Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2[N:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:15][OH:16])[O:8]2)C=CC=CC=1.[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27]C2CCCCO2)[N:21]=1>CN(C)C=O>[CH:12]([NH:11][CH2:10][CH:9]([OH:8])[CH2:15][O:16][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=1)([CH3:14])[CH3:13]
Reactant: Clc1cccc(COC2CCCCO2)n1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NCC(O)COc1cccc(CO)n1
Yield: 41.6 %

Procedure:
22.2 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine was dissolved in 130 ml of anhydrous dimethyl formamide, and with stirring, 50% sodium hydride was added. To the resulting solution was added a solution of 22.75 g of 2-chloro-6-(tetrahydro-2-pyranyloxy)methylpyridine in 250 ml of anhydrous dimethyl formamide. The mixture was stirred at 80° C. for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and 500 ml of 10% hydrochloric acid was added. The mixture was stirred at 80° C. for 20 minutes. The reaction solution was evaporated to dryness under reduced pressure to afford 10 g (yield 41.6%) of 1-isopropylamino-3-(6-hydroxymethyl-2-pyridyloxy)-2-propanol.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1CCCN>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:6][CH2:7][CH2:1][CH2:11][N:15]1[CH:16]=[CH:17][N:13]=[CH:14]1)=[O:4]
Reactant: NCCCc1ncc[nH]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)NCCCn1ccnc1
Temperature: 90 °C

Procedure:
A mixture of 2.93 g of isatoic anhydride, 2.50 g of 1H-imidazole-propanamine and 30 ml of toluene was heated at 90° C. for 45 minutes and cooled. The toluene layer was decanted and the residue was dissolved in methylene chloride, washed with dilute sodium hydroxide solution, water and dried over magnesium sulfate. The organic layer was concentrated to obtain the desired product, mp 107°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:4]([Cl:9])[CH:3]=1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(Br)cc1Cl
Product: COCCOCCOc1ccc(Br)cc1Cl

Procedure:
Prepared from 4-bromo-2-chlorophenol and 2-(2-methoxyethoxy)ethyl tosylate by the method of Example 42 (b).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 104 %

Procedure:
N,N-Dimethyl-L-prolinamide (2.50 g, 17.58 mmol) was dissolved in a mixture of CH2Cl2 (50 mL) and water (50 mL), then solid sodium bicarbonate (2.95 g, 35.16 mmol) was added, followed by benzoyl chloride (2.1 mL, 18.45 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide N,N-dimethyl-1-(phenylcarbonyl)-L-prolinamide (4.502 g, >99%). LCMS: (M+H)+: 247.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:12].[Na+:13].Cl>O1CCOCC1.O>[Na+:13].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:12])=[O:9])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)([O-])c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-3-pyridinesulfonyl chloride (5.0 g, 24 mmol) (C. Rath. Annalen. 1931, 487, 105-119) in dioxane (10 ml) and the solution cooled to 0° C. A solution of sodium hydroxide (1.88 g, 47 mmol) in water (20 ml) was added drop-wise to the stirred solution over 10 mins. After another 10 mins 0.5 pellet of NaOH was added and after a further 15 minutes the pH was adjusted to pH 7 with 2M hydrochloric acid and the solvent was vacuumed down. The material was dried on a Dean and Stark trap to give the title compound. MS (ES−) 192/194 [M−H]−.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:38]([CH3:40])[CH3:39])=[C:32]([NH:34][C:35]([NH2:37])=[S:36])[CH:33]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:38]([CH3:40])[CH3:39])=[C:32]([NH:34][C:35]([NH:37][C:2]([NH:1][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=4)[N:12]=3)[CH:6]=2)=[O:3])=[S:36])[CH:33]=1
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(C)c1ccc(Cl)cc1NC(N)=S
Product: CC(C)c1ccc(Cl)cc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) and isolated as an off-white solid (0.170 g, 38%).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[CH2:12][CH:13]=[O:14].CC(=CC)C.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[CH2:12][C:13]([OH:22])=[O:14]
Reactant: Cc1cc(C)c(CC=O)c(OC(F)F)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CC(=O)O)c(OC(F)F)c1
Reaction time: 4 h
Yield: 12.1 %

Procedure:
19.2 g of 2-difluoromethyloxy-4,6-dimethylphenylacetaldehyde (XXXIV-c-1) as the crude product were dissolved in 270 ml of tert-butanol, the solution was mixed with 90.4 g of 2-methyl-2-butene, and a solution of 90 g of sodium dihydrogen phosphate and 42 g of sodium chlorite in 353 ml of water was subsequently added dropwise at room temperature. The mixture was stirred for four hours and then stirred into 400 ml of ethyl acetate, and the phases were separated. The aqueous phase was extracted two more times using ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated. After stirring with hexane, 11 g of solid were isolated, from which 2.5 g (14% of theory via 2 steps) of 2-difluoromethyloxy-4,6-dimethylphenylacetic acid of melting point 124-127° C. were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:34])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:76]1[CH:80]=[CH:79][CH:78]=[C:77]1[C:81](O)=[O:82]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:34])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:12][NH:13][C:81]([C:77]1[S:76][CH:80]=[CH:79][CH:78]=1)=[O:82]
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.4 %

Procedure:
To a solution of (S)-3-Amino-2-{[3-bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester trifluoro-acetic acid salt (0.26 mmol) in anhydrous DMF (7 mL) was added triethylamine (0.11 mL, 0.78 mmol), HBTU (0.15 g, 0.39 mmol), HOBt (0.042 g, 0.31 mmol), and 2-Thiophenecarboxylic acid (0.050 g, 0.39 mmol). The mixture was stirred at room temperature 15 h, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (30-50% EtOAc in hexane) to give 0.0242 g (16%) colorless oil. MS m/e 567.8 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].I[CH3:20]>C1COCC1>[CH:15]1([C:5]2[C:4]([C:1](=[NH:2])[S:3][CH3:20])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:14])[CH:6]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: CI
Reactant: COC(=O)c1cc(C(N)=S)c(C2CCC2)cc1C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=N)SC)c(C2CCC2)cc1C
Reaction time: 7 h
Yield: 89 %

Procedure:
To a round-bottom flask was added methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 152.5, 861 mg, 3.27 mmol) in THF (10 mL). Iodomethane (912 mg, 6.42 mmol) was added dropwise and the reaction mixture was stiffed at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and purified by SiO2 flash chromatography (ethyl acetate to ethyl acetate/methanol=95/5) to afford methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate as a yellowish oil (807 mg, 89% yield). m/z (ES+) 278 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.40 (s, 1H), 3.88-3.71 (m, 4H), 2.57 (s, 3H), 2.44 (s, 3H), 2.22-2.19 (m, 2H), 2.12 (m, 2H), 1.98-1.86 (m, 1H), 1.82-1.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CC([O-])(C)C.[K+].[SiH:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21]>O1CCCC1>[CH2:20]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=1)[CH3:21]
Reactant: COc1ccc2ccccc2c1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2cc1OC
Yield: 58 %

Procedure:
The reaction was conducted according to the General Procedure by heating 2-methoxynaphthalene (79 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18 mmol, 0.35 equiv.) and Et3SiH (319 microliters, 2.0 mmol, 4 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 79 mg (58%) of the title compound as colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.84 (s, 1H), 7.78-7.73 (d, 1H), 7.73-7.68 (d, 1H), 7.38 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.27 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 7.15 (s, 1H), 3.90 (s, 3H), 1.01-0.90 (m, 9H), 0.68-0.53 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 163.03, 137.88, 136.83, 130.10, 128.58, 128.09, 127.29, 127.21, 124.03, 104.57, 55.25, 8.02, 7.48. HRMS: [C17H24OSi] calculated 272.1608, measured 272.1596. The HSQC spectra of the 2-methoxynaphthalene and its reaction product are provided in FIG. 5.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:44]([F:49])([F:48])C([O-])=O.[Na+].O>COCCOCCOC>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[C:44]([F:49])[F:48]
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 16 %

Procedure:
A mixture of 1.21 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.87 g of triphenylphosphine and 10 ml of diglyme was stirred at 160° C., to which a solution (5 ml) of 0.69 g of sodium chlorodifluoroacetate in diglyme heated to 60° C. was added dropwise. After stirring at 160° C. for 1.5 hours, the reaction mixture was returned to room temperature, poured into water and extracted twice with 50 ml of diethyl ether. The diethyl ether layers Were combined, washed with water, dried over magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-difluoro-2-propenyloxy)butyloxy)benzene (yield, 16%), nD23.0 1.5219.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[C:3](=[O:7])[CH:4]=[CH:5][CH3:6].CC([Mg]Br)CC.C(=O)/C=C/C>CCOCC>[CH3:1][CH:2]([CH2:8][CH3:9])[CH:3]([OH:7])[CH:4]=[CH:5][CH3:6]
Reactant: CC=CC(=O)C(C)CC
Agent: C/C=C/C=O
Agent: CCC(C)[Mg]Br
Solvent: CCOCC
Product: CC=CC(O)C(C)CC

Procedure:
5-Methyl-hept-2-en-4-one to be used according to the invention can be obtained for example by reacting 2-butyl-magnesium bromide (prepared, for example, from 2-bromo-butane and magnesium filings) with crotonaldehyde in ether solution. 5-Methyl-hept-2-en-4-ol is obtained as an intermediate and is oxidized with a mixture of sodium dichromate and sulphuric acid to give 5-methyl-hept-2-en-4-one. The 5-methyl-hept-2-en-4-one is obtained as a mixture of the cis- and trans-isomers, with the latter predominating. The isomer mixture can be separated into the cis-isomer and trans-isomer by simple methods of separation, such as, for example, fractional distillation by a packed column or slotted tube column or preparative gas chromatography. However, it has been found that the use of the individual isomers offers no advantages over the use of the mixture.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[CH3:12][N:13]([CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)[CH3:14]
Reactant: CNC
Reactant: CC(=O)Nc1nc(CCl)cs1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CN(C)C)cs1
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
N-(4-(Chloromethyl)thiazol-2-yl)acetamide (2.0 g, 10 mmol) in 20 mL THF was added in portions to dimethylamine (4.7 g, 105 mmol). After addition, the mixture was stirred for an additional 30 minutes. The solvent was removed under reduced pressure. 200 mL distilled water was then added to the resulting residue, and the mixture was extracted with EtOAc. The EtOAc solution was washed with brine solution and dried over sodium sulfate. After removing the solvent, an off-white solid was obtained as the crude product (1.3 g, yield=80%). LCMS (API-ES) m/z (%) 200.1 (100%, M++H). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 3H) 2.26 (s, 6H) 3.43 (s, 2H) 6.73 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]2[CH:13]=[N:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[N:9]=2)[CH2:2]1.O=C1CCC(=O)N1[O:30][C:31](=O)[CH2:32][C:33]#[N:34].C(N(CC)CC)C>C(Cl)Cl>[O:30]=[C:31]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]2[CH:13]=[N:12][CH:11]=[C:10]([C:14]3[CH:15]=[N:16][N:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[N:9]=2)[CH2:2]1)[CH2:32][C:33]#[N:34]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: c1cn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccncc34)n2)C1
Yield: 55.9 %

Procedure:
A solution of (R)—N-(piperidin-3-yl)-6-(pyrazolo[1,5-a]pyrazin-3-yl)pyrazin-2-amine (Preparation 30b, 0.23 g, 0.78 mmol), 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropane nitrile (prepared as described in BE875054(A1), 0.17 g, 0.94 mmol)) and triethylamine (0.13 mL, 0.94 mmol) in methylene chloride (10 mL) was stirred overnight at ambient temperature. After evaporation of the solvent, the crude mixture was purified by flash chromatography (95:5 to 93:7 methylene chloride/methanol) to yield the title compound (0.158 g, 38%) as a pale yellow solid.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(C)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: Cc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methylphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-methylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 5.7 g (0.023 mol) of Boc-PheOH dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL, 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred for 15 minutes and filtered. The filtrate is slowly added to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and then stirred for 1 hour at ice-bath temperature followed by stirring for 1 hour at room temperature. The reaction is cooled to 0° C., treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl, washed with water, dried over anhydrous MgSO4, and evaporated to dryness. The crude product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:21][C:22](=[O:36])[NH:23][C:24]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:25]=4[C:26]=3[N:27]=2)[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1.CCO>[Ni].C1COCC1>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:21][C:22](=[O:36])[NH:23][C:24]4[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:25]=4[C:26]=3[N:27]=2)[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1
Reactant: CN(C)CC#Cc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCCc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a round bottom flask were added 2-{[5-[3-(dimethylamino)prop-1-yn-1-yl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.042 g, 0.081 mmol), EtOH (5 mL), THF (1 mL), and Raney nickel (20 mg). The resulting mixture was allowed to stir under a hydrogen balloon overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography to give 2-{[5-[3-(dimethylamino)propyl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.033 g, 78%) as a solid.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:10](=[O:11])[C:9]3[CH:13]=[CH:14][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=3)=[CH:32][CH:31]=2)[N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3csc(C(=O)NC(C(=O)OC)C(C)C)n3)cc2)cc1
Yield: 56 %

Procedure:
The title compound was synthesized analogous to Example 27, using 4-pentylbenzoyl chloride and intermediate 3. Yield: 56%; 1H NMR (DMSO-d6, 300 MHz): δ 10.32 (s, 1H), 8.84 (d, 1H), 8.37 (s, 1H), 8.12 (d, 2H), 7.91 (bs, 4H), 7.37 (d, 2H), 4.37 (t, 1H), 3.70 (s, 3H), 2.66 (s, 2H), 2.32 (m, 1H), 1.61 (s, 2H), 1.29 (s, 4H), 0.98 (t, 6H), 0.87 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([O:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:33][CH:32]=1
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of 1-methyl-piperidin-4-ol (6.8 g. 59 mmoles), PPh3 (triphenylphosphine, 15.5 g, 59 mmoles) and 4-hydroxy-benzoic acid methyl ester (6 g, 39 mmoles) in THF (150 ml) at 0° C., diethyl azodicarboxylate (9.5 ml, 59 mmoles) in THF (30 ml) was slowly added. The reaction mixture was allowed to warm to room temperature over a period of 24 hours. It was then evaporated and the residue redissolved in 5% aqueous citric acid (700 ml). The solution was washed with ethyl acetate (3×250 ml), made alkaline with concentrated NH4OH (pH ˜8) and then extracted with dichloromethane (3×250 ml). The combined dichloromethane extracts were washed with brine, dried and evaporated to give an oil which was purified by flash chromatography on silica gel using dichloromethane-MeOH (90:10) as eluent, to give the title compound as a yellow oil (7.4 g, 75%).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([O:35][C:36]1[CH:41]=[C:40]([NH:42][C:43](=[O:55])[C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]3[CH2:54][CH2:53]3)=[CH:46][CH:45]=2)[C:39](O)=[CH:38][N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C(#N)C.C(N(CC)CC)C>[CH2:28]([O:35][C:36]1[N:37]=[CH:38][C:39]2[O:55][C:43]([C:44]3[CH:45]=[CH:46][C:47]([O:50][CH2:51][CH:52]4[CH2:53][CH2:54]4)=[CH:48][CH:49]=3)=[N:42][C:40]=2[CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1cc(OCc2ccccc2)ncc1O)c1ccc(OCC2CC2)cc1
Agent: Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ccc(COc2cc3nc(-c4ccc(OCC5CC5)cc4)oc3cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.6 %

Procedure:
To a solution of hexachloroethane (4.09 g), triphenylphosphine (4.53 g) and triethylamine (2.41 mL) in acetonitrile (50 mL) was added N-(2-(benzyloxy)-5-hydroxypyridin-4-yl)-4-(cyclopropylmethoxy)benzamide (2.25 g), and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.25 g).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[H-].[Na+].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN1CCCC1=O>[Si:18]([O:17][CH2:16][CH2:15][N:4]([CH2:1][C:2]#[CH:3])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C

Procedure:
The sub-titled compound was prepared from tert-butyl prop-2-yn-1-ylcarbamate (0.8 g), 60% sodium hydride (0.227 g), (2-bromoethoxy)-tert-butyldimethylsilane (1 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (25:1) to afford (0.8 g).