Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]2[CH:7]=[C:8]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:16](=[O:31])[CH2:15]3)(=[O:13])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1.Cl.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:33]=[CH:32][C:6]2[CH:7]=[C:8]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][N:24]([C:40]5[CH:39]=[CH:38][N:37]=[CH:36][CH:41]=5)[CH2:23][CH2:22]4)[C:16](=[O:31])[CH2:15]3)(=[O:13])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: Clc1ccccn1
Reactant: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCN(c2ccncc2)CC1
Yield: 51.3 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (260 mg) was added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless solid of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg). A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg), chloropyridine hydrochloride (80 mg) and triethylamine (225 mg) in ethanol (14 ml) was allowed to react in a sealed tube at 150° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid of the title compound (126 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:24]I>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18]([O:19][CH3:24])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1CCN2N=C(c3ccc(C#N)c(Cl)c3C)[C@@H](OC)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile as obtained in example 1 (50 mg, 0.16 mmol) in THF (3 mL) at 0° C. was added sodium hydride (13 mg, 0.33 mmol) for 10 min, followed by the addition of methyl iodide (0.015 mL, 0.245 mmol). The reaction mixture was stirred at room temperature for 2 h. Once the starting material had disappeared (monitored by TLC) reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate, organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 30% EtOAc in Hexane) provided the title compound (10 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:8]([CH:21]=[O:22])[CH2:7][CH2:6]2>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:8]([CH:21]=[O:22])[CH:7]=[CH:6]2
Reactant: COc1ccc(C2=C(C=O)CCc3cc(OC)ccc32)cc1
Solvent: c1ccccc1
Product: COc1ccc(-c2c(C=O)ccc3cc(OC)ccc23)cc1
Yield: 76.8 %

Procedure:
As in Example 110, 3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenecarboxaldehyde (9.7 g) and 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (9.36 g) were stirred together in benzene (150 mL) at reflux for 17 hours. The usual workup provided 9.5 g of crude product which was crystallized from 2-propanol to give 7.4 g of 6-methoxy-1-(4-methoxyphenyl)-2-naphthalenecarboxaldehyde, mp 99°-101° C. Anal. Calcd for C19H16O3 : C, 78.06; H, 5.52 Found: C, 78.05; H, 5.59
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Cn2ccc(-c3ccccc3)n2)cc1
Yield: 88.9 %

Procedure:
A mixture of 3-phenyl-1H-pyrazole (1.35 g, 9.36 mmol), 4-methoxybenzyl chloride (1.5 g, 9.7 mmol) and K2CO3 (3.3 g, 24.2 mmol) in methyl ethyl ketone was refluxed for 24 h. The salts were filtered off, and the solvent was removed in vacuo. The residue was purified by a column chromatography on silica gel to yield the title compound (2.2 g, 89%).
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[BH4-].[Na+]>CCO.C1COCC1>[Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH2:10][OH:11])[CH:12]=1
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(CO)c(O)c(C(C)C)c2)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8D (100 mg, 0.21 mmol) and NaBH4 (9.0 mg, 0.23 mmol) was dissolved in a mixture of EtOH and THF (3 mL, 2:1) at room temperature. After 1.5 hours of stirring at room temperature, the reaction mixture was concentrated and the residue suspended in CHCl3. The suspension was washed with 1N HCl and the two phases were separated with a phase separator (IST) before concentration of the organic phase. The residue was purified on column (silica gel, gradient elution: n-heptane/EtOAc from 1:0 to 7:3) to give 85 mg (85%) of 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-hydroxymethyl-6-isopropylphenol as a light yellow foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH:2]=[CH:3][C:4]=3[CH:9]=2)[CH2:11][CH3:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(O)(c1ccccc1)c1ccc2occc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(c1ccccc1)c1ccc2occc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(benzofuran-5-yl)-1-phenylpropan-1-ol (3.14 g, 12.4 mmol) and triethylsilane (2.39 mL, 14.9 mmol) in DCM (10 mL) under nitrogen at 0° C. was added trifluoroacetic acid (4.62 mL, 62.2 mmol) dropwise via syringe. The reaction mixture was stirred at 0° C. for 3 h. Additional triethylsilane (2.39 mL, 14.9 mmol) followed by trifluoroacetic acid (4.62 mL, 62.2 mmol) were added via syringe, and the reaction was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with 1M aqueous NaOH. DCM was added, and the aqueous layer was separated and extracted again with DCM. The combined organic layers were dried (MgSO4) and concentrated to give a crude oil. The crude product was purified by silica flash chromatography to give 5-(1-phenylpropyl)-benzofuran as a transparent oil. MS (ESI) m/z: Calculated: 236.1; Observed: 237.2 (M++1).
Reaction SMILES: O.Cl.[CH:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)=[CH:4][CH3:5].[OH-].[NH4+]>[Fe].C(O)C>[CH:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])=[CH:4][CH3:5]
Reactant: CC=COc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC=COc1ccccc1N

Procedure:
Iron 60 mesh (106.3 g, 1.9 mole), water (450 cc), ethanol (500 cc) and concentrated hydrochloric acid (29.5 cc) were heated to reflux under a nitrogen blanket. Then 2-prop-1-en-oxynitrobenzene (89.6 g, 0.57 mole) was added at reflux over a period of 2 hours. The reaction was maintained at reflux over a period of 2 hours. The reaction was maintained at reflux for an additional 3 hours. The pH was adjusted to 7-8 by the addition of concentrated ammonium hydroxide. The reaction mixture then was filtered at 30° C., and the filtrate was washed with 200 cc of ether. The filtrate was extracted with 4×50 cc of ether and the combined ether extracts were subjected to rotary evaporation. The crude product was fractionally distilled at 110°-112° C. at 4.5 mm Hg to yield 50.1 g. (67.2%) of product.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:29]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>CO>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[N:29]([CH:30]([CH2:31][CH3:32])[CH2:33][CH3:34])[C:8]=4[N:9]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: CCC(CC)n1c(C(=O)OC)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)n1c(C(=O)O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (19 mg, 0.041 mmol) in MeOH (1.5 mL) is added 2 N LiOH aqueous solution (0.5 mL). The reaction mixture is stirred overnight and concentrated in vacuo. The residue is purified by preparative HPLC to give 13.6 mg of 2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4]>O.[Cr]>[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([O-:8])=[O:7])[CH3:4].[Na+:2]
Reactant: CCCCC(CC)C(=O)O
Agent: [Cr]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]

Procedure:
The active chromium III salt preparation is illustrated as follows. A solution of 120g (3.0 moles) of sodium hydroxide was dissolved in 500 ml of distilled water. 2-Ethylhexanoic acid (491g, 3.3 moles) was added with stirring to form sodium 2-ethylhexanoate. In a separate container, 200g (0.5 mole) of chromium nitrate nonahydrate was dissolved in 500 ml of distilled water. The chromium nitrate solution was slowly added to the sodium 2-ethylhexanoate solution with good stirring. When the addition was complete, 500 ml of hexane were added and stirring was continued for 10 minutes. The layers were separated and the hexane layer containing the aquated chromium III tri-2-ethylhexanoate was washed with dilute sodium hydroxide solution, water, dilute sodium carbonate solution and finally with distilled water. The hexane solution was then dried over anhydrous magnesium sulfate. Most of the hexane was removed under reduced pressure and the resulting concentrate was slowly added to 500 ml of acetone. The resulting blue granular solid was filtered and air dried to yield 130g (54%) of aquated chromium tri-2-ethylhexanoate. Molecular weight determination indicated that the compound is polymeric in nature, probably due to the oxygen bridging of chromium atoms.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1.CCOCC>O1CCCC1>[S:10]=[C:24]1[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(N[C@@H]1CCc2ccccc2NC1=S)OCc1ccccc1
Yield: 73.6 %

Procedure:
Add Lawesson's Reagent (12.25 g, 30.29 mmol) to a solution of benzyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (9.4 g, 30.29 mmol) in tetrahydrofuran (470 mL) and stir the reaction under nitrogen for approximately 16 hours at ambient temperature. Remove the precipitate by filtration and discard it. Concentrate the filtrate under reduced pressure and dissolve the residue in ethyl acetate. Wash with water and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure to give a thick, yellow oil. Add ether to the thick oil and scratch it to form a solid. Collect the solid by filtration and wash it with ether. Triturate the solid with ether and collect it by filtration to give the title compound (7.28 g, 74%) as a white solid: MS (m/z): 349 (M+23).
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[C:40]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([C:44]1[CH:45]=[CH:46][C:47]([C:48]([N:37]2[CH2:38][CH2:39][N:34]([C:26]3[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[F:24])[CH2:35][CH2:36]2)=[O:49])=[CH:51][CH:52]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(C(=O)c3ccc(C(C)(C)C)cc3)CC2)cc1F

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and 4-tert-butylbenzoyl chloride (234 μL), respectively, to provide crude 1-(4-tert-butylbenzoyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (433 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14](OCC)=[O:15]>OS(O)(=O)=O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:14](=[O:15])[CH2:13][CH:12]2[CH2:11][Cl:10]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: O=C1CC(CCl)c2cc(Br)c(O)cc2O1
Yield: 52 %

Procedure:
4-Bromoresorcinol (15.12 g, 80 mmol) and ethyl 4-chloroacetoacetate (16.2 mL, 0.12 mmol) were stirred in 80 mL of conc. H2SO4 for six days. The reaction mixture was poured into crushed ice with stirring and the slurry stirred for 30 min. The crude product was then filtered and washed with cold water. It was then dissolved in ethyl acetate and washed with water, 5% aqueous sodium bicarbonate solution, water and saturated brine solution and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated to about 15 mL and the slurry cooled for 30 min and filtered to get the product (52%). The characterization data were consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[S:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:23][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:13]2[S:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:17]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc(-c2cccn2C(=O)OC(C)(C)C)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2ccc(Br)n2C(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 19 h
Yield: 60.1 %

Procedure:
Ethyl 2-[1-(t-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-thiazole-5-carboxylate (800 mg, 2.48 mmol) synthesized in Example (5a) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (442 mg, 2.48 mmol) was added with stirring under nitrogen atmosphere, and subsequently stirring was carried out at room temperature for 19 hours. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (598 mg, yield 60%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:30]([NH:31][C:32](=[O:34])[CH3:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:24][C:25]1[C:30]([NH:31][C:32](=[O:34])[CH3:33])=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:27][N:26]=1
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CC(=O)Nc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1Cl

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 222.1.1) to give the title compound as an off-white solid. (HPLC: tR 2.33 min (Method A); M+H=462 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.80 (s, 1H), 9.01 (s, 1H), 8.34-8.28 (m, 2H), 8.17-8.11 (m, 2H), 7.95-7.90 (m, 1H), 7.61-7.58 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 2.18 (s, 3H), 1.93 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5](Cl)=[CH:4][CH:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1>CN1C(=O)CCC1.C(N(C(C)C)CC)(C)C>[C:13]([CH:12]1[CH2:11][CH2:10][N:9]([C:5]2[N:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(Cl)nn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C)nn2)CC1
Yield: 44 %

Procedure:
55 mmoles of 6-methyl-3-chloropyridazine was added to 75 mmoles of ethyl isonipecotate in 5 mL NMP and 20 mL diisopropylethylamine (DIPEA) and refluxed for 6 hours. The product was isolated as described in Example 1a above to give a 44% yield of 3-(4-carboethoxy-1-piperidinyl)-6-methylpyridazine. Reduction of 18.8 mmol of this compound using 56.6 mmol DIBAL in 100 mL THF with a Rochelle's salt quench gave 3-(4-hydroxymethyl-1-piperidinyl)-6-methylpyridazine (Formula IV: R1 =CH3 ; Y=CH2) which was used unpurified in the final step. Reaction of 5 mmol of the product described in Example 1b with 4.5 mmol of the 3-(4-hydroxymethyl-1-piperidinyl)-6-methyl pyridazine according to the procedure of Example 1c afforded after recrystallization from ethyl acetate at -70° C. the compound of formula I (R1 =R4 =CH3, Y=CH 2, R2 =R3 =hydrogen) in 12% yield, m.p. 180°-185° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](Cl)=[O:24]>O1CCCC1>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][O:18]1)=[O:24]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)C1CCCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)C1CCCO1)C(C)C

Procedure:
617 g (3.68 mol) of (S)-valine methyl ester hydrochloride were suspended in about 2.2 l of tetrahydrofuran and 745 g (7.38 mol) of triethylamine were added. 451 g (3.35 mol) of tetrahydrofuran-2-carbonyl chloride in 200 ml of THF were added dropwise with stirring, the reaction temperature rising to about 65° C. After completion of the addition, the mixture was stirred at room temperature for a further 12 hours. The precipitate was filtered off with suction and thoroughly washed with tetrahydrofuran, and the combined organic phases were evaporated. The residue was dissolved in ether to remove excess (S)-valine methyl ester, shaken with water and dried in the customary manner. Vacuum distillation yields N-(2-tetrahydrofuroyl)-(S)-valine methyl ester (formula V with X=S, n=1, R=CH(CH3)2 and R'=CH3) as a colorless liquid, b.p. 98°-103° C./0.01 torr, yield: 611 g (80%).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C[O:16][C:17](=O)[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:17](=[O:16])[CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Reactant: COC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2c(C(F)(F)F)cc(=O)[nH]c21
Temperature: 110 °C
Yield: 98.2 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (2.0 g, 10.4 mmol) in AcOH (10 mL) was added 4,4,4-trifluoro-3-oxo-butyric acid methyl ester (3.5 g, 20.7 mmol). The reaction was then heated to 110° C. for 18 hr, at which time the reaction was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure to give the title compound (3.2 g, quantitative yield). This material was used without further purification. LRMS m/z (APCl) 314 (M+1); 500 MHz 1H NMR (CDCl3) δ 6.66 (s, 1H), 3.78 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.49-2.39 (m, 2H), 2.34-2.26 (m, 2H), 2.06-1.85 (m, 2H), 1.75 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)=[N:26][OH:27])=[CH:4][CH:3]=1
Reactant: O=C(CC(c1ccccc1)c1ccc(Br)cc1)c1ccnc(Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ON=C(CC(c1ccccc1)c1ccc(Br)cc1)c1ccnc(Cl)c1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(2-chloro-pyridin-4-yl)-3-phenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.6:1) as a colorless oil, MS (ESI−): m/z=413.0 ([M−H]−, 1Br,1Cl).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[OH-].[Na+]>CO>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[CH2:4][C:3]([OH:17])=[O:2])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reaction time: 8 h
Yield: 92.4 %

Procedure:
tert-Butyl (2S)-2-(2-methoxy-2-oxoethyl)-1-pyrrolidinecarboxylate (8.35 g, 34.3 mmol) was dissolved in 150 mL MeOH. Aqueous NaOH (50 mL, 1 M) was added and the reaction mixture was allowed to stand overnight. After concentration in vacuo to ca. 100 mL, the solution was added to 300 mL water and extracted with ether (2×). The carboxylate solution was acidified to pH 2 with 12 N HCl and extracted with ether (2×). The aqueous layer was saturated with salt and extracted a third time with ether. The combined organic layers were washed with water, brine and dried over MgSO4. Filtration and concentration provided the title acid as a white solid (7.28 g, 31.7 mmol, 92.6%): 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 4.16 (bs, 1H), 3.37 (bs, 2H), 3.0–2.8 (bs, 1H), 2.36 (dd, J=9.3, 15.3 Hz, 1H), 2.2–2.0 (m, 1H), 1.9–1.7 (m, 4H), 1.48 (s, 9H) ppm.