Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.7 g, 6.3 mmol), ethyl 5-bromopentanoate (1.4 g, 7.0 mmol), potassium carbonate (0.97 g, 7.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoate (2.2 g, yield 67%) as crystals.
Reaction SMILES: Cl[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[S-:15][C:16]#[N:17].[K+].O>CN(C)C=O>[C:13]([C:10]1[CH:11]=[CH:12][C:4]2[O:3][CH:2]([N:17]=[C:16]=[S:15])[C:6]([CH3:8])([CH3:7])[C:5]=2[CH:9]=1)#[N:14]
Reactant: N#C[S-]
Reactant: CC1(C)c2cc(C#N)ccc2OC1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)c2cc(C#N)ccc2OC1N=C=S
Yield: 21.6 %

Procedure:
2-Chloro-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (5 g) from Example 15 and potassium thiocyanate (4.6 g) were heated in dimethylformamide (30 ml) at 110° C. for 7 hours. The mixture, after cooling, was added to water and the product extracted into diethyl ether. The ether solution was washed with water (twice), dried over magnesium sulphate and run down under vacuum yielding 4 g of crude product. Purification by silica gel chromatography in toluene yielded 1.2 g of title product, mp 52° C.
Reaction SMILES: [CH2:1]([C:5](CCCC)([C:14]([OH:16])=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([C:14]([OH:16])=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CCCC)(CCCCCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(CCCCCC(=O)O)C(=O)O

Procedure:
The above chiral salt, an organic solvent, an alkaline aqueous medium, and dibutyl 1,6-dicarboxy-hexane are mixed in a vessel. 1.0 equivalents (based upon the moles and equivalents of dibutyl 1,6-dicarboxy-hexane) of alkalizing agent, such as sodium hydroxide, is added, optionally with heating. The hydrolysis is allowed to proceed to completion. The mono-esterified butyl 1,6-dicarboxy-hexane is contained within the aqueous phase. The phases are separated. The aqueous phase is acidified with dilute acid to pH 4.5 with cooling. The butyl 1,6-dicarboxy-hexane is isolated by filtration or extraction with diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+](C1C=CC([O:20][C:21]([N:23]2[CH2:26][CH:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])=[CH:30][N:29]=3)[CH2:24]2)=O)=CC=1)([O-])=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:21]([N:23]2[CH2:24][CH:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])=[CH:30][N:29]=3)[CH2:26]2)=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)nn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N2CC(Oc3ccc(-c4ccccc4F)cn3)C2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 6-Methyl-pyridazin-3-ylamine (60 mg, 0.55 mmol, [Cas. No 18591-82-7]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by flash chromatography (40% ethyl acetate in DCM) to give the title compound (48 mg, 49%)
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].N1C=CC=CC=1.[C:13]12([NH:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19]1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2.O>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([N:23]1[C:13]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]1=[O:24])=[O:4]
Reactant: O=C1NC2(CCCCC2)Oc2ccccc21
Reactant: CC(Br)C(=O)Br
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 89.1 ml of 2-bromopropionyl bromide in 95 ml of methylene chloride and a solution of 61.13 g of pyridine in 95 ml of methylene chloride are added dropwise to a suspension of 140 g of spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 190 ml of methylene chloride under nitrogen atmosphere at -5° C. during about 45 minutes. Then the mixture is stirred at a room temperature for 6 hours. The reaction mixture is poured into 500 ml of water and the mixture is extracted with methylene chloride. The extract is washed, dried and evaporated to remove the solvent and the residue obtained is crystallized from methanol and the crystals are collected by filtration to obtain 197.3 g of 3-(2-bromopropionyl)-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](Cl)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:15][CH3:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Clc1cc2ccc(Br)cc2cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: CNc1cc2ccc(Br)cc2cn1
Temperature: 150 °C
Reaction time: 60 h
Yield: 86.5 %

Procedure:
A mixture of 7-bromo-3-chloroisoquinoline (100 mg, 0.4 mmol), methylamine hydrochloride (139 mg, 2.06 mmol), and potassium carbonate (456 mg, 3.30 mmol) in 1-methoxy-2-(2-methoxyethoxyl)ethane (1 mL) was heated to 150° C. and stirred for 60 hours. Additional methylamine hydrochloride (100 mg, 1.5 mmol) and potassium carbonate (200 mg, 1.4 mmol) were added and heating was continued for another 40 hours. The reaction was cooled to room temperature and diluted with water. The mixture was stirred for 30 minutes. The resulting solid was filtered off, rinsed with water and dried under vacuum. Purification by flash column chromatography (10-30% ethyl acetate/heptanes) gave the title compound (82 mg) as a pale yellow solid. −APCI (M−H+1) 237.8; 1H NMR (400 MHz, CDCl3, δ): 8.70 (s, 1H), 7.84 (d, J=1.95 Hz, 1H), 7.48 (dd, J=8.97, 2.15 Hz, 1H), 7.38 (d, J=8.97 Hz, 1H), 6.39 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.7) (0.50 g, 1.53 mmol) and commercially available 3-bromo-benzene-boronic acid (0.40 g, 1.99 mmol) according to the general procedure IVb. Obtained as a light yellow oil (0.71 g, 83%). MS (EI) 447.7 [(M)+].
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])O[C:2]2=O.C(OC(=O)C)(=O)C.[CH3:20][C:21]1OC(=O)[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1.NC1C(C)=CC=CC=1>CC1C=CC=CC=1C>[CH3:20][C:21]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[CH3:2])[C:5](=[O:12])[C:31]2[C:23](=[CH:24][CH:28]=[CH:29][CH:30]=2)[N:22]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1N
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C)nc2ccccc2c1=O
Yield: 64 %

Procedure:
The isatoic anhydride and acetic anhydride were reacted under the condition described for the preparation of 2-methyl-4H-3,1-benzoxazine-4-one. The pyridine was distilled from the reaction mixture under reduced pressure. The crude reaction product was taken up in 100 ml of o-xylene and placed in a 200 ml one-necked flask equipped with a Dean-Stark trap and a reflux condenser. The o-toluidine was added to the xylene solution. The reaction mixture was heated to reflux for 4 hours. 1.8 ml of water was collected in the Dean-Stark trap. The xylene was removed from the reaction product by distillation under reduced pressure. The resulting residue was crystallized twice from methanol to give 16 parts (64% yield) of 2-methyl-3-(o-tolyl)-quinazoline-4 (3H)-one with m.p. 113°-115° C. The reaction product was characterized by melting point, IR and NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1.[OH-].[Na+].O>O1CCOCC1.C(Cl)Cl>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([N:27]([CH3:26])[CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CNC1CCN(C)CC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Yield: 30.9 %

Procedure:
To 133 (10.014 g, 26.2 mmol) in 1,4-dioxane (80 mL) was added slowly methyl-(1-methyl-piperidin-4-yl)-amine (3.8 mL, 26.2 mmol) dissolved in 1,4-dioxane (15 mL) by addition funnel. Then aqueous sodium hydroxide (10.5 mL, 2.5 N, 26.2 mmol) was added by addition funnel followed by water (26 mL). The reaction mixture was heated at reflux for about 2.5 hours under a nitrogen atmosphere. The reaction was cooled and diluted with methylene chloride. The reaction mixture was filtered using vacuum and the white solid 147 removed. The filtrate was then washed 1 time with brine. The aqueous layer was back extracted 1 time with methylene chloride. The organic layers were combined and dried over potassium carbonate. The organic solution was filtered and concentrated in vacuo to afford the crude product (5.89 g). The crude reaction product was purified by flash column chromatography (silica gel) eluting with 96:3:1 methylene chloride:methanol:15 M ammonium hydroxide. The fractions were combined, dried over sodium sulfate/potassium carbonate, filtered, and concentrated in vacuo to afford 137 as a white solid (3.84 g, 30.9%), mp 104–105° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 13.8 min, 97% purity); MS (ESI): m/z 474 (M+H, 41), 408 (2.3), 364 (2.8), 258 (13), 239 (14), 239 (47.5), 238 (100), 127 (5.3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[C:22]([C:24]#N)[CH:21]=[CH:20][C:19]=3[NH2:26])[CH2:13]2)C1)=O)(C)(C)C.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]1[S:33][CH:34]=[C:35]([C:37]([OH:39])=O)[N:36]=1.C(N(CC)C(C)C)(C)C.C[N:50]([CH:52]=[O:53])C>>[NH2:8][CH2:12][CH2:11][CH:10]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:23]=[C:22]([CH2:24][C:52](=[O:53])[NH2:50])[CH:21]=[CH:20][C:19]=2[NH:26][C:37]([C:35]2[N:36]=[C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[S:33][CH:34]=2)=[O:39])[CH2:13]1
Reactant: O=C(O)c1csc(-c2cccs2)n1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(c3cc(C#N)ccc3N)C2)C1
Solvent: CCN(C(C)C)C(C)C
Product: NCCC1CCCN(c2cc(CC(N)=O)ccc2NC(=O)c2csc(-c3cccs3)n2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the solution of 7-(2-Amino-5-cyano-phenyl)-2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester was added 2-thiophen-2-yl-thiazole-4-carboxylic acid (product of step 2, 0.98 eq,) in DMF (1 mL). Then, a solution of N,N-diisopropylethylamine (1.5 eq) HATU (1.5 eq) was added. The resulting reaction was stirred at room temperature for 15 hours and then concentrated and treated with 3 mL of (4:1) TFA:H2SO4. The reaction mixture was concentrated and purified using reverse phase HPLC to provide 2-Thiophen-2-yl-thiazole-4-carboxylic acid {2-[3-(2-amino-ethyl)-piperidin-1-yl]-4-carbamoylmethyl-phenyl}-amide. HPLC-MS RT=3.13 min, mass calculated for formula C23H25N5O2S2 467.14, observed LCMS m/z 468.21 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.C(OCC)(=O)C.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]=[CH:19][C:18]([CH:22]=[CH2:23])=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ncc(Br)cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cnc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)nc1
Temperature: 90 °C
Yield: 35.7 %

Procedure:
(S,S)-5-(5-Bromo-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (177 mg, 0.5 mmol), tributyl vinyl tin (634 mg, 2 mmol) and Cl2Pd(dppf)CH2Cl2 (60 mg) was mixed in DMF (3 mL). The mixture was heated at 90° C. over 3 days. The cooled down reaction was participate between ethyl acetate (50 mL) and H2O (10 mL). The organic layer washed with H2O (10 mL), brine (10 mL), dried (MgSO4) and filtered. The conc. filtrate was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to yield the title compound as a white solid (54 mg). MS (303, MH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH:10]1[S:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])(=[O:9])=[O:8].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[C:21]([C:29]#[C:30][CH2:31]Br)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[F:17][C:18]([F:33])([F:34])[C:19]1[CH:20]=[C:21]([C:29]#[C:30][CH2:31][C:10]2([S:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)(=[O:9])=[O:8])[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: FC(F)(F)c1cc(C#CCBr)cc(C(F)(F)F)c1
Reactant: O=C1NC(=O)C(S(=O)(=O)c2ccccn2)S1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(S(=O)(=O)c2ccccn2)S1

Procedure:
By the procedure described in Example 43, this compound was prepared from 5-(Pyridine-2-sulfonyl)-thiazolidine-2,4-dione of formula (V).Example 19 and [3-(3,5-bis(trifluoromethyl)phenyl)-prop-2-ynyl]-bromide of formula (IX), Example 31: mp 150°-152° C.: NMR (DMSO, d 6): δ8.79 (d, J=4.4 Hz, 1H, pyH), 8.16 (dr, J=1.6, 7.9 Hz, 1H, pyH), 8.11 (s, 1H, ArH), 8.05 (d, J=7.9 Hz, 1H, pyH), 7.94 (s, 2H, ArH), 7.9 (dd, J=4.9, 7.3 Hz, 1H, ArH), 3.87 (d, J=17.2 Hz, 1H, CH2), 3.71 (d, J=17.2 Hz, 1H, CH2); MS(CI): 509 (MI+1, 100%), 367 (32%), 366 (352%), 287 (35%), 194 (25%), 194 (20%); Anal. Calc. for C19H10F6N2O4S2 : C, 44.89; H, 1.98; N, 5.51; Found: C, 42.80; H, 2.09; N, 5.77.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[C:4]#[C:5][CH3:6].[N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([O:24][CH2:25][CH3:26])[C:21](O)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([O:24][CH2:25][CH3:26])[C:21]([NH:2][C:3]([CH3:8])([C:4]#[C:5][CH3:6])[CH3:7])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(Oc1ccc2ncccc2c1)C(=O)O
Reactant: CC#CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CC(C)(C)NC(=O)C(OCC)Oc1ccc2ncccc2c1
Yield: 88.7 %

Procedure:
Triethylamine (0.3 ml) was added to a stirred solution of 4-amino-4-methylpent-2-yne hydrochloride (0.054 g) in N,N-dimethylformamide (2 ml) giving a white suspension. 2-(6-Quinolinoxy)-2-(ethoxy)acetic acid (0.1 g) was added followed by N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (0.077 g) and a catalytic amount of 1-hydroxybenzotriazole (0.005 g), and the white suspension was stirred at ambient temperature for 18 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulphate and evaporated under reduced pressure to give a yellow oil (0.117 g). The oil was purified by flash chromatography (silica gel; ethyl acetate/hexane, 1:1 by volume) to give the required product (0.096 g) as a colourless oil.
Reaction SMILES: [Cl-].[NH4+].[CH:3]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH2:5][CH2:4]1.CO>C1COCC1.C(Cl)(Cl)Cl.[Zn]>[CH:3]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[NH2:12])[CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1cnccc1C1CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cnccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 787.3 %

Procedure:
Zinc powder (223.2 mg, 3.41 mmol) and ammonium chloride solution (365 mg, 6.8 mmol) were added to a stirred solution of 4-cyclopropyl-3-nitropyridine (70 mg, 0.426 mmol) in dry THF (2 mL) at 0° C. and the resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (10% methanol in CHCl3). The organic layer was concentrated and washed with pentane to afford 450 mg of the product (100% yield).
Reaction SMILES: CN.CO[C:5]1[C:9]([NH:10][CH3:11])=[N:8][S:7](=[O:12])[N:6]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1)[CH3:15]>>[CH3:15][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:24][CH2:25][NH:26][C:5]2[C:9]([NH:10][CH3:11])=[N:8][S:7](=[O:12])[N:6]=2)=[CH:19][CH:18]=1)[CH3:13]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CNC1=NS(=O)N=C1OC
Agent: CN
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
Reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadizole 1-oxide [prepared in Example 4, Step A] with one equivalent of methylamine and treatment of the resultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1-oxide with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine yields the title compound, which is identical to the product prepared in Example 18.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([CH3:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:22])=[CH:16][CH:17]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCC1(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.6 mmol) in dichloromethane (40 mL) at about 0° C. was added trifluoroacetic acid (10 mL). The solution was stirred for about 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was neutralized with saturated sodium bicarbonate, and washed with brine and dried over magnesium sulfate. The solvent was removed to give a yellow solid. No purification was needed.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-])=O)=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1n[nH]cc1N
Reaction time: 20 h
Yield: 98.4 %

Procedure:
A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (6.40 g, 34.6 mmol) and 10% Pd/C (650 mg) in EtOH (150 ml) was stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through a plug of Celite, reduced in vacuo and dried through azeotrope with toluene to afford 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester as a pink solid (5.28 g, 98%). (1H NMR (400 MHz, DMSO-d6) □ 12.7 (s, 1H), 7.1 (s, 1H), 4.8 (s, 2H), 4.3 (q, 2H), 1.3 (t, 3H)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=4)[N:25]=3)=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(Oc3ccc4ncc([N+](=O)[O-])n4n3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
8.0 g (30 mmol) of 4-[(5-chloro-2,6-dimethylpyrimidin-4-ylamino)methyl]phenol, 6.0 g (30 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine and 20.7 g (150 mmol) of potassium carbonate in 150 ml of anhydrous dimethylformamide are heated at 80° C. with vigorous stirring for 1 h. After cooling to room temperature, the mixture is poured into water (1 l) and extracted with ethyl acetate (3×500 ml). The combined organic extracts are washed with water (500 ml), dried over sodium sulfate and concentrated. The beige solid (12.5 g) remaining is purified by chromatography on silica gel (mobile phase: toluene/acetone=2:1). The fractions with Rf=0.4 are collected and concentrated. The residue is suspended in 100 ml of methanol and the suspension is stirred for 30 min. Following filtration, this operation is repeated. After drying in a vacuum drying cabinet at 40° C., 7.8 g (61%) of the title compound are isolated as an almost white powder. m.p.: 203° C.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+].O>>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[CH:14]=2)[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC(C4CCCC4)CC3)ccc2c1
Yield: 62 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-Cyclopentyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 114 mg the desired product as a white solid (90%). ESI-MS: 351 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=7.87 (s, 1 H), 7.81-7.55 (m, 3 H), 7.31-7.21 (m, 1 H), 7.18-7.00 (m, 1 H), 4.98-4.59 (m, 3 H), 4.43-4.27 (m, 0.63 H), 3.57-3.14 (m, 4 H), 2.19-0.84 (m, 17 H)