Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[NH:28][N:27]=3)[CH:22]=[CH:21][C:20]=2[F:37])[C:14](=[O:38])[CH2:13]1)C1C=CC=CC=1.CO>O.[Pd]>[F:37][C:20]1[CH:21]=[CH:22][C:23]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[NH:28][N:27]=2)=[CH:24][C:19]=1[N:15]1[C:14](=[O:38])[CH2:13][NH:12][CH2:17][C:16]1=[O:18]
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: O=C1CNCC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C

Procedure:
A solution of ammonium formate (0.55 g, 8.8 mmol) in water (5 ml) was added to a stirred mixture of 4-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (1 g, 2.2 mmol; prepared in a manner similar to that described in Example 31), 10% palladium on carbon catalyst (0.33 g) and methanol (15 ml), the mixture was heated under reflux for 1 hour, then it was cooled to ambient temperature and filtered through a pad of Celite filter aid. The filter pad was washed with methanol (50 ml), then the combined filtrate and washings were concentrated in vacuo. The residue was diluted with water (20 ml), the product was extracted into ethyl acetate (4×20 ml), the combined extracts were dried (MgSO4) and the solvent was removed in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (0.8 g) as a pale brown solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.3 (2× overlapping d, 4H) (2×ring CH2), 4.25 (s, 2H) (ArCH2—), 6.95–7.2 (m, 2H) (2×ArH), 7.7–7.9 (m, 3H) (3×ArH), 7.95 (d, 1H) (ArH), 8.2 (d, 1H) (ArH), 9.7 (s, 1H) (piperazine NH), 12.6 (s, 1H) (CONH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[F:24])=[C:11]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:38][N:37]=[N:36][N:21]=4)=[CH:18][C:17]=3[F:24])=[C:11]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2nnn[nH]2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 5, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (example 14.2) was treated with sodium azide and triethylamine hydrochloride in DMF to give the title compound as white solid. MS: m/e=535.7 [M+H+].
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[O-:23][C:24]#[N:25].[Na+]>O1CCCC1>[N:25]([SiH:2]1[N:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][N:3]1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:24]=[O:23]
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Reactant: N#C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1N=C=O
Reaction time: 18 h
Yield: 89 %

Procedure:
In an argon atmosphere, 7.57 g (22.0 mmol) of Si(tOctNCHCHNtOct)(H)Cl was dissolved in 30 mL of tetrahydrofuran and after adding 2.14 g (purity: 96%, 31.6 mmol) of sodium cyanate, the mixture was stirred for 18 hours under heating and refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 117° C./73 Pa) to obtain 2-isocyanato-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NCO) as a colorless liquid (yielded amount: 6.91 g, yield: 89%).
Reaction SMILES: Cl.[CH2:2]1[O:11][C:10]2[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=2[O:3]1.N([O-])=O.[Na+].[CH3:16][N:17]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]1=[O:23].C(=O)(O)[O-].[Na+]>O.Cl.CC(C)=O>[O:11]1[C:10]2[CH:9]=[CH:8][C:6]([C:19]3[C:18](=[O:23])[N:17]([CH3:16])[C:21](=[O:22])[CH:20]=3)=[CH:5][C:4]=2[O:3][CH2:2]1
Reactant: CN1C(=O)C=CC1=O
Reactant: Nc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: CN1C(=O)C=C(c2ccc3c(c2)OCO3)C1=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
A 30.9 g amount of 3,4-methylenedioxyaniline hydrochloride was dissolved in 90 ml of water and 40 ml of concentrated hydrochloric acid. The solution was cooled to 5° C. in an ice-salt bath and a solution of 12.3 g of sodium nitrite in 35 ml of water was added dropwise to the reaction mixture over a 25 minute period. A solution of 20.0 g of N-methylmaleimide and 2.4 g of cupric chloride in 150 ml of acetone was added to the reaction mixture portionwise with stirring. The reaction mixture temperature was maintained at 3° C. and the pH was adjusted to 3.2 by the addition of about 30 g of sodium bicarbonate. After standing at room temperature for 16 hours the mixture was filtered to collect a black solid. The solid was dried. Then the solid was dissolved in 500 ml of isopropanol containing 19.5 g of 2,6-lutidine. The mixture was heated to boiling and filtered hot to collect 4.8 g of isoluble material. The filtrate was cooled and an additional 2.6 g of precipitate was collected. This filtrate was reduced in volume to 200 ml and cooled and filtered to collect 2.7 g more of precipitate. The final filtrate was diluted with water and filtered to collect 0.9 g of additional material. The precipitates were combined and subjected to preparative liquid chromatography using a silica gel column and ethyl acetate:hexane (1:1) as eluent. The second cut, 0.6 g was recrystallized from ethyl acetate to give 0.1 g of 3-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrrole-2,5-dione as a brown solid, mp 210°-215° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:12]([CH3:15])([O-:14])=[O:13].CN(C)C(=N)N(C)C.S(=O)(=O)(O)O>O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH:3]([CH2:15][N+:12]([O-:14])=[O:13])[C:2]([F:10])([F:11])[F:1])[CH3:9]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CC(C[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 98 %

Procedure:
A mixture of 4.203 g (25 mmol) of ethyl 4,4,4-trifluoro-crotonate, 20 mL of nitromethane and ca. 0.576 g (5 mmol) of tetramethyl guanidine was stirred for 13 h at room temperature, and then diluted with water and acidified by the addition of 0.5 M sulfuric acid. The mixture was extracted three times with diethyl ether. The combined ether extracts were washed with water, and then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. to give 5.601 g (98%) of 4,4,4-trifluoro-3-nitromethyl-butyric acid ethyl ester as an amber oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.15 Hz, 3H) 2.76 (dd, J=6.53, 1.76 Hz, 2H) 3.61-3.84 (m, 1H) 4.13 (q, J=7.11 Hz, 2H) 4.83-5.01 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[F:21][C:22]1[C:27](C(Cl)=O)=[CH:26][CH:25]=[CH:24][N:23]=1>C(#N)C>[F:21][C:22]1[C:27]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=C(Cl)c1cccnc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cccnc1F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Potassium 3-(ethoxy)-3-oxopropanoate (6.06 g, 35.6 mmol) was suspended in acetonitrile (100 mL), cooled to 0° C. and treated successively with triethylamine (4.96 mL, 35.6 mmol, 1 equiv) and anhydrous magnesium(II) chloride (3.39 g, 35.6 mmol, 1 equiv). The ice bath was removed and the mixture was warmed to ambient temperature and stirred for 2.5 hours. An acetonitrile (5 mL) solution of 2-fluoropyridine-3-carbonyl choride (5.68 g, 35.6 mmol) was added and the mixture was stirred for 72 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was concentrated from toluene (1×75 mL). The residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous). After 15 minutes, the mixture was warmed to ambient temperature and stirred for an additional 45 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:12]([O:24][CH3:25])[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[C:12]([O:24][CH3:25])[CH:11]=1
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.6 %

Procedure:
To a solution of protected alcohol 7 (242.4 mg, 0.66 mmol) in THF (2.5 ml) was added a solution of 1M tetrabutylammonium fluoride in THF (0.73 ml, 0.73 mmol) and the mixture was stirred at room temperature for 24 hrs. The crude product was adsorbed on silica gel and purified by MPLC, eluting with hexanes/ethyl acetate 40%-50% gradient to give the title alcohol (92.9 mg, 56% yield). H-NMR (400 MHz, CD2Cl2): 8.85 (1H, brs) 7.78 (1H, d, J=8 Hz) 7.09 (1H, s) 6.82 (1H, dd, J=8 Hz, 0.4 Hz) 4.58 (2H, d, J=4 Hz) 3.5 (1H, t, J=4 Hz) 1.18 (9H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][C:2]([F:13])([F:12])[F:1])[CH:5]=2)[CH2:16][CH2:15]1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: NC1CC1
Product: FC(F)(F)Oc1cccc(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 3-trifluoromethoxy-benzaldehyde and cyclopropylamine.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.BrC1C=CC([C:19]2([O:22]C)CC2)=CC=1.[Li]CCCC.CN(C=O)C>>[CH3:19][O:22][C:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: COC1(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COC1(c2ccc(C=O)cc2)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 1-bromo-4-(1-methoxycyclopropyl)-benzene (250 mg, 1.10 mmol), n-BuLi (722 μl, 1.6M solution in hexane, 1.16 mmol) and DMF (171 μl, 2.20 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 4-(1-methoxycyclopropyl)-benzaldehyde (90 mg, 58%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): δ 10.0 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 3.29 (s, 3H), 1.35-1.30 (m, 2H), 1.09-1.05 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:7]2[CH:8]=[CH:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:11][CH:6]=2)=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: FC(F)(F)c1cccc(Br)c1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-3-trifluoromethyl-benzene. MS m/z 477 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][SH:17]>>[C:1](=[O:12])([S:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCS
Product: CCCCCCC/C=C/C(=O)SCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(dimethylamino)ethanethiol as starting materials to give the aimed compound.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:40])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:30])=[O:31])=[CH:37][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(-c3nccs3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(-c3nccs3)cc2)Cc2cccc(OCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-{[(4-methoxy-benzenesulfonyl)-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester of Step A in CH2Cl2 (2mL) at 0° C. was added cold TFA (1 mL) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated using a stream of nitrogen. Additional CH2Cl2 (1 mL) was added and the solution was concentrated using a stream of nitrogen. This procedure was repeated and the residue was dried in vacuo to provide the title compound (24.6 mg). MS 524 (M−1).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Br:16])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:17])=[O:5]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A cooled (0° C.) solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (1.00 g; 3.11 mmol) in DCM (22 mL) was treated with trifluoroacetic acid (2.38 mL; 31.1 mmol). The reaction mixture was stirred at room temperature for 5 hours, the solvents were removed under vacuum to give the title compound (825 mg, quant.).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](/[C:17]([OH:19])=[O:18])=[CH:15]/[CH3:16])[N:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:13][N:12]=[C:11](/[C:14](/[C:17]([OH:19])=[O:18])=[CH:15]/[CH3:16])[N:10]=1
Reactant: C/C=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: C/C=C(\C(=O)O)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
340 mg (1.2 mMol) of Z-1-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)propene-1-carboxylic acid were dissolved in 4 ml of trifluoroacetic acid at 0° C. and stirred at 0° C. for 2 hours. The trifluoroacetic acid was now removed in vacuo, and the residue was dissolved 2×in CH2Cl2 which was again removed in vacuo each time. The residue was dissolved in 5 ml of water, the pH was adjusted to 4 with 1N NaOH, and the mixture was extracted 3×20 ml of ethyl acetate, which was discarded. The evaporated aqueous phase was filtered through 25 g of silica gel using CHCl3 /CH3OH (3:1) and the solvent was evaporated.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[NH:4].[CH2:12](OC(OCC)OCC)C>O>[O:1]1[CH:12]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)=[N:2]1
Reactant: N=C(NO)c1ccc(O)cc1
Reactant: CCOC(OCC)OCC
Solvent: O
Product: Oc1ccc(-c2ncon2)cc1
Reaction time: 8 h
Yield: 23.1 %

Procedure:
A mixture of 6.2 parts of N,4-dihydroxybenzenecarboximidamide and 44.6 parts of triethoxymethane was stirred overnight at reflux temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 99:1). The eluent of the desired fraction was evaporated, yielding 1.5 parts (23.1%) of 4-(1,2,4-oxadiazol-3-yl)phenol (interm. 10).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:33]([NH2:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:33]([NH:41][C:28]1[N:27]=[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:31]=[CH:30][N:29]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccccc3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with phenethylamine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 466. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.1 (d, 2H) 7.7 (d, 2H) 7.5 (t, 2H), 7.2 (m, 3H), 7.1 (d, 1H), 4.6 (s, 2H), δ 3.4 (t, 2H), 3.09 (s, 3H), δ 3.05 (m, 7H), 2.0 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[C:4]=1[F:9]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1c(Cl)ccc(Br)c1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-chloro-2,3-difluorobenzene (720 mg, 3.17 mmol) in tetrahydrofuran (10 mL) was added i-propylmagnesiumchloride (1.90 mL, 3.80 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (0.98 mL, 4.75 mmol) in tetrahydrofuran (5.0 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred at RT for 1 h. The mixture was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)C>[Br:18][CH2:17][C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c(C)c2nc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)(Cl)Cl
Product: COc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OC
Yield: 89.3 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-methylquinoxaline (from step (f), 22.0 g, 80.5 mmol), N-bromosuccinimide (17.2 g, 96.6 mmol) and α,α-azoisobutyronitrile (1.3 g, 8.0 mmol) was heated at reflux in 1,1,1-trichloroethane (400 ml) for 4 h under irradiation from a 500 W sunlamp. The mixture was cooled, silica gel (50 g, 60-230 m) was added, and the solvent was removed under reduced pressure. The residue was applied to the top of a silica gel chromatography column, and the product was eluted using a hexane/ethyl acetate gradient. The product was triturated with hexane to give 5-bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (25.3 g, 87%) as a fluffy white solid. Found: C, 37.72; H, 2.40; N, 7.40; C11H9 BrCl2N2O2 requires C,37.53; H, 2.58; N, 7.96%.
Reaction SMILES: [NH3:1].[N:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[C@@H:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27]([CH3:36])([CH3:35])[O:26][C:25]4=[O:37])=[CH:20][CH:19]=3)[CH:14]=[N:15][C:16]=1F)=[N:6]2>CS(C)=O>[N:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[C@@H:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27]([CH3:36])([CH3:35])[O:26][C:25]4=[O:37])=[CH:20][CH:19]=3)[CH:14]=[N:15][C:16]=1[NH2:1])=[N:6]2
Reactant: N
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cnc(F)c(-c4ccc5nncn5n4)c3)cc2)[C@H]1c1ccccc1
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(-c4ccc5nncn5n4)c3)cc2)[C@H]1c1ccccc1
Temperature: 120 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia (2 M solution in 2-propanol) (63.2 μL, 2.91 mmol) (commercially available from Sigma-Aldrich, Milwaukee, Wis.) and (S)-3-(4-(5-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (14 mg, 0.029 mmol) in DMSO (291 μL). The reaction mixture was stirred and heated at 120° C. overnight. LC-MS indicated clean and complete conversion to desired product. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water (2×) and brine and dried over MgSO4. The solution was filtered and concentrated under reduced pressire. The residue was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(5-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6-aminopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.44 (d, J=2.24 Hz, 1H), 8.39 (d, J=9.72 Hz, 1H), 8.27 (d, J=2.56 Hz, 1H), 8.03 (d, J=9.94 Hz, 1H), 7.67 (d, J=8.76 Hz, 2H), 7.55 (d, J=8.87 Hz, 2H), 7.35-7.41 (m, 2H), 7.27-7.34 (m, 3H), 7.23 (s, 2H), 5.47-5.53 (m, 1H), 1.66 (s, 3H), 0.92 (s, 3H). m/z (ESI) 478.2 (M+H)+.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([N:30]([CH3:32])[CH3:31])[CH2:28][NH2:29].CCN(C(C)C)C(C)C>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([N:30]([CH3:32])[CH3:31])[CH2:28][NH:29][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CN(C)C(CN)c1ccccc1Cl
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1)c1ccccc1Cl

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(2-chloro-phenyl)-2-dimethylamino-ethylamine and DIEA to give 2-[2-(2-chloro-phenyl)-2-dimethylamino-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 438 (MH+).