Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C1SC(C2N=CNN=2)=CC=1C)=O)C1C=CC=CC=1.[CH3:22][C:23]1[CH:27]=[C:26]([C:28]2[N:32]=[CH:31][NH:30][N:29]=2)[S:25][C:24]=1[C:33]([NH:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:34].[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1>>[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][N:30]2[CH:31]=[N:32][C:28]([C:26]3[S:25][C:24]([C:33]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:34])=[C:23]([CH3:22])[CH:27]=3)=[N:29]2)=[CH:46][CH:45]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cc(-c2nc[nH]n2)sc1C(=O)NCc1cccnc1
Agent: Cc1cc(-c2nc[nH]n2)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-c2ncn(Cc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Yield: 24 %

Procedure:
Following the procedure as described in Example 23, making variations as necessary to replace N-benzyl-3-methyl-5-(1H-1,2,4-triazol-3-yl)thiophene-2-carboxamide with 3-methyl-N-(pyridin-3-ylmethyl)-5-(1H-1,2,4-triazol-3-yl)thiophene-2-carboxamide to react with 4-fluorobenzyl bromide, the title compound was obtained as an off-white solid in 24% yield: mp 154-155° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.45 (s, 1H), 7.33-7.24 (m, 3H), 7.11-7.02 (m, 2H), 6.27 (br s, 1H), 5.30 (s, 2H), 4.62 (d, J=5.6 Hz, 2H), 2.52 (s, 3H); MS (ES+) m/z 408.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[O:8])[C:3]=1[N+:17]([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+]>O1CCCC1.Cl>[NH2:17][C:3]1[C:4]([C:7]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2c(F)cccc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C(=O)c2c(F)cccc2F)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (5-methyl-4-nitroisoxazol-3-yl)-2,6-difluorophenylmethanone of Example XIIIb (82.6 g, 308 mmoles) in tetrahydrofuran (THF) (200 ml) was added to a mixture of SnCl2.2H2O (210 g, 938 mmoles) in concentrated hydrochloric acid (400 ml) and THF (400 ml) at 15° C. The reaction mixture was stirred at room temperature for 3 hours and poured into a mixture of 50% sodium hydroxide (700 g) and ice with stirring. The organic phase was separated and the aqueous was extracted with ethyl acetate. The organics were combined, washed with saturated sodium chloride, dried (sodium sulfate), and evaporated to give 63 g of an oil. The residue was flash chromatographed (20% ethyl acetate:hexane) to yield 51 g (70%) of an oil that crystallized on standing. The amine (4.0 g) was chromatographed by high pressure liquid chromatography (20% ethyl acetate:hexane) to yield 2.3 g (40%) of a solid, melting point 63°- 68° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:15][CH2:14]1.ClCCl>O1CCOCC1>[O:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([NH:25][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=Cc1cnn2ccc(Nc3cccc(OCCN4CCOCC4)c3)nc12
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.221 mmol) in dioxane was added 3-(2-morpholinoethoxy)aniline (147 mg, 0.663 mmol). The mixture was heated in microwave at 120° C. Dichloromethane was added, and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 5-(3-(2-morpholinoethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. The solid was used in the next step without further purification. LCMS (M+1=368)
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([Br:16])[CH:12]=[C:13](F)[CH:14]=1>CC(N(C)C)=O>[Br:16][C:11]1[CH:10]=[C:9]([F:8])[CH:14]=[C:13]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)Oc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butanol (28.2 g) is dissolved in dimethyl acetamide (200 ml). NaH (15.6 g, 60% dispersion in oil) is added over 15 minutes. The reaction mixture is stirred at room temperature for 2 hours. 3,5-difluorobromobenzene (50 g) is added drop wise over 30 minutes. The reaction mixture is stirred at room temperature until shown to be complete by HPLC. The reastion mixture is quenched by addition of water (10 ml), washed with water (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.00 (ddd, 1H), 6.95 (dd, 1H), 6.68 (ddd, 1H), 1.4 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]1[O:26][C:13]1([CH3:14])[CH3:15]
Reactant: COC(=O)C=CC=CCC(C)CCC=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C=CC=CCC(C)CCC1OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.4 g of 7,11-dimethyl-2,4,10-dodecatrienoic acid methyl ester is dissolved in 30 ml of methylene chloride and mixed portionwise at 0°C., with stirring, with 2.4 g of m-chloroperbenzoic acid (ca 80% by wt.). Subsequently the mixture is stirred for a further 1.5 hours at 0°C. The mixture is poured on to ice, treated with 1-N sodium hydroxide, and extracted with diethyl ether. The ethereal phase is washed to neutrality, dried and evaporated. The product is chromatographed on a 50-fold amount of Kieselgel, using hexane/20% by volume ethyl acetate as the eluant. There is obtained 10,11-epoxy-7,11-dimethyl-2,4-dodecadienoic acid methyl ester, as a colorless oil; boiling point ca. 62°C/0.05 mmHg (bulb tube); nD25 = 1.4958.
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(=O)NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)=CC=2C(O)=O)C=1C.[Cl:44][C:45]1[C:46]([N:79]([CH2:83][CH2:84][CH3:85])[CH2:80][CH2:81][CH3:82])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:78])[NH:63][S:64]([C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[C:70]([Cl:77])[CH:71]=[CH:72][CH:73]=4)[CH:68]=3)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([O:55]CC)=[O:54])[C:49]=1[CH3:50]>>[Cl:44][C:45]1[C:46]([N:79]([CH2:80][CH2:81][CH3:82])[CH2:83][CH2:84][CH3:85])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:78])[NH:63][S:64]([C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[C:70]([Cl:77])[CH:71]=[CH:72][CH:73]=4)[CH:68]=3)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([OH:55])=[O:54])[C:49]=1[CH3:50]
Reactant: CCCN(CCC)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(Cl)c4c3)cc2C(=O)OCC)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCN(CCC)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(Cl)c4c3)cc2C(=O)O)c(C)c1Cl

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 91F, ethyl 2-(4-chloro-3-(dipropylamino)-5-methyl-1H-pyrazol-1-yl)-5-(8-chloronaphthalen-2-ylsulfonylcarbamoyl)benzoate (76 mg, 0.12 mmol) was converted to the title compound and used in the subsequent step without purification. 1H NMR (CDCl3) δ 9.14 (d, J=1.8 Hz, 1H), 8.67 (s, 1H), 8.19 (td, J=8.5, 2.2 Hz, 2H), 8.01 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.69 (dd, J=7.4, 1.0 Hz, 1H), 7.62-7.54 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 3.59-3.41 (m, 6H), 2.14 (s, 3H), 1.73-1.50 (m, 4H), 0.91 (t, J=7.3 Hz, 6H); MS(ESI+) m/z 603.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Cl.CON.O.[NH2:24][NH2:25]>COCCOC>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:4]2[C:3]=1[NH:25][N:24]=[CH:5]2
Reactant: NN
Reactant: COc1ccc(Cl)c(F)c1C=O
Agent: CON
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)c2[nH]ncc12
Temperature: 45 °C

Procedure:
To a solution of 3-chloro-2-fluoro-6-(methyloxy)benzaldehyde (10 g, 53.0 mmol) in 1,2-dimethoxyethane (105 mL) was added potassium carbonate (8.06 g, 58.3 mmol) and O-methylhydroxylamine hydrochloride (4.43 g, 53.0 mmol) and the mixture was stirred and heated at 45° C. for 4 hrs. After cooling, the mixture was filtered and concentrated to ˜40 mL and hydrazine monohydrate (58.3 mL, 1856 mmol) was added and the reaction was refluxed under argon over the weekend. The mixture was concentrated to 10-15 mL on the rotary evaporator and then poured into water and stirred for 10 mins. The precipitated solid was collected by filtration and washed with water (3×), sucked dry and then dried in the vacuum oven at 60° C. for 1 hr to give the title compound (D28) as an off white solid (8.83 g)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:27][S:26](=[O:29])(=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:8]=2[N:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[C:8]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[S:26](=[O:29])(=[O:28])[CH2:27][C:7]=3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:10]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1nn(-c2ccc(C(=O)O)cc2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2ccc(CO)cc2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(ethoxycarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1 (4H)-yl]benzoic acid (21.88 g; 53.05 mmol; 1 eq.) in THF (350 ml) is added triethylamine (14.71 ml; 106.11 mmol; 2 eq.) followed by isobutyl chloroformate (13.83 ml; 106.11 mmol; 2 eq.) at 0° C. under nitrogen. The reaction mixture is stirred at rt for 30 min then cooled at 0° C. Sodium borohydride (10 g; 265.27 mmol; 5 eq.) is added portionwise. After 5 h, THF (100 mL) is added and the reaction mixture is heated at 35° C. for 1 day then at rt for 2 days. Sodium borohydride is added (1 eq) and after 6 h stirring the reaction is quenched by dropwise addition of water at 0° C. over 2 h. The product is extracted with EtOAc, the organic layers washed with HCl 1 m (2×) and brine then dried over MgSO4. After evaporation of the solvent, the residue is taken up in DCM and HCl 1 m. The precipitate formed is filtered off and recrystallized in DCE to afford the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.05-8.02 (m, 1H), 7.68-7.48 (m, 6H), 6.88-6.84 (m, 1H), 5.76 (s, 2H), 4.99 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.90 (s, 1H), 1.35 (t, J=7.1 Hz, 3H). HPLC (max plot) 68.2%; Rt 3.02 min. MS (ESI+): 398.9
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:16])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:17]([NH2:19])[CH3:18]>C1COCC1>[CH2:17]([NH:19][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:16])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)[CH3:18]
Reactant: CCN
Reactant: COc1cc2cc(C=O)c(Cl)nc2cc1F
Solvent: C1CCOC1
Product: CCNc1nc2cc(F)c(OC)cc2cc1C=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a stirred solution of 2-chloro-7-fluoro-6-methoxyquinoline-3-carbaldehyde SMA 44034 (219 mg, 0.91 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added ethylamine (2 M in THF, 4.50 mL, 9.00 mmol) and the mixture was stirred at 150° C. for 2 h under microwave irradiation. After cooling to RT, the volatiles were removed under vacuum at 40° C. and the resulting yellow oil was taken up in a 2 N aq. HCl solution (15 mL) and stirred for 15 min at RT then neutralised with a 2 N aq. NaOH solution (15 mL). The mixture was extracted with CH2Cl2:MeOH=9:1 (50 mL) and the organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 2-(ethylamino)-7-fluoro-6-methoxyquinoline-3-carbaldehyde CCH 42068 as a yellow oil (105 mg, 46% yield).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][CH:17]=O>O>[O:7]=[C:3]1[C:2]2[CH:16]=[CH:17][O:8][C:1]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 45 h
Yield: 68 %

Procedure:
To a mixture of 1.12 g (10 mmoles) of 1,3-cyclohexanedione and 8 ml of water was added 1.38 g (10 mmoles) of potassium carbonate, and then 2 ml of 40% aqueous solution of chloroacetaldehyde was added thereto. The resulting mixture was stirred at a room temperature for 45 hours. The reaction mixture was maintained at a pH of from 7.75 to 9.50 throughout the reaction. After completing the reaction, the obtained reaction mixture was treated and analyzed in the same manner as in Example 1. It was proved from the results of the analysis that 4-oxo-4,5,6,7-tetrahydrobenzofuran was produced in a 68% yield.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]2[N:16]=[C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C)=[C:19]([CH3:26])[CH:18]=3)[O:14][C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:5][C:6]1[C:7]2[N:16]=[C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:26])[CH:18]=3)[O:14][C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1
Reactant: COc1c(C)cc(-c2nc3c(Cl)nc(SC)nc3o2)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(Cl)c2nc(-c3cc(C)c(O)c(C)c3)oc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At −20° C., 5.30 g of boron tribromide were added dropwise with stirring to a solution of 6.72 g of 7-chloro-2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyloxazolo[5,4-d]pyrimidine in 140 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. With ice cooling, another 1.33 g of boron tribromide were then added dropwise. After a further 2 hours, the reaction was once more cooled to −20° C., and sat. aqueous sodium bicarbonate solution was carefully added dropwise. The phases were separated at room temperature. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diisopropyl ether, filtered off with suction and air-dried. This gave 6.20 g (96%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:8])([CH3:5])([CH3:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[C:29]([C:30](Cl)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[C:2]([O:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:30]([C:29]1[C:25]([C:19]2[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[N:26][O:27][C:28]=1[CH3:33])=[O:31])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Agent: Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCCCCNC(=O)OC(C)(C)C
Yield: 100.6 %

Procedure:
N-t-butyloxycarbonyl-1,6-diaminohexane hydrochloride salt (1.02 g, 4.03 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.11 g, 4.03 mmol) were converted to 1.84 g of the title compound by the procedure of Preparation 1. (100%). EA calculated for: C22H29N3O4ClF: C, 58.21; H, 6.44; N, 9.26. Found: C, 57.97; H, 6.20; N, 9.43. MS(IS) m/z 454 (M+)
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CC(C)c1noc(N2CCC(=O)CC2)n1
Product: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. Mass spectrum (ESI+): m/z=251 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][C@@H:27]3[O:41][C:31]4=[C:32]5[C:37](=[CH:38][CH:39]=[C:30]4[O:29][CH2:28]3)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]5)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C[C@H]3COc4ccc5nc(C)ccc5c4O3)CC2)cc1
Yield: 83.7 %

Procedure:
This compound was prepared as described for Example 5, using 4-methoxyphenyl piperazine (880 mg, 4.58 mmol) and 742 mg (1.65 mmol) of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzene-sulfonate, to afford 560 mg (84%) of the title compound as a white solid: mp 164–165° C.; MS (ESI) m/z406 [M+H]+.
Reaction SMILES: [C:1]([C:5]([O:22][SiH:23]([CH3:25])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH2:29][C:30]1[S:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH2:39])=[CH:32][C:31]=1[CH3:40])[CH3:28]>>[C:1]([C:5]([O:22][SiH:23]([CH3:25])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)[CH2:6][NH:7][C:8]([NH:39][CH2:38][CH2:37][S:36][CH2:35][C:33]1[S:34][C:30]([CH2:29][N:27]([CH3:26])[CH3:28])=[C:31]([CH3:40])[CH:32]=1)=[CH:9][N+:10]([O-:12])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSC(=C[N+](=O)[O-])NCC(O[SiH](C)C)(c1cccc(C)c1)C(C)(C)C
Reactant: Cc1cc(CSCCN)sc1CN(C)C
Product: Cc1cccc(C(CNC(=C[N+](=O)[O-])NCCSCc2cc(C)c(CN(C)C)s2)(O[SiH](C)C)C(C)(C)C)c1
Yield: 80 %

Procedure:
In the same manner as in Example 6-(2), 3.8 g of 1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethene and 2.6 g of 2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylamine were reacted and treated to obtain 4.6 g (yield 87%) of oily N-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([O:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:16]([O:32][C:33]1[S:34][C:35]([CH:9]=[O:10])=[CH:36][CH:37]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CN(C=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOc1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(C=O)s1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To a cooled mixture of 27 g of N-methylformanilide and 27 g (0.176 mole) of phosphorus oxychloride is added 32.5 g (0.1 mole) of 2-hexadecyloxythiophene. The mixture is warmed to 70° C under vacuum (10 mm Hg). The mixture is allowed to stand at 60°-70° C for 7 hours, the overnight at room temperature after which the mixture is stirred into 100 g of ice. The mixture is extracted into benzene, washed with water, dried over sodium sulfate and distilled in vacuo to give 5-hexadecyloxy-2-thiophenecarboxaldehyde. The carboxaldehyde (7.1 g, 0.02 mole) is stirred vigorously with 4 g of potassium hydroxide in 2.6 ml of water for 24 hours. The mixture is diluted with water and extracted into ether. The aqueous layer is separated and acidified with hydrochloric acid precipitating 5-(hexadecyloxy)-2-thiophenecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:15]([NH:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1)=[O:20])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])=[N:22][CH:23]=2)=[O:26])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)NC(=O)c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to isopropylamine via Procedure G. Crude methyl 6-(isopropylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 227 mg of 6-(isopropylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(isopropylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-isopropylpyridine-2,5-dicarboxamide. MS (Q1) 395.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a 2 l three necked flask fitted with mechanical stirrer and dropping funnel under inert atmosphere, 106.2 g (755 mmoles, 1 eq) of 3-chlorobenzaldehyde are dissolved in 1I of THF and cooled down to 0° C. 341.9 g (980 mmoles, 1.3 eq) of ethyl (triphenylphosphoranylidene)acetate are then added under efficient stirring, the temperature raising to 10° C. The mixture is kept under stirring one hour at 0° C., and then overnight at room temperature. The mixture is concentrated to dryness, the residue suspended in diethyl ether, the triphenylphospine oxide is filtered off and the filtrate concentrated to dryness. The residue is purified by PrepLC (1 kg SiO2, pet. ether/EtOAc, 75:35) to give 191.8 g of pure 375, 92% yield. 1H NMR (250 MHz, (CD3)2SO): 1.30 (t, 3H), 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7.70 (m, 2H), (s(broad), 1H).
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:34][C:31]([F:33])([F:32])[C:27]1[CH:26]=[C:25]2[C:30]([C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]3[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[O:8][CH:9]=3)=[CH:22][CH:23]=[N:24]2)=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3cc(C(F)(F)F)ccc23)co1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2cc(=O)c(OCCCCCOc3ccnc4cc(C(F)(F)F)ccc34)co2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(7-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 17 (130 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL). 1-Methyl-piperazine (75 μL, 0.67 mmol) was added via syringe. The mixture was stirred at 45° C. for 3 h. After cooling to room temperature CH2Cl2 (75 ml) was added and the mixture was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 5-(5-(7-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one EHT 0079 was obtained (30 mg, 23% yield) as a yellow oil.