Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:7][CH2:6]1.C(S(F)(F)([F:34])(CC)N)C>ClCCl>[F:34][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:7][CH2:6]1
Reactant: CCS(N)(F)(F)(F)CC
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(O)c2ccccc2)CC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(F)c2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 1 g of trans-2-[4-(2-hydroxy-2-phenyl-ethoxy)-cyclohexyl]-isoindole-1,3-dione in 100 mL of dichloromethane cooled to −78° C. under nitrogen atmosphere was added 1.2 g of diethyl-amino sulfur-trifluoride. The mixture was allowed to warm and stir for 24 h, then quenched with 25 mL of saturated sodium carbonate. After stirring for 15 min, the mixture was diluted with 25 mL of dichloromethane and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 0.7 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.7 (t, 1H), 7.4-7.3 (m, 5H), 5.6 (dd, 1H), 4.1 (m, 1H), 3.9-3.65 (complex m, 2H), 3.45 (m, 1H), 2.3 (dd, 2H), 2.2 (m, 2H), 1.8 (d, 2H), 1.4 (dd, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[NH2:5].N1C=CC=CC=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:30](=[O:31])[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3F)CC2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 4 (0.32 g, 1 mmol) and pyridine (0.12 mL, 1.5 mmol) in acetonitrile (4 mL, 0.25M), phenyl chloroformate (0.16 mL, 1.2 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for overnight. Then water was added and the mixture was stirred for 30 min. The precipitated white solid was filtered and the solid was washed with acetonitrile and then dried under vacuum to obtain compound 5 (0.35 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11].O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-chlorobenzaldehyde (1 eq.) in MeOH was added ethylamine 70% in water (10 eq.). The reaction was stirred for 15 h at 20° C. under argon then NaBH4 (2 eq.) was added. The reaction was stirred at 20° C. for 5 h. The reaction was quenched with water then acidified with aqueous HCl (2M). The aqueous layer was washed with EtOAc. The organic layer was discarded. Aqueous NaOH (2M) was then added to the aqueous layer until pH=10 and the crude was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford (4-chloro-benzyl)-ethyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([CH3:18])[C:7]1=[O:11]
Reactant: COc1ccccc1C=C1CCNC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1C=C1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate 3-(2′-methoxybenzylidene)-2-pyrrolidone (5.0 g) obtained in Example 317 was dissolved in dimethylformamide (50 ml) and sodium hydride (0.99 g) was added thereto under ice-cooling. The mixture was stirred at room temperature for 30 min. Methyl iodide (1.72 ml) was added under ice-cooling and the mixture was stirred for 8 hr at room temperature. After completing of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]1([O:33][C:34]([O:36][CH2:37]I)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(OCI)Oc1ccccc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)Oc3ccccc3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 93.4 %

Procedure:
In the same manner as in Example 81, 278 mg of the title compound was prepared from 226 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 243 mg of phenyloxycarbonyloxymethyl iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C@:19]12[CH2:27][O:26][C@H:25]([CH2:28][F:29])[C@H:24]1[CH2:23][S:22][C:21]([NH:30]C(=O)OC(C)(C)C)=[N:20]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([CH2:28][F:29])[O:26][CH2:27][C@:19]2([C:3]2[CH:4]=[C:5]([NH:8][C:9]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=3)=[O:10])[CH:6]=[CH:7][C:2]=2[F:1])[N:20]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](CF)[C@H]3CSC(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl ((4aS,5S,7aS)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate, synthesized in preparation example 2-(2), (6.71 g, approx. purity 90%) was dissolved in DCM (20 mL) and TFA (10 mL) was added. After stirring at RT for 2 h, the reaction mixture was evaporated and sodium bicarbonate (sat., aq., 50 mL) was added. The mixture was extracted with EtOAc (2×100 mL), and the combined organic portions dried over MgSO4, evaporated, and purified by silica gel chromatography (0% to 50% EtOAc in DCM) to afford the title compound as a white solid (3.26 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.81 (dd, J=13.4, 3.8 Hz, 1H), 3.08 (dt, J=7.7, 3.7 Hz, 1H), 3.18 (dd, J=13.4, 3.3 Hz, 1H), 3.88 (dd, J=8.6, 2.5 Hz, 1H), 4.09 (s, 3H), 4.43-4.73 (m, 6H), 7.10 (dd, J=11.9, 8.8 Hz, 1H), 7.55 (dd, J=7.1, 2.8 Hz, 1H), 7.91-8.00 (m, 1H), 8.17 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.0 Hz, 1H), 9.51 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4.[CH:24]1[C:32]2[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[O:29][C:28]=2[C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:24]1[C:32]2[C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[O:29][C:28]=2[C:27]([C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[C:8]4[C:15]([CH3:23])([CH3:22])[C:16]5[C:21]([C:7]4=[CH:6][C:5]3=2)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2oc2ccccc24)cc13

Procedure:
32 g (90.6 mmol) of 7-bromo-12,12-dimethyl-10,12-dihydro-10-azaindeno-[2,1-b]fluorene, 19.9 g (94 mmol) of dibenzofuran-4-boronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1640 ml of toluene and 164 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh)3 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The yield is 26.7 g (59 mmol), corresponding to 65% of theory.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=O)(=[O:3])[CH3:2].[C:11]1([S:17]([C:20]#[N:21])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(OCCCC)(OCCCC)OCCCC.C(O)CCC>>[C:1]([O:4][C:5]1[C:20]([S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:19])=[O:18])=[N:21][CH:8]=[C:7]([CH3:10])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Product: CC(=O)Oc1cc(C)cnc1S(=O)(=O)c1ccccc1
Temperature: 108 °C
Yield: 22.7 %

Procedure:
First, 5.0 g (39.6 mmol) of 4-acetoxy-2-methyl-2-butenal, 7.05 g (39.6 mmol) of benzenesulfonyl cyanide, 0.91 g (4.0 mmol) of tributyl borate and 1-butanol (0.59 g, 7.9 mmol) were introduced to a 3-necked flask (100 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver and a condenser tube. Toluene (20 ml) was added as the solvent. Then the mixture was heated under reflux for 22 hours while agitating at an internal temperature of 108° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=1/3) to give 2.62 g of 3-acetoxy-2-benzenesulfonyl-5-methylpyridine with the following properties as a brown, oily substance (yield of 24% based on benzenesulfonyl cyanide).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:14])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=c1cc(Cl)c(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ccccc3)c(Cl)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a mixture of 5-chloro-6-phenylpyridazin-3(2H)-one (207 mg, 1.0 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (415 mg, 3.0 mmol), and followed by addition of 1-(bromomethyl)-4-methoxybenzene (241 mg, 1.2 mmol). The resulting reaction mixture was stirred at room temperature overnight. Water (25 mL) was added to the reaction mixture and stirred for 1 hour. The product was collected by filtration and dried overnight under reduce pressure to yield 278 mg (81%) of 5-chloro-2-(4-methoxybenzyl)-6-phenylpyridazin-3(2H)-one as a tan solid. MS (ESI) 327 (M+H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])[CH:10]=1>C(O)=O>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][CH:5]=[O:7])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)nc(-n2ccnc2SCc2ccccc2N)c1
Solvent: O=CO
Product: Cc1cc(C)nc(-n2ccnc2SCc2ccccc2NC=O)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
1.4 g of acetic acid anhydride are added to 2.5 ml of formic acid, and the mixture is stirred at 60° C. for 30 minutes. The reaction solution is cooled in an ice bath, a solution of 1.07 g of 1-(4,6-dimethyl-2-pyridyl)-2-(2-aminobenzylthio)imidazole in 4 ml of formic acid is added thereto, and the mixture is stirred at room temperature for 1 hour. After the reaction, the solvent is distilled off. Water is added to the residue, and the aqueous mixture is made alkaline with potassium carbonate. The mixture is then extracted with ethyl acetate, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:1). The crude crystals obtained above are recrystallized from a mixture of ethyl acetate and n-hexane, whereby 0.64 g of 1-(4,6-dimethyl-2-pyridyl)-2-(2-formylaminobenzylthio)imidazole is obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Li+].Cl>O1CCCC1.O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CCCCn1ccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCn1ccnc1
Yield: 130.1 %

Procedure:
Stir a solution of methyl 5-imidazol-1-ylpentanoate (0.60 g; 1.0 equiv; 3.29 mmoles) and lithium hydroxide (0.553 g; 4 equiv; 13.17 mmoles) in tetrahydrofuran (20 mL) and water (15 mL) for 18 hours. Add 3 ml of 5N hydrochloric acid then concentrate the mixture. Purify the crude product by column chromatography (0 to 15% methanol in dichloromethane) to afford 5-imidazol-1-ylpentanoic acid (0.72 g; 19%) as a yellow oil: MS (m/z): 169(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:19]=2)=[CH:4][CH:3]=1.C1COCC1.Cl[C:37]([CH2:39][O:40]C(=O)C)=[O:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:37](=[O:38])[CH2:39][OH:40])[CH2:27][CH2:26]3)[N:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1nccn2c(-c3ccnc(NC4CCNCC4)n3)c(-c3ccc(F)cc3)nc12
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Product: Cc1nccn2c(-c3ccnc(NC4CCN(C(=O)CO)CC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-[2-(4-Fluorophenyl)-8-methylimidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylpiperidin-4-ylamine (Example #H.1.1; 0.2 g, 0.5 mmol) in THF (1.1 mL, 1.4 mmol) was cooled to about 0° C. Then TEA (0.13 mL, 0.94 mmol) was added followed by acetic acid chlorocarbonylmethyl ester (0.077 g, 0.56 mmol). After about 16 h, the mixture was allowed to warm to ambient temperature and filtered, washing with MeOH. The filtrate was treated with 2.50 M aqueous sodium hydroxide (0.20 mL) at ambient temperature. After about 16 h, the mixture was treated with additional 2.50 M aqueous sodium hydroxide (0.16 mL). After about 6 h, the mixture was acidified to pH 5 using 1 N HCl. The mixture was treated with DCM and water, and the layers were separated. The aqueous layer was washed with DCM (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude material was taken up in DCM/MeOH and purified via FCC using DCM/2.5% NH4OH in MeOH (95:5) to yield the title compound as a white solid after drying (0.115 g, 50%): LC/MS (Table 1, Method b) Rt=1.6 min; MS m/z: 462.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:42][CH2:43][CH:44]([OH:56])[CH2:45][N:46]1[CH2:55][CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47]1>C(Cl)Cl>[CH2:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:54][CH2:55][N:46]1[CH2:45][CH:44]([OH:56])[CH2:43][NH:42][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NCC(O)CN2CCc3ccccc3C2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
To a solution of 2-methyl-3-nitrobenzoic acid (1.0 g, 5.5 mmol) in DCM (20 mL) was added EDCI (1.58 g, 8.25 mmol), HOBt (1.11 g, 8.25 mmol), Et3N (1.11 g, 11.0 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (1.36 g, 6.6 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (1.6 g, 78.8%). LCMS (m/z): 370.2 (M+1).
Reaction SMILES: Cl.[Cl-].[NH4+].C([N:6](CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([C:40]([C:44]3[S:45][C:46]([C:55](O)=[O:56])=[C:47]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:48]=3)=[C:41]([CH3:43])[N:42]=2)[N:39]=1>CN(C)C=O.O>[ClH:33].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([C:40]([C:44]3[S:45][C:46]([C:55]([NH2:6])=[O:56])=[C:47]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:48]=3)=[C:41]([CH3:43])[N:42]=2)[N:39]=1
Reactant: Cc1nc2ccc(Cl)nn2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(Cl)nn2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 131.5 %

Procedure:
A mixture of ethyl 2-(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylate (520 mg, 1.3 mmol) produced above, 1N aqueous sodium hydroxide solution (1.6 mL), ethanol (5 mL) and tetrahydrofuran (10 mL) was stirred at 50° C. for 3 hr. To the reaction mixture were added 1N hydrochloric acid (1.6 mL) and water, and the resulting precipitate was collected by filtration, washed with water and diethyl ether and dried. Ammonium chloride (346 mg, 6.5 mmol), triethylamine (0.9 mL, 6.5 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (383 mg, 2.0 mmol), 1-hydroxybenzotriazole (270 mg, 2.0 mmol) and N,N-dimethylformamide (10 mL) were added to the obtained 2-(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylic acid (408 mg), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the obtained residue, and the resulting precipitate was collected by filtration, washed with water and ethyl acetate and dried. 4N Hydrogen chloride ethyl acetate solution (0.5 mL) and methanol (10 mL) were added to the obtained crude product (379 mg), and the mixture was heated, and concentrated under reduced pressure. The obtained residue was washed with methanol to give the title compound (294 mg, 56%) as a yellow solid.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[OH:14][C@@H:15]([CH2:20][O:21][C@H:22]([CH3:35])[CH2:23][O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:16](OC)=[O:17]>C1(C)C=CC=CC=1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([NH:5][C:16](=[O:17])[C@@H:15]([OH:14])[CH2:20][O:21][C@H:22]([CH3:35])[CH2:23][O:24][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:27])[CH3:28])[CH:32]([CH3:33])[CH3:34])=[N:7][CH:8]=1)#[N:11]
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccc(C#N)cn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
Trimethylaluminium (5.98 mL, 11.96 mmol) was added to 6-aminonicotinonitrile (1.424 g, 11.96 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-Methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (2 g, 5.98 mmol) in toluene (6 mL) was added and the reaction was allowed to warm to room temperature and then refluxed for 6 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 mL), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.760 g, 69.8%).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=1[NH2:16])C.[N+]([O-])(O)=O.C[C:23]1C=C(C)N(C(N)=N)[N:24]=1>C(O)C>[Cl:14][C:13]1[C:12]([Cl:15])=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:17])[NH:24][C:23]1=[N:16]2
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Yield: 39.8 %

Procedure:
A mixture of N-(2-amino-5,6-dichlorobenzyl)glycine ethyl ester (2.77 g, 0.01 mole) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.01 g, 0.01 mole) in absolute ethanol (30 ml) was heated at reflux for 24 hours. The mixture was filtered and the product was washed successively with ethanol, acetone and ether to yield the title compound (1.02 g, 40%); identical (ir, nmr) with authentic material prepared by a prior art procedure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:8]([CH:17]=1)[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-])=O.N#N>[Pd].CO>[F:24][C:18]([F:23])([C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:19]([F:22])([F:21])[F:20]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: Nc1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A flask was charged with 1-[2-(5-nitro-2-pentafluoroethyl-phenoxy)-ethyl]-pyrrolidine (1.8 g) and MeOH (25 mL) and placed under argon. Pd/C was added carefully and the atmosphere was replaced with H2. The reaction was stirred for 2.5 days at RT. The reaction was blanketed with N2, filtered through a pad of Celite and evaporated. The mixture was taken up into a small amount of acetone, and filtered through a plug of silica gel using 90:10:1 (CH2Cl2:MeOH:NH4OH). The titled compound was isolated as a yellow solid.