Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:26])[CH:14]=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CCO.O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:26])[CH:14]=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH:11]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CC(CCC(=O)OC)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCN1CC(CCC(=O)O)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
N-[(1-Octyl-3-(2-methoxycarbonylethyl)-4,6-dimethylindolin-7-yl)]-2,2-dimethylpropanamide (1.1 g) was dissolved in EtOH (10 ml) and a solution of NaOH (494 mg) in water (3 ml) was added, which was followed by stirring at room temperature for 30 min. EtOH was evaporated under reduced pressure and CHCl3 (50 ml) was added. After washing successively with 5% aqueous citric acid and saturated brine, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 800 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([CH2:23][CH2:24][OH:25])[CH2:20]2)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:35]#[C:34][C:32]([C:29]4[CH:28]=[C:27]([CH3:26])[O:31][N:30]=4)([OH:36])[CH3:33])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([CH2:23][CH2:24][OH:25])[CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OC3CN(CCO)C3)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OC4CN(CCO)C4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
A mixture of 2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-ol (80 mg, 0.20 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg, 1.06 mmol), bis(triphenylphosphine)palladium(II) dichloride (160 mg, 0.23 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) was stirred under nitrogen for 2 hr at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to give 7 mg (7%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[[1-(2-hydroxyethyl)azetidin-3-yl]oxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid: 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.17 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (s, 2H), 7.01 (d, J=5.6 Hz, 1H), 6.45 (s, 1H), 6.37 (s, 1H), 5.37 (t, J=5.2 Hz, 1H), 4.44 (t, J=5.4 Hz, 1H), 3.75 (t, J=7.2 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 3.28 (t, J=6.8 Hz, 2H), 2.57 (s, 2H), 2.41 (s, 3H), 1.81 (s, 3H); LC-MS: m/z=+476 (M+H)+.
Reaction SMILES: [CH2:1]([N+:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH3:24])([CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:4]=1[CH3:25])[CH3:2].Cl>C(O)(=O)C>[NH:3](/[CH:4]=[CH:5]/[CH:16]=[CH:25]/[C:4]1[C:5]([CH3:24])([CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([O-:15])(=[O:13])=[O:14])[CH:7]=2)[N+:3]=1[CH2:1][CH3:2])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC[N+]1=C(C)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21
Agent: Cl
Solvent: CC(=O)O
Product: CC[N+]1=C(/C=C/C=C/Nc2ccccc2)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21

Procedure:
1-Ethyl-2,3-dimethyl-3-(4-sulphobutyl)-3H-indolium-5-sulphonate, crude (1.1 g), malonaldehyde bis(phenyl)mine) HCl (0.5 g) and acetic acid (20 ml) were heated under nitrogen at 130° C. for 8 hrs to give a dark orange-red solution. The solvent was then evaporated under vacuum; the residue was partitioned in a water/dichloromethane/methanol mixture. UV/Vis analysis (ethanol) confirmed the presence of the product in the upper, aqueous layer (λmax=524 nm) while the malonaldehyde starting material was present only in the lower, organic layer (λmax=384 nm). The aqueous layer was evaporated under vacuum and purified by HPLC (water/0.1% TFA and acetonitrile/0.1% TFA eluants). Fractions containing the product were pooled and evaporated, with final drying under high vacuum over phosphorus pentoxide to give the title product.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O-])=O.C(O)C>[Fe].O>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C=O
Yield: 96.7 %

Procedure:
Iron powder (39 g; 700 mmol) and concentrated hydrochloric acid (0.583 mL; 7 mmol) were added to a solution of 2-nitrobenzaldehyde (10.58 g; 70 mmol) in a mixture ethanol (210 mL)-water (52 mL). The well-stirred reaction mixture was heated to reflux for 5 h. After cooling, the suspension was filtered on a plug of celite, washed with ethanol and the filtrate was concentrated under reduced pressure until the organics were removed. The remaining aqueous layer was extracted with ethyl acetate, the organics were combined, dried over sodium sulfate, concentrated under reduced pressure to furnish 8.2 g (96%) of 2-aminobenzaldehyde as a yellow oil, which crystallized slowly. ESI/APCI(+): 122 (M+H). NMR 1H (CDCl3) (ppm): δ 9.87 (s, 1H, CHO); 7.48 (dd, 1H, Harom.); 7.31 (td, 1H, Harom.); 6.75 (td, 1H, Harom.); 6.51 (dd, 1H, Harom.); 6.11 (bs, 2H, NH2).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([OH:14])[C:10]([CH3:13])=[CH:11][CH:12]=1>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([OH:14])[C:10]([CH3:13])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1ccc(Cl)cc1O
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1O
Reaction time: 0.17 h
Yield: 2.4 %

Procedure:
To a solution of chlorosulfonic acid (3.69 g, 31.65 mmol) dissolved in 30 mL of dichloromethane was added 3-chloro-6-methylphenol (3.0 g, 21.1 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 120 mg (2.4%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:16]([O:18][CH3:19])=[O:17])[N:11]=[C:12]2I)=[CH:7][CH:6]=1.[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:16]([O:18][CH3:19])=[O:17])[N:11]=[C:12]2[C:25]#[N:26])=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3Cl)ccc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3Cl)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 7-(2-chlorophenoxy)-4-hydroxy-1-iodoisoquinoline-3-carboxylate (0.2 g, 0.44 mmol) and CuCN (79 mg, 0.88 mmol) were suspended in DMF (1.8 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and then stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 150 mg. MS: (−) m/z 353.24 (M−1).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl

Procedure:
A mixture of 2-hydroxy-3-nitro-5-(trifluoromethyl)pyridine (5.0 g), thionyl chloride(28 mL) and N,N-dimethylformamide (3 mL) was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo, and ice was added to the residue. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The separated organic layer was washed with brine, dried over.magnesium sulfate, and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (5:1) and then to an aluminum oxide (activated, basic) column chromatography eluting with ethyl acetate to give 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (4.89 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.C1C=C([O:35]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@@H:21]([CH2:23][NH+:24]([O-:35])[C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (VIII-A, R1═COCH3, R2═H, X1═F, X2═H) (11.8 g) is dissolved in 200 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 18.5 g) is added and the resulting suspension is stirred at 25° C. for two hours. The reaction is filtered and the filtrate is concentrated to afford a white solid. This solid is chromatographed on silica gel using 20% methanol in chloroform as eluent to afford the N-oxide. Lyophilization of this material affords the purified product as a hydrate (9.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.731 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.181 mL, 4.49 mmol) dissolved in water (2 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.247 mL, 4.49 mmol) was added dropwise and stirring continued for 3 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (23.18 mL, 139.09 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated and DCM (200 mL) and water (200 mL) were added. The phases were shaken, separated and the organic phase dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.921 g, 57.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.87 (m, 1H), 2.06-2.15 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.37 (m, 1H), 3.00-3.09 (m, 1H), 3.31-3.40 (m, 1H), 3.66 (s, 3H), 4.07-4.16 (m, 1H), 5.00-5.07 (m, 1H), 5.56 (s, 1H), 6.87-6.91 (m, 1H), 6.95 (dd, 1H), 7.29 (t, 1H). MS m/z 355 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.[ClH:11].O1CCO[CH2:14][CH2:13]1>CCO>[ClH:11].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH2:13][CH3:14])=[O:9])[N:3]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc(N)n1

Procedure:
A suspension of 2-aminopyridine-6-carboxylic acid (2 g) in EtOH (10.0 mL) and 4N HCl/dioxane (10.0 mL) was heated to reflux for 16 hours under anhydrous conditions. The reaction mixture was then concentrated to dryness and the residue was dried in a desiccator under vacuum to afford 2-amino-6-carbethoxypyridine hydrochloride as a white powder (1.6 g). 1H-NMR (DMSO-d6) δ 8.3 (br), 7.94 (m, 1H), 7.37 (d, 1H, J=7.2 Hz), 7.22 (dd, 1H, J=8.7 Hz), 4.37 (q, 2H, J=7.2 Hz), 1.32 (t, 3H, J=7.2 Hz); FAB MS m/z 167 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].Cl.[O:24]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]1>>[O:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:3]([C:5]2[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:25]1
Reactant: N[C@H]1CCOC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Agent: Cl
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N[C@H]2CCOC2)nn1
Yield: 77 %

Procedure:
As described for example 1e, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) was converted, using (S)-tetrahydrofuran-3-amine hydrochloride instead of isopropylamine, to the title compound (100 mg, 77%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 3.5% methanol in dichloromethane). MS: m/e=361.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:9]2[N:10]=[C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:24]S(O)(=O)=O>>[C:1]([C:5]1[N:9]2[N:10]=[C:11]([CH2:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[O:24])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Reactant: O=S(=O)(O)O
Product: CC(C)(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
To a round bottom flask was added 3-tert-butyl-6-((2,4-difluorophenyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.20 g, 13.5 mmol, Example #9, Step D) and concentrated H2SO4 (50 mL, 560 mmol). The reaction mixture was heated to about 90° C. for about 2 h. The reaction mixture was quenched with ice (500 g) and extracted with DCM (500 mL). The aqueous layer was neutralized to pH of about 7.0 with solid NaOH and additional ice (1000 g) was added to maintain a temperature of about 0-10° C. The aqueous layer was extracted with DCM (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using MeOH/DCM (10:90) to give the title compound (4.4 g, 99%) as a solid. LC/MS (Table 1, Method a) Rt=3.20 min; MS m/z: 331.1 (M+H)+.
Reaction SMILES: [N:1]#[C:2][CH:3]=[CH:4][C:5]1[C:10]2[O:11][C@@H:12]([CH2:15][O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][O:14][C:9]=2[CH:8]=[CH:7][C:6]=1[N+:27]([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([O:16][CH2:15][CH:12]2[O:11][C:10]3=[C:5]4[C:6](=[CH:7][CH:8]=[C:9]3[O:14][CH2:13]2)[N:27]=[C:2]([NH2:1])[CH:3]=[CH:4]4)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=CC#N)c3O2)cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(N)ccc4c3O2)cc1

Procedure:
To a solution of 2.5 g (6.0 mmole) of toluene-4-sulfonic acid (2R)-8-(3-nitrilo-propenyl)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in 200 mL of ethyl acetate was added 6.8 g (30 mmole) of tin (II) chloride dihydrate and the mixture was refluxed under nitrogen for 5 hours. The solvent was then removed in vacuum and replaced with 250 mL of methanol. Concentrated HCl (5 mL) was added and the mixture was refluxed under a nitrogen atmosphere for 15 hours. The solvent was again removed in vacuum and 500 mL of saturated aqueous sodium bicarbonate added. This was extracted twice with 250 mL portions of ethyl acetate and the combined organics washed with 400 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 5% methanol in chloroform as eluant to give 0.80 g of the (R)-enantiomer of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32](O)=[O:33])[CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32]([C:28]5[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1ccnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccnc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)c1
Yield: 24.4 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.371 mmol), 4-methylpyridine-2-carboxylic acid (76 mg, 0.557 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol), triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (40 mg, 24%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CC(O)=O.[Pd].[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1=CNCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CNCCN1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
Ethyl 1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazinecarboxylate (60 g) was dissolved in AcOH (400 ml), and the solution was subjected to catalytic reduction using 10% palladium on carbon (12 g)-H2O (30 ml), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in AcOEt (1000 ml), and the organic layer was washed with saturated aqueous NaHCO3 solution by stirring carefully to avoid foaming. The organic layer was further washed with saturated brine, and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give 59.2 g of ethyl 1-tert-butoxycarbonyl-2-piperazinecarboxylate as an oil (yield 97.9%).
Reaction SMILES: [CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I(O)(=O)(=O)=[O:15].[Na].O>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH:2]([CH2:1][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:15]
Reactant: C=CCC1(C(=O)OC)CCCCC1
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CC=O)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.7 %

Procedure:
To a solution of methyl 1-allylcyclohexanecarboxylate (340 mg) in tetrahydrofuran (7 mL) were added an aqueous solution of sodium periodic acid (3.4 g, 16.0 mmol) and osmium tetraoxide (100 mg) successively under ice cooling. The solution was stirred at room temperature for 20 hours. Water was added to the reaction solution and insolubles were filtered off. The filtrate was extracted with ethyl acetate, and it was washed in turn with water, sodium thiosulfate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (250 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:30]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([Br:30])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-(4-methoxybenzoyl)phenylacetate (490 mg, 1.2 mmol) obtained in Example 134, Step 2 was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (220 mg, 1.2 mmol) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain methyl 3,5-bis(methoxymethoxy)-2-bromo-6-(4-methoxybenzoyl)phenylacetate (520 mg, 89%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:28])=[C:8]([C@H:14]2[CH2:16][C@H:15]2[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[C:9]=1[O:10]COC)(=[O:3])[CH3:2].Cl.O>O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:28])=[C:8]([C@H:14]2[CH2:16][C@H:15]2[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: COCOc1c(C(C)=O)ccc(F)c1[C@H]1C[C@H]1NC(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(F)c([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1O
Reaction time: 0.25 h

Procedure:
(+,-)-N-(cis-2-(5-Acetyl-2-fluoro-6-methoxymethoxy)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea (Example 56) was dissolved in dioxane and concentrated hydrochloric acid was added. The solution was stirred for 15 minutes, was diluted water and evaporated. The residue was co-evaporated with water to yield the title product as a solid. 1H-NMR DMSO-d6 δ 1.2 (m, 1H) 1.3-1.5 (m, 1H) 2.0 (q, 1H) 2.6 (s, 3H) 3.4 (m, 1H) 6.8 (t, 1H) 7.4 (d, 1H) 7.7 (m, 1H) 7.8-8.0 (m, 2H) 9.2 (s, 1H) 11.1 (bs, 1H).