

Procedure:
5.0 g of the ester from Example 9 and 1.4 g of potassium hydroxide in 10 ml of water and 20 ml of ethanol are stirred at room temperature. When the reaction is complete, the mixture is diluted with water and extracted with dichloromethane. Thereafter, the aqueous phase is acidified with hydrochloric acid and extracted with dichloromethane, and the organic phase is evaporated down. 3.0 g of 5-diethylaminocarbonyl-3-methylisoxazole-4-carboxylic acid are obtained as a pale oil (compound No. 4).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccco3)c2n1
Product: c1coc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)c1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(furfuryl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 139°-141° C.) and piperazine.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([O:20][Si](C(C)(C)C)(C)C)[CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)(=O)C.O1CCCC1.[OH-].[Na+]>O>[O:1]=[C:2]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(=O)N1CCCC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCC(=O)N1CCCC(O)C1
Temperature: 75 °C

Procedure:
Mix 1-oxododecyl-3-(O-tert-butyldimethylsilyloxy)piperidine (3.5 mmol) with a solution of acetic acid (9 mL), tetrahydrofuran (6 mL) and water (6 mL). Heat at 75° C. overnight. Cool to room temperature and make basic with cold 10% sodium hydroxide and extract into methylene chloride. Wash with water, then with brine and dry (Na2SO4). Evaporate the solvent in vacuo and purify by flash chromatography (5% methanol/methylene chloride) to give the title compound.