Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]3OCC[O:19]3)=[CH:14][CH:13]=1)=[N:7]2.Cl>O1CCOCC1>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=1)=[N:7]2
Reactant: Clc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 3-3 (16 g, 41.1 mMol) in anhydrous 1,4-dioxane (75 mL) at 0° C. was added 3N HCl (27 mL). The reaction was then allowed to reach room temperature and was stirred for around 3 hours. Upon completion, the reaction was quenched with saturated NaHCO3 solution to reach a pH of >7. The product was extracted into ethyl acetate (3×150 mL). The combined organic layers were washed with brine, dried with Na2SO4 and MgSO4, filtered and concentrated in vacuo to yield 4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)benzaldehyde 9-1 as a tan solid. LC/MS (M+1) calculated: 345.8; observed: 345.0
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[N:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.C(OCC)(=O)C>[CH3:22][N:21]1[C:13]2[CH:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH:2]=[O:1])=[C:6]([C:23]([F:25])([F:24])[F:26])[CH:7]=3)[N:16]=[C:15]([C:17]#[N:18])[C:14]=2[N:19]=[N:20]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(CCCO)c(C(F)(F)F)c3)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(CCC=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To 6-(4-(3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.65 g) in DMSO (10 ml) was added the DCM solution of Dess-Martin (15%, w/w) (10 ml). The mixture was stirred at rt for 2 hours. After diluting with ethyl acetate (150 ml), the mixture was washed with water (20 ml×4), brine (20 ml), dried over sodium sulphate, solvent removed under reduced pressure. The residue was then dissolved in ethyl acetate (20 ml). After standing overnight, precipitate was then filtered off, filtrate concentrated to give methyl-6-(4-(3-oxopropyl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (620 mg). 1H NMR (CDCl3) δ: 9.88 (s, 1H), 8.36 (s, 1H), 8.26 (d, 1H), 8.05 (s, 1H), 7.55 (d, 1H), 4.46 (s, 3H), 3.22 (t, 2H), 2.86 (t, 2H). MS m/z 360 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:10][CH2:9]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C=CCC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1.57 g (4.82 mmol) 4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-but-2-enoic acid ethyl ester and 200 mg of Pd/C (10%) in 20 ml of MeOH was stirred at RT under H2-atmosphere for 3 h. After filtration, the solution was concentrated under reduced pressure to dryness, to give 1.58 g of clean trans-4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-butyric acid ethyl ester. 1.58 g (4.82 mmol) trans-4-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-butyric acid ethyl ester in 20 ml of THF, was treated at RT with 390 mg of LiAlH4. After stirring the solution for 30 min at RT, the excess of LiAH4 was destroyed by adding dropwise 10 ml of saturated brine under ice-cooling. The reaction mixture was partitioned between Et2O/1M HCl and H2O. The ether-solution was concentrated in vacuo, to give 1.37 g (99%) of pure trans-[4-(4-Hydroxy-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32]([O:33][CH2:34][CH3:35])=[O:36])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CCOC(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and ethyl 1H-indol-5-ylcarbamate (intermediate-52) (6.0 g, 35%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH:17]=[CH:16][N:15]=[CH:14]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.CC1OCCC1.CC(OC)(C)C.C(O)C>[CH:17]1[N:13]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][C:26](=[O:28])[C:14]2=[N:15][CH:16]=1
Reactant: CCOC(=O)CCc1ccccc1-n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=C1CCc2ccccc2-n2ccnc21
Temperature: -75 °C
Reaction time: 2 h

Procedure:
Charge a reactor with 281 kg of 2-MeTHF and 31 kg of Diisopropylamine Cool to −80 to −70° C., and charge 86 kg of n-butyl lithium in n-hexane slowly maintaining the temperature a at −80 to −70° C. and stir for 1 to 3 h. Charge 195.8 kg solution of ethyl 3-(2-(1H-imidazol-1-yl)phenyl)propanoate in 2-MeTHF into the reactor slowly at −80 to −70° C., and stir for 2 to 4 h at −80 to −70° C. (in process HPLC<3%, ethyl 3-(2-(1H-imidazol-1-yl)phenyl)propanoate). Charge 47.8 kg of ethanol into the reactor slowly at −80 to −70° C., and stir for 0.5 to 2 h at −80 to 70° C. Charge 310 kg of MTBE into the reactor slowly, maintaining internal temp below −25° C. Adjust pH to 7.5 with 292 kg of 10% Citric acid aqueous solution. Adjust the temperature to about 0° C. Separate out aqueous layer, and wash organic layer with 202 kg of 25% NaCl aqueous. Separate the layers, concentrate the organic layer under reduced pressure to 41 to 82 L, maintaining the internal temp below 40° C. Extract the aqueous layer with 200 kg of dichloromethane. Combine the organic layers, and stir for 0.5 to 1 h at 15 to 25° C. Filter through a pad of silicon dioxide (20 kg), and wash the pad with 60 kg of dichloromethane. Concentrate the filtrate under reduced pressure to 82 to 123 L, maintaining the internal temperature below 40° C. Charge 170 kg of MTBE to the residue, and concentrate under reduced pressure to 82 to 123 L, maintaining the internal temperature below 50° C. Charge 208 kg of MTBE, and stir for 10 to 15 minutes (in-process control indicated 10.8% 2-MeTHF and 4.6% DCM). Charge 279 kg of MTBE and concentrate under reduced pressure to 82 to 123 L, maintaining an internal temperature below 50° C. (residual 2-MeTHF %=1.6%, residual DCM %=2.7%). Charge 14.5 kg of Methyl acetate into the residue, and heat the mixture to reflux for 30 to 60 minutes. Cool the mixture to 0 to 15° C. and stir for 6 to 8 h at 0 to 15° C. Isolate the solid by centrifugation, and wash the cake with 35 kg of MTBE. Dry the resulting solid to give 15.8 kg of 5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one. LC/MS=199 (M+1), 419 (2M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:26][CH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CBr)c1
Temperature: 90 °C
Yield: 758.3 %

Procedure:
In 130 ml of carbon tetrachloride was dissolved 10 g of ethyl 2-methylbiphenyl-4-carboxylate, the whole was heated to 90° C. and then 1.0 g of NBS and 136 mg of 2,2′-azobisisobutyronitrile were added thereto. After the reaction solution was heated under reflux, 6.78 g of NBS was added thereto and the whole was heated under reflux for 1 hour and a half. After the reaction solution was cooled to room temperature, precipitate was removed by filtration, water was added to the filtrate, and the organic layer was extracted with carbon tetrachloride. After the resulting organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation to obtain 13.6 g of ethyl 2-(bromomethyl)biphenyl-4-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 120 °C
Yield: 170.6 %

Procedure:
The two reactions were performed in parallel. Two microwave vials were set up in parallel. In a large 30 mL microwave vial, 3-(ethyloxy)phenol (2 times 1.25 g, 9.045 mmol) was dissolved in 6 mL of dimethylformamide. 1-Fluoro-4-nitrobenzene (2 times 1.28 g, 9.045 mmol) and potassium carbonate (2 times 3.75 g, 27.15 mmol) were added. The reaction mixture was heated under microwave irradiation during 1 hour at 120° C. The combined reaction mixtures were filtered. The filtrated solid was washed with dichloromethane. The volatiles were evaporated under vacuum. Some dichloromethane and brine were added to this crude. The compound was extracted with dichloromethane (2 times) and ethyl acetate (2 times). The combined organic phases were dried over sodium sulphate. This afforded the title compound (4 g).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([Cl:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[CH3:30])[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:31](Cl)(=[O:34])[CH2:32][CH3:33].O>N1C=CC=CC=1.Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([Cl:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[CH3:30])[C:6](=[O:9])[CH2:7][O:8][C:31](=[O:34])[CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 1 h

Procedure:
A solution of 17-acetoxy-11β-chloro-21-hydroxy-16β-methylpregna-1,4-diene-3,20-dione (67 mg.) in pyridine (1 ml.) at 0° was treated with propionyl chloride (0.03 ml.). After one hour, a little water was added and the solution was diluted with dilute hydrochloric acid. The precipitated solid was collected and recrystallized from methanol to give the title compound, m.p. 213°-215° (K), [α]D + 108.4° (c 0.6, chloroform) λmax 240 nm (ε 15,760) (Found: C, 65.9; H, 7.2. C27H35Cl O6 requires C, 66.0; H, 7.2).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6]1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([C:13]1[CH:12]=[CH:11][C:10]2[O:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:14]=1)=[O:18]
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2c(c1)CCCO2
Reaction time: 3 h
Yield: 35.5 %

Procedure:
Aluminium chloride (III) (1.9 g, 14.25 mmol) was added portion wise at 0° C. to a solution of 3,4-dihydro-2H-1-benzopyran (9a) (450 mg, 3.35 mmol) and 2-chloroacetyl chloride (270 μL, 3.4 mmol) in dichloromethane (10 mL). After 3 hours, the mixture was quenched by a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/cyclohexane 40/60) to afford the desired product (9b) as a white yellow oil (250 mg, 1.19 mmol, 35%).
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7]>>[Cl:1][Ge:2]([CH:6]([CH3:7])[C:5]([OH:9])=[O:8])([Cl:4])[Cl:3]
Reactant: Cl[GeH](Cl)Cl
Reactant: C=CC(=O)O
Product: CC(C(=O)O)[Ge](Cl)(Cl)Cl

Procedure:
Trichlorogermane (Cl3GeH) was added to acrylic acid (CH2CHCOOH) to obtain trichlorogermylpropionic acid (Cl3GeCH2CH2COOH). It was hydrolyzed to synthesize an organogermanium compound (1). In the same manner were synthesized organogermanium compounds (2) to (51).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 39.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 570 mg, 4.1 mmol), 3-fluorophenylboronic acid (Aldrich; 673 mg, 4.6 mmol), copper(II) acetate (750 mg, 4.1 mmol) and triethylamine (1.4 mL, 10.0 mmol) in 1,2-dichloroethane (20 mL) was heated in an oil bath at 60° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 10-20% ethyl acetate/hexanes, to give N′-(3-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (386 mg, 39%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C23CCN(C(=O)OC(C)(C)C)CC2O3)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of (±)-6-(3-methoxy-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (2 g) in methanol (115 mL) was added palladium on carbon 10% (10:90, palladium:carbon black, 400 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (50 PSI) overnight. Filtration through Celite and evaporation of the solvent provided the crude product. The product was purified by flash chromatography (Silicagel, EtOAc/hexanes) to give (±)-3-hydroxy-4-(3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.79 g, 89% yield). 1H NMR (CDCl3): δ ppm 7.26 (s, 1H), 6.72-6.92 (m, 3H), 4.31 (br. s., 2H), 3.96 (br. s., 1H), 3.81 (s, 3H), 3.01 (d, J=13.4 Hz, 1H), 2.70-2.92 (m, 2H), 2.13-2.34 (m, 1H), 1.64 (br. s., 2H), 1.49 (s, 9H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11])=O)(C)(C)C>Cl.CCOC(C)=O>[ClH:21].[NH2:8][CH2:9][C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 137.4 %

Procedure:
(S)-4-(2-(2-(tert-butoxycarbonylamino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (80 mg, 0.17 mmol) was dissolved in HCl 4M in EtOAc (2 ml) and stirred at RT for 3 hours. The solvent was evaporated under vacuum, and the crude product was crystallized from EtOAc/Hexane to give 60 mg of the desired product (Yield: 69%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([CH3:27])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:33]>C(OCC)(=O)C>[ClH:33].[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[C:13]([CH3:27])=[N:12][N:11]2[C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=[C:10]2[C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCNC(=O)OC(C)(C)C)c(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCN)c(C)nn12
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate (25 mg) was added 4N hydrogen chloride in ethyl acetate (1 mL) at ambient temperature. After 1 hour, the mixture was evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-[3-(4-aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile hydrochloride as dark green amorphous (18 mg)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:3]=1.C(Cl)(Cl)Cl.[Br:26]N1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][Br:26])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1cc(Cl)c2cc(CBr)ccc2n1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To 27.6 g (92.4 mmol) of the 4-chloro-6-methyl-2-(2-nitrophenyl)quinoline obtained in Example 1, 110 ml of chloroform was added. After stirring, 15.6 g (87.8 mmol) of N-bromosuccinimide (NBS) was added thereto. Then, 15 ml of chloroform containing 0.78 g of 2,2'-azobis(2,4-dimethylvaleronitrile) was added dropwise thereto, and the thus-prepared mixture was heated under reflux for 1 hour. After cooling to room temperature, the mixture was poured into 220 ml of water and separated out, and the organic layer was washed with 110 ml of water twice. Next, the washed organic layer was evaporated and dried in an evaporator and recrystallized from toluene to obtain 14.7 g of 4-chloro-6-(bromomethyl)-2-(2-nitrophenyl)quinoline.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[N:12]([CH:15]([CH2:18][F:19])[CH2:16][OH:17])=[N+:13]=[N-:14].C1COCC1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O>[F:19][CH2:18][CH:15]([N:12]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:14]=[N:13]1)[CH2:16][OH:17]
Reactant: [N-]=[N+]=NC(CO)CF
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1nccn1Cc1cn(C(CO)CF)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A solution of 10 (1.9 g, 12.6 mmol) and 29 (1.5 g, 12.6 mmol) in t-BuOH:THF:H2O (22.5 mL, 1:1:1) was treated with CuSO4.5H2O (0.31 g, 1.26 mmol) and sodium ascorbate (0.5 g, 2.52 mmol) and stirred for 1 hr at room temperature. Organic solvents removed under vacuum, the residue dissolved in CH2Cl2 and consecutively washed with H2O, then brine, then dried over MgSO4. The solvent was then concentrated in vacuo and the residue was purified on silica gel using 10% MeOH:CH2Cl2 as the solvent to afford 1 (3.00 g, 88%) as white solid. The product was further purified via recrystallization from EtOAc/hexanes. 1H NMR ((CD3)2CO, 400 MHz) δ: 8.15 (s, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.11 (d, J=1.2 Hz, 1H), 5.79 (s, 2H), 4.87-5.05 (m, 2H), 4.82 (dd, J=4.0, 10.0 Hz, 1H), 4.17-4.45 (m, 1H), 4.03 (t, J=5.6 Hz, 2H). 13C NMR ((CD3)2CO, 100 MHz) δ: 141.8, 127.9, 127.1, 123.5, 83.0, 81.3, 63.0 (d, J=18.69 Hz, 1C), 60.5 (d, J=6.73 Hz, 1C), δ: 44.8; 19F NMR ((CD3)2CO, 376 MHz) 230.2 (ddd, J=19.18, 19.55, 21.60 Hz, IF); Mass Spec (lo-res): Calc'd for C9H11FN6O3: 270.09; found: 271.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:50](O)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:50]([O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8])=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 38.5 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide(compound of Example 1(1)) and N-[N-(tert-butoxycarbonyl)-L-leucyl]-L-phenylalanine as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][N:25]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[O:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1c(C=O)c(=O)n(C)c(=O)n1C
Reactant: NOCc1ccccc1
Agent: Cl
Product: CCOc1c(C=NOCc2ccccc2)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-Ethoxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.074 mg, 0.35 mmol) (Example 16, Step 1) and O-benzyl-hydroxyl-amine hydrochloride (0.073 mg, 0.46 mmol) were used to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]=[S:12]1(=[O:33])[C:17]2[CH:18]=[C:19]([O:22]C3C=C(O)C=CC=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:30][CH2:31][CH2:32][C:14]2=[N:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]2[N:15]3[CH2:30][CH2:31][CH2:32][C:14]3=[N:13][S:12](=[O:33])(=[O:11])[C:17]=2[CH:18]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(O)c3)cc21
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(Br)c3)cc21

Procedure:
The procedure is as in Step B of Example 1, using as starting materials (3-bromophenyl)boronic acid and the product obtained in Step A of Example 1.