Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.Cl>C1C=CC=CC=1>[C:5]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11]2)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)CCC2
Temperature: 6.5 °C
Yield: 66.4 %

Procedure:
Anhydrous aluminum trichloride (25 g) is added dropwise to a stirred mixture of acetylchloride (11.8 g), indane (24 g) and dry benzene (100 ml) stirred at 5-8° C. The stirring is continued for 6 hours at this temperature until the evolution of hydrogen chloride is over; then, the mixture is partitioned with ice (200 g) and 6N hydrochloric acid (100 ml), the organic phase is separated, the aqueous phase is extracted with benzene. The organic benzene layers are collected, washed until neutral, dried on MgSO4 and the excess solvent is evaporated under vacuum. The residue (28.5 g) is distilled in high vacuum (1 mmHg) and the fractions with b.p. 80°-85° C. are collected affording 16 g of 5-acetylindane. I.R.=1680 cm-1. H-NMR (CDCl3 /TMS): 7.1-7.8 (m, 3H, Ar); 2.9 (t, 4H); 2.55 (s, 3H, CH3); 1.9-2.4 (m, 2H). A solution of 5-acetylindane (15 g) in ethanol (50 ml) is treated with a solution of hydroxylamine hydrochloride (15 g) and potassium acetate (21.5 g) in ethanol (50 ml) for 20 minutes at the reflux temperature. The excess of the solvent is evaporated in vacuum and the mixture is diluted with water. The precipitate is collected by filtration affording 15.01 g of 5-acetylindane oxime m.p. 104° C. I.R.=3200 cm-1. H-NMR (CDCl3 /TMS): 8.15 (s, 1H, N--OH); 2.3 (s, 3H, CH3).
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:19]=[O:20])=[C:10]([CH:18]=1)[O:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH3:5].[BH4-].[Na+].Cl>CO>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:19][OH:20])=[C:10]([CH:18]=1)[O:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH3:5]
Reactant: CCc1ccc(C=O)c(OC(C)C(=O)OC)c1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CCc1ccc(CO)c(OC(C)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 0.2 gram (0.004 mole) of sodium methoxide in 20 mL of methanol was cooled to about 5° C., and a solution of 4.7 grams (0.020 mole) of methyl 2-(5-ethyl-2-formylphenoxy)propanoate in 30 mL of methanol was added. Upon completion of addition, 0.2 gram (0.006 mole) of sodium borohydride was added. The reaction mixture was then allowed to warm to ambient temperature where it stirred for one hour. After this time the reaction mixture was poured into 40 mL of aqueous 0.25N hydrochloric acid solution. The mixture was extracted with methylene chloride, and the combined extracts were concentrated under reduced pressure to a residue. The residue was purified using column chromatography, yielding methyl 2-(5-ethyl-2-hydroxymethylphenoxy)propanoate. The methyl 2-(5-ethyl-2-hydroxymethylphenoxy)propanoate, 1.1 grams (0.005 mole), was dissolved in 60 mL of methylene chloride, and one drop of pyridine and 0.4 mL of thionyl chloride were added. Upon completion of addition, the reaction mixture was warmed to 50° C. where it stirred for about two hours. After this time the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was then washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was passed through a pad of silica gel. The eluate was concentrated under reduced pressure, yielding 0.9 gram of title compound.
Reaction SMILES: C(OC([N:8]1[CH:13](C)[CH2:12]C(=O)[CH2:10][CH:9]1C)=O)(C)(C)C.[CH3:17][CH2:18][O:19][C:20]([CH2:22][C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[O:21].C(=O)C>>[CH3:10][CH:9]1[CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:23](=[O:24])[CH:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])[CH:13]([CH3:12])[NH:8]1
Reactant: CC1CC(=O)CC(C)N1C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC=O
Product: CCOC(=O)C1C(=O)C(C(=O)OCC)C(C)NC1C
Reaction time: 8 h
Yield: 54 %

Procedure:
Compound 5-3 was made in a manner similar to Hall, H. K. Jr.; J. Am. Chem. Soc., 1957, 79, 5444-5447. Step 2a: Into a mixture of diethyl acetonedicarboxylate (103.6 g, 0.512 mol) and acetaldehyde (45.3 g, 1.33 mol) was bubbled ammonia gas until that liquid was saturated at −30° C. The solution was stored in freezer overnight. The yellow sludge was dissolved in dichloromethane (15 mL), filtered though silica gel and washed with EtOAc. The organic layer was concentrated to give diethyl 2,6-dimethyl-4-oxopiperidine-3,5-dicarboxylate as a thick yellow oil (92 g, 54%). Step 2b: A solution of the diester (90 g, 0.332 mol) in 10% aqueous hydrochloric acid solution (400 mL) was refluxed for overnight. Water was evaporated to yield 2,6-Dimethyl-4-piperidone/HCl, which was used for the next step without further purification. Step 2c: 2,6-Dimethyl-4-piperidone HCl salt (25.0 g, 0.153 mol) was partitioned into dioxane (250 mL) and H2O (250 mL), and sodium bicarbonate (50 g, 0.59 mol) was added in several portions. Boc anhydride (80 g, 0.37 mol) was added and the resulting reaction mixture was stirred at rt overnight. The reaction mixture was evaporated to remove dioxane. The residue was extracted with Et2O and the organic layer was washed with brine and dried over sodium sulfate. After evaporation, the crude product was purified by chromatography (gradient elution of 9-14% EtOAc in hexane) to give Compound 5-3 as a white solid (18.0 g, 52%, mixture of 70:30 trans:cis) (based on comparison to NMR spectra of trans Compound 5-3 reported by Beak, P.; Lee, W. K.; J. Org. Chem. 1993, 58, 1109-1117). MS (ES+) m/z 128 (M-Boc+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])[C@H:30]([NH:41][CH3:42])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])[C@H:30]([N:41]([CH3:42])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (90 mg, 0.28 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine (77 mg, 0.26 mmol) and ethyl-diisopropyl-amine (0.07 ml, 0.38 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 80 mg (54%) of the title product as colorless oil. ES-MS m/e: 581.2 (M+H+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl.[Br:21]Br>ClC(Cl)=C(Cl)Cl.C(Cl)Cl.O>[Br:21][C:18]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[C:6]([F:5])[CH:19]=1
Reactant: Oc1ccc(Oc2ccccc2F)cc1
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)=C(Cl)Cl
Product: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a 250 mL flask equipped with a nitrogen purge, mechanical stirrer, thermometer, condenser and gas scrubber was added 100 mL of perchloroethylene and 16 g (0.12 moles) of AlCl3. The slurry was heated to 60° C. and a solution of 20.4 g (0.10 moles) of 4-(2-fluorophenoxy)phenol in 100 mL of perchloroethylene was added slowly. During the addition HCl gas was given off as the complex with AlCl3 formed. At the end of the addition the temperature was 75° C. The clear, rose-colored solution was cooled to 13° C. with an ice-water bath. To the cooled, rapidly stirred solution was added a total of 16 g (0.1 moles) of liquid bromine dropwise over a 1 hour period at 12°-16° C. After stirring for an additional 30 min, 80 mL of water and 50 mL of methylene chloride were added and the layers were separated. The organic phase was further extracted with 2-50 mL portions of 10% aqueous HCl and then 2-50 mL portions of water. Stripping the solvent under vacuum gave 27.9 g (98.5%) yield of crude product. This crude product was recrystallized from 20 mL of perchloroethylene to give after precipitation, filtration, and drying, 24.2 g (88% yield) of 4-(4-bromo-2-fluorophenoxy)phenol, mp 81-83.5. The identity to the product was confirmed by C13NMR, IR and mixed mp with an authentic sample.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15](O)=[O:16])=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)(=O)C.O>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]2[CH2:13][CH2:14][C:15](=[O:16])[NH:22][N:23]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)OC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C)Cc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A solution of 3-[4-(2-acetoxypropyl)benzoyl]propionic acid (0.8 g) in glacial acetic acid (10 ml) was treated with hydrazine hydrate (1 ml). The resulting solution was stirred and heated under reflux for 1 hr., cooled, diluted with water, and extracted into ethyl acetate. The organic layer was washed with NaHCO3 solution, dried (MgSO4) and evaporated to give 4,5-dihydro-6-[4-(2-acetoxypropyl)phenyl]-3(2H)-pyridazinone as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Reactant: BrCCCCCBr
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCBr)ccc21
Yield: 63 %

Procedure:
In analogy to example 2.2, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and 1,5-dibromopentane were converted to yield 6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (63%) as colorless oil, MS: 397 (M, 1Br);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=Cc1cnc2ccc(Br)cn12
Product: O=Cc1cnc2ccc(-c3ccc(Cl)nc3)cn12
Yield: 44 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 6-chloropyridin-3-ylboronic acid. Yield: 44%; 1H NMR (DMSO-d6; 300 MHz): δ 10.02 (s, 1H), 9.76 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.93 (bs, 2H), 7.79 (d, 1H, J=9 Hz), 7.52 (d, 1H, J=8.1 Hz); MS: m/z 258(M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[C:11](OC)([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)N>>[N:13]1([CH:11]=[N:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[OH:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(N)(OC)N1CCCCC1
Reactant: Nc1ccncc1O
Product: Oc1cnccc1N=CN1CCCCC1
Temperature: 100 °C

Procedure:
4-Amino-3-pyridinol (3.3 g) was added to 1-piperidinylformamide dimethyl acetal (50 ml) and the mixture was stirred at 100° C. until it became homogeneous (approximately one minute). The reaction mixture was cooled, and placed in an ice bath for a half hour. The crystallized product was filtered, washed well with diethyl ether, and air dried to yield 4.64 g of product. This was recrystallized from ethyl acetate and dried under high vacuum and refluxing ethanol overnight to yield 3.39 g of fluffy needles, m.p. 171°-172.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Cl)c2)CC1
Yield: 89.6 %

Procedure:
Using general procedure A, 3-chlorobenzylamine (0.27 mL, 2.2 mmol) and 1-Boc-4-piperidone (484 mg, 2.4 mmol) afforded 4-(3-chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (640 mg, 89%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccccc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and phenylboronic acid. The title compound was obtained in 77% yield as yellow foam. MS (m/e): 448.2 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][Na]>CN(C=O)C.[Cu]Br>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: CO[Na]
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu]Br
Solvent: CN(C)C=O
Product: COc1cnc2[nH]ccc2c1
Temperature: 140 °C
Yield: 78.3 %

Procedure:
To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL) was added 25% (w/w) MeONa (48 mL, 210 mmol) followed by copper (1) bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at 140° C. for 2.5. It was then cooled and concentrated to remove DMF. Water (100 mL) was added followed by saturated aqueous NaHCO3 (20 mL). The mixture was extracted with AcOEt (3×), the combined organic extracts dried (MgSO4) and concentrated. The solid residue was purified by SGC using AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green solid (0.58 g, 78%); 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.45 (d, J=2.3 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:31].[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[S:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:29])[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:26][CH:27]=2)=[CH:19][CH:20]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1csc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCCCC5)cc4)cc3)n(C)c(=O)c12
Yield: 77.9 %

Procedure:
A solution of 3,5-dimethyl-2-[4-(4-hydroxybenzoyl)benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one (255 mg), 1-(2-chloroethyl)piperidine hydrochloride (122 mg) and potassium carbonate (250 mg) in DMF (8 ml) was stirred at 60° C. for 15 hours. This reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried. Then, HCl/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (268 mg).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=O)O[CH2:11][CH2:10]1>>[CH2:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:1]1=[O:8])[CH:10]=[CH2:9]
Reactant: O=C1CCCCCO1
Reactant: O=C1CCO1
Product: C=CCC1CCCCOC1=O

Procedure:
10.02 g of 3-(2-propenyl)-2-oxepanone of interest were prepared in the same manner as in Preparation Example 2Z-5 except that 11.41 g (100.0 mmol) of ε-caprolactone were used instead of β-propiolactone described in Preparation Example 2Z-5.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[Br:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1.CS(C)=O.C(OCC)(=O)C>O>[Br:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:27]=1
Reactant: Brc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(Br)c3)cc2c1=O
Temperature: 120 °C
Yield: 21.7 %

Procedure:
A mixture of 20 mg (0.062 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide, 56 mg (0.372 mmol) of 4-bromo-1H-imidazole and 0.1 ml of DMSO is heated to 120° C. for 16 hours. After cooling to room temperature, the reaction mixture is distributed between ethyl acetate and water, the organic phase is separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel using dichloro-methane-methanol (95:5) and the fractions containing the desired product are combined and evaporated yielding 6 mg (21%) of the title compound. MS (ES−): m/e=445 (M−).
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([O:35][CH2:36][C:37]([CH3:43])([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>C1(C)C=CC=CC=1>[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][N:24]([C:33]([O:35][CH2:36][C:37]([CH3:42])([CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)COC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)COC(=O)N1C[C@H](CN[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.5 ml toluene solution of 227 mg of 3-methoxy-2,2-dimethyl-3-oxopropyl (3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate was mixed with 1.5 ml of 4 M hydrogen chloride/1,4-dioxane at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was mixed with toluene, washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (toluene-methanol) to obtain 3-methoxy-2,2-dimethyl-3-oxopropyl (3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a crude product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[Cl:39]>C(O)C.O.Cl>[Cl:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1)[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)=[O:28]
Reactant: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(Cl)c2)CC1
Yield: 16 %

Procedure:
A mixture of 0.1 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.1 g (0.38 mmole) of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide in 10 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, and then heated in a pressure tube at 130 degrees for 3 hours. After removal of the solvents under reduced pressure, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.028 g of 3-chloro-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-179) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[BrH:17].OO>>[NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([Br:17])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5]
Reactant: Br
Reactant: CCCCCOC(=O)c1cccc(C)c1N
Agent: OO
Product: CCCCCOC(=O)c1cc(Br)cc(C)c1N
Yield: 899.4 %

Procedure:
The above-described method (Example 1) was repeated to react pentyl 2-amino-3-methylbenzoate (2.28 g, 10 mmol) with hydrogen bromide (2.21 g, 13 1 mmol, 48% in water) and hydrogen peroxide (1.72 g, 15.0 mmol, 30% in water). Following working up similar to Example 1 and additional column chromatography, pentyl 2-amino-5-bromo-3-methylbenzoate (2.7 g, 88.3% of theory, >99 area% LC) was obtained as a yellow solid.