Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[C:29]1([S:39](Cl)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>N.CO>[C:29]1([S:39]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cccc2ccccc12)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Naphthalene-1-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.5 mg). MS m/z 379 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[NH2:9][C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3]1)=[O:8]
Reactant: NC(=O)C1CCNCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)N1CCC(C(N)=O)CC1

Procedure:
The title compound was prepared according to the procedure described in the Example 17 from piperidine-4-carboxamide and ethyl 2-bromo-2-methylpropanoate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+:20].[K+]>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]#[N:15])=[CH:2][C:1]([O-:5])=[O:4])=[CH:9][CH:8]=1.[K+:20]
Reactant: O=CC(=O)O
Reactant: N#CCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
133 g (0.9 mol) of 50% strength aqueous glyoxylic acid was added dropwise with stirring to 91.2 g (0.6 mol) of (4-chlorophenyl)acetonitrile and 210 g (1.5 mol) of potassium carbonate in 1.2 1 of methanol such that the reaction temperature increased to 35° C. The mixture was stirred at room temperature for 6 h and then filtered, and the residue was washed with methylene chloride and dried under reduced pressure. At room temperature, the crude product was stirred with 3 1 of water for 1.5 h, and the residue was filtered off, washed with water and dried. Yield: 138 g of a solid of m.p. 241-242° C.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:30])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11](=[O:30])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccc(F)cc1
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccc(F)cc1
Yield: 47 %

Procedure:
A solution of Compound 19 (5 g, 12.24 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.90 g (47%) of yellow solids. M.P. 206° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 5.52 (s, 2H), 7.12-7.15 (m, 2H), 7.30-7.33 (m, 2H), 7.46 (d, J=8.7 Hz, 1H), 7.64 (dd, J=1.2, 8.7 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H). EIMS m/z 327 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[F:50][C:51]1[CH:52]=[CH:53][C:54]([NH2:57])=[N:55][CH:56]=1>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:57][C:54]3[CH:53]=[CH:52][C:51]([F:50])=[CH:56][N:55]=3)=[O:17])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: Nc1ccc(F)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours at 0° C. After this time, 5-fluoro-2-pyridinamine (146 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the remaining residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The remaining residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (350 mg, 0.78 mmol, 78% yield) as a yellow oil. MS: 447 ([M+H]+).
Reaction SMILES: [F-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].Br[C:15]([CH3:22])([CH3:21])[C:16](OCC)=[O:17]>CN(C)C=O>[CH3:21][C:15]1([CH3:22])[C:16](=[O:17])[NH:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=2[O:13]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a suspension of potassium fluoride (4.71 g) in N,N-dimethylformamide (40 mL) was added 2-amino-5-nitrophenol (5.00 g), and the mixture was stirred at room temperature for 1 hour. To the suspension was added dropwise a solution of ethyl α-bromoisobutyrate (6.33 g) in N,N-dimethylformamide (10 mL) over a period of 20 minutes, and the mixture was stirred at 60° C. for 20 hours. After cooling, to the reaction mixture was added cool, water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous 10% HCl solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was suspended in ethyl acetate, and the precipitates were collected by filtration and washed with ethyl acetate to give 2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (2.80 g) as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([O:32]C)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)s2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(c1cc(-c2cnc(Oc3ccc(O)cc3Cl)s2)no1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
To a solution of Example 30E (1.2 g, 2.5 mmol) in dichloromethane (20 mL) was added boron tribromide (0.95 mL, 10 mmol) at −78° C. Upon addition, the mixture was allowed to stir at 25° C. for 16 hours. The reaction was then cooled to 0° C., treated with methanol (5 mL) and diluted with dichloromethane (80 mL). The resulting mixture was washed with water (120 mL) and brine (150 mL). The organic layer was dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 20% to 60% ethyl acetate in hexanes to yield 900 mg of the title compound (77%) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.81 (d, J=6.99 Hz, 3H) 5.55-5.70 (m, 1H) 6.84 (dd, J=8.82, 2.94 Hz, 1H) 6.99 (d, J=2.57 Hz, 1H) 7.17 (s, 1H) 7.42 (d, J=8.82 Hz, 1H) 7.80-7.98 (m, 5H); MS (ESI) m/z 468.0 (M+H)+, 500.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.C[O-].[Na+].Br[CH2:17][CH2:18]Br>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:17][CH2:18][O:11][C:6]=2[CH:5]=1
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2

Procedure:
A solution of 4.20 g. of 3,4-dihydroxybenzoic acid methyl ester in 10.0 ml. of methanol is combined with 7.0 g. of sodium methoxide and then 15.0 g. of 1,2-dibromoethane is added. The resulting mixture is refluxed under nitrogen for 24 hours, then cooled, filtered, evaporated in vacuo and the resulting oil dissolved in 50 ml. of chloroform. The resulting solution after again filtering is chromatographed over 100 ml. of silica gel eluting with chloroform to obtain 3,4-ethylenedioxybenzoic acid methyl ester, m.p. 43°-45° C.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1>>[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][N:29]1[C:11]([C:10]1[CH:9]=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH:14]=1)=[O:13]
Reactant: c1ccc2c(c1)CCNC2
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCc4ccccc4C3)c2)cc1
Yield: 85.2 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.24 mmol) and 1,2,3,4-tetrahydro-isoquinoline (0.3 g, 2.26 mmol) were used to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 2.82 (2H, m), 3.58 (1H, m), 3.80 (1H, m), 4.08 (1H, m), 4.74 (1H, m), 7.10 (3H, m), 7.20 (4H, m), 7.28 (4H, d), 7.90 (2H, d).
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([O:10][CH2:11][C:12]2([OH:31])[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:39]>CO.O1CCOCC1>[C:32]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][C:12]2([OH:31])[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O-:27])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])COc1cccc2c1CCCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl {[(5SR,6SR)-6-(N,N -diphenylcarbamoyloxy)methyl-5,6-dihydroxy-6,7,8,9-tetrahydro -5H-benzocyclohepten-1-yl]oxy}acetate (70 mg) in a mixture of MeOH and 1,4-dioxane (1:1, 4 ml) was added 1N sodium hydroxide solution (0.138 ml) at 5° C. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated followed by addition of Et2O. The resulting solid was collected by filtration to give sodium {[(5SR,6SR)-6-(N,N -diphenylcarbamoyloxy)methyl-5,6-dihydroxy-6,7,8,9-tetrahydro -5H-benzocyclohepten-1-yl]oxy}acetate (65.8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([S:8]([N:10]1[CH2:13][CH2:12][CH2:11]1)=[O:9])([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[C:5]([S:8]([N:10]1[CH2:11][CH2:12][CH2:13]1)(=[O:23])=[O:9])([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)(C)S(=O)N1CCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)S(=O)(=O)N1CCC1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of 4.62 g (21 mmol) of 2-(azetidine-1-sulfinyl)-2-methyl-propionic acid ethyl ester in DCM (100 mL) at room temperature are added 5.46 g (32 mmol) of meta-chloroperbenzoic acid. The reaction is stirred for 1 h before Ambersep 900-OH resin (2.9 g) is introduced. The suspension is shaken for 2 h and then filtered. The filtrate is concentrated under reduced pressure. The residue is dissolved in DCM (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic layer is dried (Na2SO4) and filtered. The solvent is removed under reduced pressure to provide 5 g of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid ethyl ester as an orange oil, which is used in the next step without further purification. Yield 100%, ES-MS: m/z 236 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25](O)[CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N+:29]([C:28]1[CH:23]=[CH:24][C:25]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-Benzyloxycarbonyl-L-phenylalanine (2.99 g) and p-nitrophenol (1.39 g) are dissolved in tetrahydrofuran (30 ml), and dicyclohexylcarbodiimide (2.1 g) is added thereto under ice-cooling. The mixture is stirred at room temperature for four hours and insoluble materials are filtered off. Ethyl acetate is added to the filtrate and the mixture is washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried, and then concentrated to remove solvent. Hexane is added to the residue to give N-benzyloxycarbonyl-L-phenylalanine-p-nitrophenyl ester as crystals. The product is dissolved in tetrahydrofuran (20 ml), and a solution(15 ml) of L-histidine methyl ester dihydrochloride (2.4 g) and triethylamine (2.8 ml) in water is added thereto under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) and crystallized with ethyl acetate to give N-benzyloxycarbonyl-L-phenylalanyl-L-histidine methyl ester (2.8 g) as colorless crystals. Yield ; 64.1%
Reaction SMILES: [Cl:1][C:2]1[C:29]([CH2:30][CH2:31][OH:32])=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:25][CH2:24][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:25][CH2:24][C:8]3([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]4[N:17]=[C:18]([CH:21]([CH3:22])[CH3:23])[S:19][CH:20]=4)=[O:15])[CH2:9]3)[CH2:7][CH2:6]2)=[CH:26][CH:27]=[CH:28][C:29]=1[CH2:30][CH:31]=[O:32]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4Cl)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(2-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 80, step e) (0.386 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.125 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.519 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 35 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a pale yellow gum. Yield 0.494 g.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:12][C:13]([F:20])([F:19])[C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:16]2[CH:17]=[CH:18][C:14]([C:13]([F:20])([F:19])[F:12])=[N:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccn(-c2ncccc2C(F)(F)F)n1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 2-chloro-3-trifluoromethylpyridine (3.62 g., 21 mmol), 3-trifluoromethylpyrazole (2.7 g., 20 mmol), and potassium carbonate (6.0 g, 43 mmol) were heated at 100° C. for 18 h. The cooled reaction mixture was added to ice/water (100 mL). The mixture was extracted twice with ether (100 mL) and the combined ether extracts were washed twice with water (100 mL). The organic layer was dried with magnesium sulfate and concentrated to an oil. Chromatography on silica gel with hexanes:ethyl acetate 8:1 to 4:1 as eluent gave the title compound (3.5 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]=[C:32]=[O:33])=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]3)=[O:33])=[CH:28][CH:29]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 1-bromo-4-(isocyanatomethyl)benzene (0.201 g, 0.95 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.272 g, 85%). MS (ESI+) m/z 4.15 (M+H)+; MS (ESI−) m/z 413 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.95 (s, 3H), 4.36 (d, J 5.6, 2H), 7.23 (t, J 5.6, 1H), 7.33 (m, 2H), 7.56 (m, 2H), 7.76 (t, J 7.8, 1H), 7.85 (d, J 8.3, 1H), 8.41 (dd, J 1.5, 7.8, 1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.35 (s, 1H); Anal. Calcd for Cl9H16BrN3O3: C, 55.09; H, 3.89; N, 10.14. Found: C, 55.06; H, 3.56; N, 9.84.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:26]2[CH:20]1[CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:25]=12.[CH3:33][N:34]([Si](C)(C)C)[S:35]([CH2:38][CH3:39])(=[O:37])=[O:36]>>[C:31]([C:28]1[CH:29]=[CH:30][C:24]2[O:23][CH2:22][CH2:21][C@@H:20]([OH:19])[C@H:26]([N:34]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH3:33])[C:25]=2[CH:27]=1)#[N:32]
Reactant: CCS(=O)(=O)N(C)[Si](C)(C)C
Reactant: N#Cc1ccc2c(c1)C1OC1CCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCS(=O)(=O)N(C)[C@@H]1c2cc(C#N)ccc2OCC[C@H]1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
1.5 g of tetrabutylammonium fluoride were added with stirring to a mixture of 4 g of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepine-7-carbonitrile (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 7.0 g of N-methyl-N-trimethylsilylethanesulfonamide. The reaction mixture was then heated for 3 h at 60° C., stirred overnight at RT and poured onto ammonium chloride solution. It was extracted several times with EA, and the organic phase was washed with water and dried over sodium sulfate. After concentration and recrystallization of the solid residue from cyclohexane/EA (1:5), 3.2 g of trans-7-cyano-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepin-4-ol were obtained, m.p. 142-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(O)cc1

Procedure:
To a solution of 4-hydroxyphenylacetic acid (10 g) in methylene chloride (66 mL) and methanol (26 mL) was added p-toluenesulfonic acid (1.25 g), and the resulting solution was heated at reflux overnight. The solvent was evaporated, the residue dissolved in ethyl acetate, and the the solution washed (H2O), dried (MgSO4), and evaporated to give crude methyl 4-hydroxyphenylacetate (10.4 TLC: Rf =0.72, ethyl acetate:dichloromethane (10:90); MS: m/z=167(M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]1[C:27]([CH2:28][C:29](Cl)=[O:30])=[C:26]([F:32])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2>CN(C)C=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:29](=[O:30])[CH2:28][C:27]2[C:18]([F:17])=[C:19]3[C:24](=[CH:25][C:26]=2[F:32])[N:23]=[CH:22][CH:21]=[CH:20]3)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1c(F)cc2ncccc2c1F
Reactant: NNc1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1c(F)cc2ncccc2c1F)NNc1ccc(Cl)nn1

Procedure:
(6-Chloro-pyridazin-3-yl)-hydrazine (531 mg, 3.67 mmol) was added to an oven-dried round-bottom flask and dissolved in dimethylformamide (7 mL) and triethylamine (1.54 ml, 11.01 mmol). The solution was cooled to 0° C. (5,7-Difluoro-quinolin-6-yl)-acetyl chloride (887 mg, 3.67 mmol) was dissolved in dimethylformamide (8 mL) and added to the reaction mixture dropwise. The reaction was complete upon addition of the acid chloride. The solution was concentrated down under vacuo to dryness to afford (5,7-difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide. LCMS [M+H+]=350.0. (5,7-Difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide (1.28 g, 3.67 mmol) was suspended in acetic acid (30 mL) and the solution heated to 60° C. for 16 hours. The mixture was then concentrated in vacuo and the residue dissolved in dichloromethane (125 ml) and washed with saturated NaHCO3 (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was triturated with methanol and the title compound was collected in quantitative via filtration and dried. Analytical data presented in Table 1.