Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=4)=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 5 (57 mg, 0.095 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80° C. for 1 h, and then cooled to room temperature. The “pH” of the mixture was adjusted to 5-6 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid as a off white solid (46 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.ClC1C=CC([N+]([O-])=O)=C(C=1)N.CO[C:28]1([CH2:35]OC)[CH2:32][CH2:31][CH:30]([O:33][CH3:34])O1>CC(O)=O>[CH3:34][O:33][CH2:30][C:31]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:8])[CH:7]=2)[CH:35]=[CH:28][CH:32]=1
Reactant: COCC1(OC)CCC(OC)O1
Reactant: CC(=O)Nc1cc(N)ccc1[N+](=O)[O-]
Agent: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COCc1cccn1-c1ccc([N+](=O)[O-])c(N)c1

Procedure:
The title compound was prepared from N-(5-amino-2-nitro-phenyl)-acetamide [prepared from commercially available 5-chloro-2-nitroaniline as described in Example F6] and 2,5-dimethoxy-2-methoxymethyl-tetrahydro-furan [CAS-no. 98560-90-8] in HOAc at 60° C. for 2 h according to the general procedure F. Obtained as a light brown solid (620 mg). Deacetylation of this material was perfomed by stirring with 2 eq. 2 N NaOH-sol. in 1,4-dioxane at 60° C. for 21 h. Obtained as a yellow solid (511 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:19]=[CH:18][C:17]2[NH:16][C:15]3[N:20]=[CH:21][C:22]([Br:24])=[CH:23][C:14]=3[C:13]=2[CH:12]=1)=O>C1COCC1>[Br:24][C:22]1[CH:21]=[N:20][C:15]2[NH:16][C:17]3[CH:18]=[N:19][C:11]([CH2:9][OH:8])=[CH:12][C:13]=3[C:14]=2[CH:23]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2c(cn1)[nH]c1ncc(Br)cc12

Procedure:
Lithium aluminium hydride (1M solution in THF, 16.3 mL, 16.3 mmol) was added dropwise to a suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (500 mg, 1.63 mmol) in THF (10 mL). After 10 minutes the reaction mixture was quenched with a solution of saturated ammonium chloride, diluted with DCM and water and the solid removed by filtration. The layers of the resultant filtrate were separated and the aqueous phase was further extracted with DCM. The combined organic layer was concentrated in vacuo and purified by flash chromatography (silica, 1-15% methanol in DCM).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]([OH:8])[CH:5]([CH3:7])[CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:20][CH:21]([CH:31]=[CH2:32])[CH2:22]OS(C(F)(F)F)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]([O:8][CH2:20][CH:21]([CH3:22])[CH:31]=[CH2:32])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](O)C(C)C
Reactant: C=CC(C)COS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)CO[C@H](C(=O)OC)C(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
A solution of (S)-2-hydroxy-3-methyl-butyric acid methyl ester (1.32 g, 10 mmol) in tetrahydrofuran (30 mL) was stirred at −10° C. under nitrogen. Sodium bis(trimethylsilyl)amide (6 mL, 12 mmol, 2 M in tetrahydrofuran) was added dropwise and the reaction mixture was stirred at −10° C. for 10 min. Trifluoro-methanesulfonic acid 2-methyl-but-3-enyl ester (2.18 g, 10 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 2 h. Saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/diethyl ether 20:1 to 10:1 to afford the title compound (429 mg, 21% over 2 steps) as an oil, as a 1:1 mixture of two diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.96-0.99 (m, 6H), 1.05 (d, J=6.9 Hz, 1.5H), 1.08 (d, J=6.6 Hz, 1.5H), 2.01-2.12 (m, 1H), 2.45-2.56 (m, 1H), 3.06-3.21 (m, 1H), 3.44-3.60 (m, 2H), 3.76 (s, 3H), 5.00-5.11 (m, 2H), 5.74-5.88 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:6]1.O.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:6]1
Reactant: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Temperature: 40 °C

Procedure:
To a solution of methyl 1-(2,4-difluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (2000 mg 5.123 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (430 mg 10.246 mmol, 2 eq.) and water (10 mL) and the clear solution was warmed to 40° C. for 3 hours. THF was removed under vacuum and 1 M HCl added (10.3 mL 10.3 mmol, 2 eq.). The crude product was extracted into EtOAc (3×30 mL), then DCM:MeOH 100:5 (3×30 mL). The organics were dried (Na2SO4), volatiles were removed in vacuo to give the title product as a cream colored powder 1563 mg (82%). LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, ESI, +mode): RT—0.91 min, m/e=377.2 (M+H+, base). 1H-NMR (300 MHz, DMSO): δ=3.42 (s, 3H), 3.46 (m, 2H), 3.60 (m, 2H), 4.69 (s, 2H), 5.66 (s, 2H), 7.07 (m, 1H), 7.36 (m, 2H), 7.82 (s, 1H), 8.36 (s, 1H), 8.98 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:11][N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[O:8])[CH:9]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)c1ccc(-c2ccc(O)c(C=O)c2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Within a vacuum tube, 5-bromo-2-hydroxybenzaldehyde (0.5 g, 2.49 mmol), 4-dimethylaminophenyl boronic acid (0.62 g, 3.73 mg), dichloro[1,1′-ferrocenylbis(diphenyl-phosphine)]palladium(II)dichloromethane (Pd(dppf)Cl2, 0.33 g, 0.40 mmol, ‘dppf’=1,1′-bis(diphenylphospino)ferrocene) and sodium carbonate (0.53 g, 4.98 mmol) were dissolved in ethylene glycol dimethylether:water (15 ml:5 ml), followed by stirring at 100° C. for 4 hours. The reaction product thus obtained was diluted in ethyl acetate, washed with brine, dried over anhydrous MgSO4, and concentrated. The concentrate was purified through column chromatography (10% ethyl acetate/hexane) and the fraction was concentrated to give 4′-dimethylamino-4-hydroxybiphenyl-3-carbaldehyde (0.383 g, 64%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](O)=[O:20].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)ccc1Cl
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
N-methyl-N-methoxylamine hydrochloride (3.41 g, 35 mmol) was dissolved in 140 mL methylene chloride. Triethylamine (14.6 mL, 105 mmol) was added and the reaction mixture was stirred for 10 minutes. Then the reaction mixture was stirred for 16 hours after 5-bromo-2-chloro-benzoic acid 6a (8.24 g, 35 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (10.69 g, 42 mmol) were added in turn. Thereafter, the reaction mixture was extracted with ethyl acetate (80 mL×3) after 120 mL water were added. The organic extract was washed with saturated sodium chloride solution (60 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 5-bromo-2-chloro-N-methoxy-N-methyl-benzamide 6b (7.50 g, pale yellow solid), yield: 76.9%. MS m/z (ESI): 280.0 [M+1]; 1H NMR (400 MHz, CDCl3): δ 7.46-7.44 (m, 2H), 7.29-7.26 (m, 1H), 3.49 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: BrC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(c1cccc(Cl)c1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of diisopropylamine (1.80 mL, 12.9 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.4 M in hexanes, 5.4 mL, 12.9 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (1.0 g, 5.9 mmol) in tetrahydrofuran (6 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. Cyclopentyl bromide (0.76 mL, 7.1 mmol) was then added via syringe, and the resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×15 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×15 mL), and the combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 40% EtOAc/hexane) to yield 1.08 g (79%) (3-chlorophenyl)(cyclopentyl)acetic acid as a clear oil. HRMS: calcd for C13H15ClO2-H, 237.06823; found (ESI, [M−H]−), 237.0682.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+]>Cl>[CH2:4]([CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2][C:1]([OH:8])=[O:9]
Reactant: [OH-]
Reactant: O=C1CCCCCN1
Agent: Cl
Agent: [Na+]
Product: NCCCCCC(=O)O

Procedure:
5 g of ε-caprolactam was dissolved in 10% HCl (20 g) and heated to reflux until the starting material was reacted completely. The pH of the mixture was adjusted to 7.6 by adding 10% NaOH(aq). The mixture was concentrated at 55° C. and then recrystallized in methanol to obtain aminocaproic acid containing inorganic salts.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Reactant: BrCc1ccc2ccccc2c1
Product: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc3ccccc3c2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
Compound 70 was prepared from 70a and 2-(bromomethyl)naphthalene, according to procedures described in the synthesis of Compound 56. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.21 (s, 3H) 3.54 (s, 3H) 3.67 (s, 3H) 4.69 (d, J=14.7 Hz 1H) 4.92 (d, J=14.7 Hz, 1H) 6.64 (dd, J=8.2, 2.9 Hz, 1H) 6.98 dd, J=4.3, 9.1 Hz, 1H) 7.03-7.11 (m, 1H) 7.37-7.42 (m, 1H) 7.44-7.50 (m, 1H) 7.69-7.86 (m, 5H). MS [m+H] calc'd C28H27FN5O3 450; found 450.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([N:24](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:16])[NH:17][NH2:24])=[N:6]1
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Reactant: CCN(CC)CC
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ncc2c(C(=N)NN)nn(Cc3ccccc3F)c2n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
688 mg (approx. 2.20 mmol, purity 92%) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 10 ml of ethanol and cooled to 0° C. 891 mg (8.80 mmol) of triethylamine and 138 mg (2.20 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 654 mg (purity 93%, 92% of theory) of the target compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]1[O:11][C@@H:10]1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:11])[CH2:12][OH:13])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: OC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Temperature: 120 °C
Yield: 34.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (Intermediate 2, 205 mg, 1.81 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) was treated with (R)-glycidol (148 mg, 2.00 mmol) and potassium carbonate (770 mg, 5.58 mmol). The mixture was heated in a sealed vial at 120° C. for 1 h. After this time, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (6×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (Teledyne Isco RediSep Flash Column 40 g, 15-100% ethyl acetate/hexanes) afforded (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (118 mg, 34%) as a thick yellow oil. 1H-NMR (400 MHz, CD3OD) δ 3.55 (2H, d, J=5.2 Hz), 4.02-4.05 (1H, m), 4.20 (1H, dd, J=13.6 Hz, 7.6 Hz), 4.39 (1H, dd, J=14.0 Hz, 3.6 Hz), 6.92 (1H, d, J=2.0 Hz), 7.79 (1H, d, J=2.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:14]=[CH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=[O:26])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCN(c2cccc(C(=O)O)c2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CCC1CCCN(c2cccc(C(=O)O)c2)C1

Procedure:
10% Palladium on activated carbon (5 mg) was added to 3-[3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethenyl]piperidin-1-yl]benzoic acid (35.0 mg, 0.0797 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for hours in a hydrogen atmosphere. Subsequently, the mixture was filtered through Celite and the solvent was evaporated to give 35.1 mg (quant.) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([NH2:24])=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:6]([O:8]CC)=O.[CH:25]([NH2:27])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[N:24]=[CH:25][NH:27][C:6]2=[O:8]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1N
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 125 °C
Yield: 68 %

Procedure:
A solution of ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-aminobenzoate (130 g, 384 mmol) in formamide (280 ml) was heated at 180° C. for 3 hours, during which time a small amount (25 ml) of liquid distilled out of the reaction. The reaction was cooled to 125° C. and the excess formamide was evaporated in vacuo. Trituration of the solid residue with isopropanol (100 ml), followed by drying in vacuo, yielded 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (83.0 g, 68% yield) as a pale brown solid:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:15]1(=[N:2][NH:1][C:3]2[N:8]=[N:7][C:6]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=3[CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NNc1cc2c(nn1)CCCCCC2
Reactant: O=C1CCCCC1
Product: c1c(NN=C2CCCCC2)nnc2c1CCCCCC2

Procedure:
A solution of 10.0 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 100 cc of cyclohexanone is boiled at reflux at a bath temperature of 180° for 1 hour and 45 minutes. The mixture is concentrated in a vacuum, whereby the crystalline title compound is obtained and is recrystallized from isopropanol. M.P. 160°-162° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH:3]=1
Reactant: N
Reactant: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)C)n1
Solvent: CO
Product: CC(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 109.6 %

Procedure:
Methyl 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (99 mg, 322 μmol) was added to a pressure tube followed by ammonia (7M in methanol, 3.94 g, 5 mL, 35.0 mmol). The mixture was heated to 50° C. for 18 h, and then additional 7 N ammonia in methanol (7.5 mL) was added. After 24 h, the mixture was cooled, filtered and dried to afford 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (103 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.58 (br. s., 1H) 9.41 (s, 1H) 8.20 (br. s., 1H) 7.60 (t, J=7.83 Hz, 1H) 6.90 (d, J=7.33 Hz, 1H) 6.77 (d, J=8.08 Hz, 1H) 5.72 (br. s., 1H) 3.01-3.16 (m, 1H) 1.37 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 292 [M+H].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].Cl[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].O>CN(C=O)C>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cccc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (14.27 g) in DMF (143 mL) was added sodium hydride (60% dispersion in mineral oil, 6.6 g) at 0° C., and the mixture was stirred under argon atmosphere at 0° C. for 2 hr. To the reaction mixture was added a solution of (2-(chloromethoxy)ethyl)(trimethyl)silane (27.5 g) in DMF (20 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30 g).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[NH4+].[Cl-]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution containing 2-iodo-4-nitroaniline (25 g; 95 mmol) and triethylamine (43 ml; 312 mmol) in CH2Cl2 (250 ml), a solution containing methanesulphonyl chloride (36 g; 312 mmol) was added dropwise. The reaction mixture was left under stirring at room temperature for 18 hours, then NH4Cl (saturated solution) was added (250 ml). The biphasic solution was transferred into a separating funnel, the organic phase was separated, dried over Na2SO4 and the solvent was removed by evaporation under reduced pressure. The residue was suspended in EtOH (200 ml) and heated under stirring until a yellow solid precipitated. The crude product was filtered, washed with EtOH (750 ml), and dried under vacuum to give N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (32 g) which was used in the following reaction without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24](I)[CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:24][CH2:25][CH3:26])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2)on1
Product: CCCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccc(Cl)cc1
Yield: 47 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazole (0.4 g) and propyl iodide (0.14 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.21 g, 47%) as a colorless powder.