Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[OH:10])=[CH:5][C:4]=1[F:35])#[N:2]>C(Cl)Cl.O=[Mn]=O>[C:29]1([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:14]2[CH:15]=[C:11]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:35])[CH:5]=3)=[O:10])[N:12]=[CH:13]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F

Procedure:
To a solution of (4-cyano-3-fluorophenyl)[1-(triphenylmethyl)imidazol-4-yl]methanol from Step D (10.0 g, 21.8 mmol) in CH2Cl2 (300 mL) was added MnO2 (18.9 g, 218 mmol) and the resulting mixture was heated to reflux for 18 hrs. The mixture was allowed to cool, then filtered through a pad of celite, washing with CH2Cl2. The filtrate was concentrated under reduced pressure to provide the titled product as a white solid that was sufficiently pure for use in the next step.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1([F:30])[CH2:25][CH:24]([C:26]([NH:28][NH2:29])=[O:27])[CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:29][NH:28][C:26]([CH:24]1[CH2:25][C:22]([F:30])([F:21])[CH2:23]1)=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C1CC(F)(F)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.25 g, 0.90 mmol) in dry dichloromethane (30 mL) were added 3,3-difluorocyclobutanecarbohydrazide 282 (0.20 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give 283 (0.32 g, 87%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Reactant: O=C1CCC(=O)O1
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)CCC(=O)O)CC1(C)C
Reaction time: 2 h
Yield: 75 %

Procedure:
Following the general procedure of Example 9, 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine is added to succinic anhydride over a 30-minute period. The reaction mixture is then stirred for two hours. The crude product is purified by flash chromatography on silica gel (9:1, ethyl acetate:methanol) followed by trituration with heptane to give the title compound in 75% yield as a white powder melting at 96°-103° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C=CC=CC=1.ClC(OCC)=O>C(N(CC)CC)C>[CH2:1]([C:7]1[CH:19]=[CH:18][C:10]([CH:11]2[N:13]=[CH:14][C:15](=[O:17])[O:16]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)NCC(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCc1ccc(C2N=CC(=O)O2)cc1

Procedure:
In a 50 ml-three-necked flask, 1.00 g (3.80 mM) of N-(4-hexylbenzoyl)glycine and 19 ml of dry benzene were placed. To the mixture, 0.53 ml (3.81 mM) of triethylamine was added at room temperature under stirring, followed by addition of 0.37 ml (3.87 mM) of ethyl chloroformate and further stirring for 20 minutes at room temperature to precipitate triethylamine hydrochloride. The resultant hydrochloride was filtered off and the solvent of the filtrate was distilled off. The residue was dried under reduced pressure to obtain 2-(4-hexylphenyl)-5-oxazolone.
Reaction SMILES: [CH3:1][CH2:2][OH:3].[K].Cl[C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1>O>[CH2:2]([O:3][C:6]1[C:7]([C:16]([F:17])([F:19])[F:18])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH2:12])[CH:11]=1)[CH3:1]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [K]
Solvent: O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Yield: 96 %

Procedure:
To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion and the resulting dark red mixture was stirred at 55-60° C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HC1 to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60° C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M−H].
Reaction SMILES: [F:1][C:2]([F:18])([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[CH2:19]([OH:22])[CH:20]=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O.C([O-])(=O)C.[Ag+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:18])([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:3]1[CH:8]=[CH:7][C:6](/[CH:21]=[CH:20]/[CH2:19][OH:22])=[CH:5][CH:4]=1
Reactant: C=CCO
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(I)cc1
Agent: [Ag+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(/C=C/CO)cc1
Temperature: 25 °C

Procedure:
To a solution of diethyl difluoro(4-iodophenyl)methylphosphonate T. R. Burke Tetrahedron Letters, 551,1994, (2.50 g, 6.91 mmol) in DMF (25 ml) was added allyl alcohol (1.3 ml), silver acetate (1.1 g), palladium acetate (0.075 g), and triphenyl phosphine (0.175 g). The reaction mixture was refluxed for 2 hours. After cooling to room temperature the reaction was diluted with water and extracted with ethyl acetate. The mixture was filtered through a pad of celite. The organic layer was separated and washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified using flash chromatography with hexane/ethyl acetate 75% to give 0.6 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([S:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[CH:18][C:17]([CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)=[CH:16]2)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.Cl>ClCCl.O1CCOCC1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[N:15]([S:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:38])=[O:37])(=[O:14])=[O:13])[CH:16]=[C:17]([CH2:27][NH:28][CH3:29])[CH:18]=1
Reactant: CN(C)C(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)N(C)C)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl ((1-((3-(2-(dimethylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 9c (54 mg, 0.10 mmol) was dissolved in 4 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of a solution of hydrogen chloride in 1,4-dioxane (4 N, 4 mL). After removing the ice bath, the reaction solution was stirred at room temperature for 3h. A saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7 to 8, 5 mL of water were added, and then the reaction solution was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N,N-dimethylacetamide 9 (20 mg, a yellow solid) in 45% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CCCOc1ccc(CO)cc1[N+](=O)[O-]
Yield: 86.6 %

Procedure:
4-Hydroxy-3-nitrobenzyl alcohol (1 g, 5.91 mmol) is treated with 1.44 g (7.39 mmol) of ethyl 4-bromobutyrate, 2.86 g (20.69 mmol) of potassium carbonate and a catalytic amount (88 mg 0.59 mmol) of sodium iodide as described in Preparation 3 to give 1.45 g of 4-[4-(hydroxymethyl)2-nitrophenoxy]butanoic acid, ethyl ester as a light yellow oil (86%). The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 3400, 1730, 1710, 1630, 1580 cm-1 ; MS (CI) m/e 84 (M+H), 238; Analysis calculated for C13H17 O6N: C, 55.12; H, 6.05; found: C, 55.36; H, 6.03.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([CH2:29][CH2:30]O)[N:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Br:2][CH2:30][CH2:29][C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=2)[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2nc(CCO)nc3cc(OC)c(OC)cc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(-c2nc(CCBr)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 75 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Phosphorus tribromide (PBr3)(0.95 g) was added dropwise to a solution of 4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-6,7-dimethoxyquinazoline (2.6 g) in benzene (50 ml) at room temperature. The mixture was stirred at 75° C. for 1 hour, poured into ice-cold water, neutralized with an aqueous saturated solution of sodium bicarbonate, and then extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (3:1, v/v) gave 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.1 g, 37%). This was recrystallized from ethyl acetate. Colorless needles, mp. 166°-167° C.
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[N:7]2[N:6]=[C:5]1[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:39].[Na+].OO>C1COCC1.O.[Cl-].[Na+].O>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH2:9][CH:8]3[C:4]([CH2:1][CH2:2][CH2:3][OH:39])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:5]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:6][N:7]3[C:12]=2[CH:13]=1
Reactant: [OH-]
Reactant: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(F)ccc3OCC21
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Allyl-8-fluoro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-6; a racemic mixture, 3.7 g, 9.35 mmol) was dissolved in anhydrous THF (50 mL) and treated with a 0.5M solution of 9-BBN (37.4 mL, 18.7 mmol) and stirred at 50° C. for 2 h. The reaction was cooled to 0° C. and treated with 3N NaOH (5 mL) and 30% H2O2 in water (5 mL), and stirred an additional hour. Upon completion, the reaction was treated with brine (50 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude residue was subjected to flash column chromatography (ISCO Redisep 120 g SiO2 column, 0-100% EtOAc/hexanes gradient) to provide pure 8-fluoro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (5-7; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.36-7.19 (m, 5H), 7.15 (dd, J=9.6, 2.9 Hz, 1H), 6.78 (dd, J=8.8, 5.1 Hz, 1H), 6.56 (dt, J=8.8, 3.0 Hz, 1H), 4.00 (dd, J=10.5, 3.5 Hz, 1H), 3.91 (s, 3H), 3.76 (m, 2H), 3.56 (dd, J=11.0, 3.3 Hz, 1H), 3.31 (s, 3H), 2.92 (t, J=10.6 Hz, 1H), 2.60 (dt, J=12.1, 4.9 Hz, 1H), 2.42 (dt, J=12.1, 4.9 Hz, 1H), 1.81 (m, 1H), 1.62 (m, 1H); MS (M+H+, C22H24FN3O4) 414.3 found 414.4 required.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([C:12]#[N:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]#[N:13])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC[O-]
Agent: [Na+]
Product: N#CC(=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution sodium ethoxide is added benzyl cyanide and N-benzyl-4-piperidone (XI-1) and the reaction is run at 85° C. for 3 h. Workup with concentrated hydrochloric gives the intermediate (1-benzyl-piperidin-4-ylidene)-phenyl-acetonitrile which is treated with potassium cyanide. The obtained intermediate N-benzyl protected spiropiperidine is treated with hydrogen and palladium on charcoal. After stirring in a hydrogen atmosphere at room temperature (CF3)2C6H3COCl is added to give a compound of formula I-12.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16].C1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl.O>[Cl:17][C:15]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:16]
Reactant: CC(C)[C@H](Nc1ccccc1)C(=O)O
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)[C@@H](C(=O)O)N(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the m-phenoxybenzyl ester of N-phenyl valine (1.2 mmole) is added 12.5% phosgene in benzene (2.3 mmole), cooled in an ice bath, and then dimethylaminopyridine (1.22 mmole). The reaction mixture is stirred at RT for 3 days. Then one ml of benzene, 0.15 g of dimethylaminopyridine and 2 ml of phosgene are added and the reaction stirred overnight at RT. The reaction is worked up using chloroform/water. The chloroform layer is washed with dilute sulfuric acid, water and brine, dried over sodium sulfate and filtered. The solvent is removed by rotoevaporation to yield the m-phenoxybenzyl ester of N-chloroformyl,N-phenyl valine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:5][CH:4]=1.[Br:18]N1C(=O)CCC1=O>CO>[Br:18][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[C:7]([CH3:9])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2cccc(C#N)c2)c(C)n1
Solvent: CO
Product: COc1nc(C)c(-c2cccc(C#N)c2)cc1Br
Temperature: 25 °C
Reaction time: 66 h
Yield: 29.5 %

Procedure:
A mixture of 3-(6-methoxy-2-methylpyridin-3-yl)benzonitrile (3.00 g, 13.4 mmol), N-bromosuccinimide (2.89 g, 16.08 mmol) and methanol (150 mL) is stirred 66 hr at room temperature. The solids are collected by filtration to give 3-(5-bromo-6-methoxy-2-methylpyridin-3-yl)benzonitrile (1.20 g, 30%) as a white solid. LC/MS RT 4.19 min; MS m/e=303/305 (M); NMR (CDCl3) 7.65 (2H, m), 7.60 (1H, s), 7.56 (2H, m), 4.02 (3H, s), 2.37 (3H, s).
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[C:10]([I:14])[C:11]([F:13])=[CH:12][C:7]=2[CH:6]2[CH2:15][CH:4]([CH2:5]2)[C:3]1=[O:16].CS(C)=[O:19]>>[F:13][C:11]1[C:10]([I:14])=[CH:9][C:8]2[C:2](=[O:19])[C:3](=[O:16])[CH:4]3[CH2:15][CH:6]([C:7]=2[CH:12]=1)[CH2:5]3
Reactant: CS(C)=O
Reactant: O=C1C2CC(C2)c2cc(F)c(I)cc2C1Br
Product: O=C1C(=O)C2CC(C2)c2cc(F)c(I)cc21

Procedure:
A solution of crude 9-bromo-3-fluoro-2-iodo-6,7-dihydro-5H-5,7-methanobenzo[7]annulen-8(9H)-one (1.400 g at 87% purity LCMS-UV215) in dimethylsulfoxide (15 mL) was warmed to 80° C. for 1 hr under an atmosphere of nitrogen. Evaporation in vacuo furnished the crude title compound (2.855 g) containing residual DMSO as a golden-brown oil which was carried through to the next synthetic step without further purification: 1H NMR (500 MHz, CDCl3) δ 2.25-2.30 (m, 2H), 3.12-3.18 (m, 2H), 3.48-3.51 (m, 1H), 3.61-3.65 (m, 1H), 6.94 (d, J=8.2 Hz, 1H), 8.55 (d, J=6.6 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[CH2:27]([C:29]1[S:30][CH:31]=[C:32](/[CH:34]=[CH:35]/[C:36]2[C:37]([OH:47])=[N:38][N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:40]=2)[N:33]=1)[CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:27]([C:29]1[S:30][CH:31]=[C:32](/[CH:34]=[CH:35]/[C:36]2[C:37]([O:47][CH2:2][C:3]3[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=5)[C:18]#[N:19])[O:12][C:13]=4[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=3)=[N:38][N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:40]=2)[N:33]=1)[CH3:28]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C#N)c4)oc3C)c(OC)c2)cs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A mixture of 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (3.32 g), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (2.95 g), potassium carbonate (1.37 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4, v/v) to give 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzonitrile (4.10 g, yield 72%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-140° C.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH:17](=O)[CH2:18][CH3:19].C([BH3-])#N.[Na+]>C(O)C>[CH2:17]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH3:19]
Reactant: CCC=O
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: CC[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCCNC(C(=O)OCC)C(=O)OCC
Yield: 115.5 %

Procedure:
Diethyl aminomalonate (21.1 g, 0.1 mol) was dissolved in ethanol and sodium ethoxide in ethanol (50 mL of I M) was added. Propionaldehyde (6.6 g, 0.11 mol) and sodium cyanoborohydride (3.6 g, 0.058 mol) were added to the stirred solution. After 30 minutes additional propionaldehyde (6.0 g) and sodium cyanoborohydride (2.6 g) were added to complete the reaction. The solution was evaporated, and the residue was partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave 25.1 g of diethyl (propylamino)malonate. This was mixed with di t-butyl dicarbonate (34 g, 0.156 mol) and the mixture was heated at 100° C. for 1 hour. The crude product was chromatographed on silica gel using ethyl acetate:hexane as the eluant to give 21.2 g of diethyl (N-(1,1-dimethylethoxycarbonyl)propylamino)malonate as an oil.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])(=[O:4])=[O:3].[OH-].[Na+]>C1COCC1>[CH3:19][O:18][C:16]([C:8]1[CH:9]=[C:10]([CH:15]=[C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=1)[C:11]([OH:13])=[O:12])=[O:17]
Reactant: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a 0° C. solution of dimethyl 5-[(methylsulfonyl)oxy]isophthalate (1.37 g, 4.75 mmol) in THF (150 mL) was added 0.1 N NaOH solution (46.6 mL, 4.66 mmol) dropwise in an addition funnel. Reaction stirred at 0° C. for 2 hours and then warmed to room temperature. Reaction was concentrated in vacuo. Crude material was acidified with 1N HCl and extracted with EtOAc (3×). The combined organics were dried with MgSO4, filtered, concentrated and purified by flash chromatography (40 g silica, 0-5% MeOH/DCM/1% acetic acid) to give 0.74 g (57%) of 3-(methoxycarbonyl)-5-[(methylsulfonyl)oxy]benzoic acid. 1H NMR (400 MHz, CDCl3) δ 8.72 (m, 1H), 8.18 (m, 2H), 3.98 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][CH:2]=1.[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](=[O:23])[CH2:21]Br)([O-:16])=[O:15]>CN(C=O)C>[N+:14]([C:17]1[CH:18]=[C:19]([C:20](=[O:23])[CH2:21][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2]2)[CH:24]=[CH:25][CH:26]=1)([O-:16])=[O:15]
Reactant: O=c1[nH]cnc2ccccc12
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2ccccc2c1=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4(3H)-quinazolinone (2.19 g, 15.0 mol) in anhydrous DMF (10 mL) was added NaH (60% dispersion in mineral oil, 0.719 g, 18.0 mmol) in two portions with caution. The mixture was stirred at rt for 30 min. 3-Nitrophenacyl bromide (4.39 g, 18.0 mmol) was added and the resulting suspension was stirred at rt for 16 h. Solvent was removed under reduced pressure. To the residue were added water (10 mL) and 4 N HCl (aq) to adjust the pH to ≈6. The solid material was collected by filtration, washed with water (20 mL) and dichloromethane (3×20 mL) to afford the title compound as a white powder. 1H-NMR (CD3OD, 400 MHz): δ=5.70 (d, J=10.0 Hz, 2H), 7.60 (d, J=7.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.86-7.91 (m, 2H), 8.25 (d, J=8.0 Hz, 1H), 8.30 (s, 1H), 8.51-8.58 (m, 2H), 8.90 (t, J=1.2 Hz, 1H). MS (ES+): m/z 310.06 [MH+]. HPLC: tR=2.90 min (ZQ2000, polar—5 min).