Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([NH2:13])=[O:12].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[NH:10][C:11](=[O:12])[NH:13][C:14]12[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(F)c(NC(N)=O)c1
Reactant: O=C1CCCCC1
Product: COc1ccc(F)c2c1C1(CCCCC1)NC(=O)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a stirred solution of polyphosphoric acid (20 g) at 100° C. was added N-(2-fluoro-5-methoxyphenyl)urea (900 mg, 4.89 mmol) over 5 minutes followed by cyclohexanone (719 mg, 7.33 mmol) in one portion under N2. The mixture was stirred at 100° C. for 2 hours, cooled to 35° C. and quenched into water (400 mL). The crude product was filtered and washed with water (100 mL). The isolated solid was slurred in a mixture of tert-butylmethylether (8 mL) and ethyl acetate (4 mL) at 50° C. for 10 minutes, filtered, washed with tert-butylmethylether (10 mL) and dried in vacuo at 40° C. to give 8′-fluoro-5′-methoxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one (900 mg, 70%) as a light-brown solid, purity (97.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[F:16][CH:17]([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([CH:17]([F:16])[F:27])=[CH:26][CH:25]=2)=[C:3]([OH:9])[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(Cl)c1ccc(C(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(difluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]([CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19])=[N+:12]=[N-:13].C(N(CC)CC)C>ClCCl.O>[N:11]([CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=[O:19])=[N+:12]=[N-:13]
Reactant: CC(C)(CCO)CCN=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(CC=O)CCN=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
Step D To a solution of oxalyl chloride (0.24 mL, 2.7 mmol) (Aldrich) in dichloromethane (12 mL) at −78° C. was added the solution of dimethyl sulfoxide (0.38 mL, 5.5 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 5-azido-3,3-dimethyl-pentan-1-ol (0.39 g, 2.5 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (1.2 mL, 9 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-azido-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.38 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]([CH3:25])[CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH:11]=[C:10]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:8].O.C(OCC)(=O)C>C1COCC1>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:9]2[C:7](=[O:8])[CH2:6][C@@H:5]([CH3:25])[CH2:4][C:3]([OH:26])=[O:2])=[CH:13][CH:14]=1
Reactant: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@@H](C)CC(=O)OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@@H](C)CC(=O)O
Reaction time: 30 h

Procedure:
To the solution of 5-(6-Chloro-2-hexyl-indol-1-yl)-3-(R)-methyl-5-oxo-pentanoic acid methyl ester in THF was added 1.2N HCL and was stirred at 60 0 C for 30 hours. The reaction mixture was then treated with water and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:8][C:9]3[CH:15]=[C:14]([CH:16]([C:20]#[N:21])[C:17]([CH3:19])=[O:18])[CH:13]=[CH:12][C:10]=3[O:11][C:3]=12.[CH3:22]I>CN(C)C=O>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:8][C:9]3[CH:15]=[C:14]([C:16]([C:20]#[N:21])([CH3:22])[C:17](=[O:18])[CH3:19])[CH:13]=[CH:12][C:10]=3[O:11][C:3]=12
Reactant: CC(=O)C(C#N)c1ccc2c(c1)Cc1cccnc1O2
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)C(C)(C#N)c1ccc2c(c1)Cc1cccnc1O2

Procedure:
2.9 g of sodium salt of 1-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-1-cyano-acetone is dissolved in 15 ml of dried dimethylformamide, 1.6 g of methyl iodide is added to the solution with stirring, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is concentrated, and water is added to the oily residue. The crystalline precipitate is filtered off and recrystallized from ethanol to give 2.2 g of 3-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)-3-cyano-2-butanone as white needles melting at 163.5°-164.5°C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CCCCO>[CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc[nH]c12
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: c1ccc(CSc2nc(Nc3ccccc3)c3[nH]cnc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzylthio-6-chloropurine (3.9 g) and aniline (3.42 g) in n-BuOH (100 ml) in the presence of triethylamine (7.5 ml) were refluxed for 2 h. Reaction mixture was cooled to room temperature, dried at a rotary vacuum evaporator, cooled with ice and 400 ml water was added with vigorous shaking. At standing overnight at −16° C. crude dark-brown solid was formed, which was dried into constant weight and chromatographically purified over 100 g silica packed in chloroform. The column was eluted with 500 ml 100% chloroform followed by 500 ml 1.25% MeOH/chloroform and then 1.5 L 2.5% MeOH/chloroform; 100 ml fractions collected and fractions 12 to 15 were dried to yield light-brown solid which were recrystallized from MeOH in the presence of active carbon. Yield 1.18 g of white, amorphous solid. TLC (2.5% MeOH/chloroform) shows only a single spot with no contaminants. HPLC purity: 98+%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]2(OCC[O:7]2)[CH2:5][N:4]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3]1=[O:19].Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:20][C:2]1([CH3:1])[C:6](=[O:7])[CH2:5][N:4]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3]1=[O:19]
Reactant: C[C@H](c1ccccc1)N1CC2(OCCO2)C(C)(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)=O
Product: C[C@H](c1ccccc1)N1CC(=O)C(C)(C)C1=O
Yield: 77.4 %

Procedure:
A mixture of 18.23 g of 9,9-dimethyl-8-oxo-7-[1-(R)-phenylethyl]-7-aza-1,4-dioxaspiro[4.4]nonane, 70 ml of 1N hydrochloric acid and 20 g of p-toluenesulfonic acid in 250 ml of acetone was heated under reflux for 20 hrs. During the reaction, 20 g of p-toluenesulfonic acid was further added. Solvent was removed under reduced pressure and the residue was extracted with chloroform. The extract was washed with a saturated sodium bicarbonate aqueous solution and dried. Solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (300 g of silica gel in a column) while eluting with a mixture of n-hexane and ethyl acetate (4:1, v/v) to yield 11.85 g of the titled compound.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromoheptane (0.199 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), brine (1× 30 mL), dry the organic layer over NaSO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 382.2 (M+H)+, HRMS calcd for C23H32N3O2 382.2495 (M+H)+, found 382.2489, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.6 min, 98.6% purity.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.P([O-])([O-])([O-])=O.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)O
Yield: 58 %

Procedure:
To a solution of 345 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 34 dissolved in 20 ml of acetone was added 220 ml of 0.1M phosphate buffer of pH 8. While the mixture was stirred, 24 mg of pig liver esterase was added thereto, and the mixture was stirred at 30-35° C. for 150 hours. After the pH was adjusted to 4 with 0.1N hydrochloric acid, ammonium sulfate was added to saturation and ethyl acetate was added, followed by filtration. The filtrate was extracted with ethyl acetate, and the organic layers were combined and washed with saturated aqueous sodium chloride. The product was dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel chromatography to give 193 mg (yield 58%) of 2-methylthio-5-(6-carboxyhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13][CH:14]([OH:17])[CH2:15]O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:17][CH:14]([CH2:13][Cl:12])[CH2:15][O:11]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Yield: 99 %

Procedure:
97.0 g (0.597 mol) of 4-t-butylcyclohexanone and 134.7 g (1.184 mol) of 3-chloro-1,2-propanediol are dissolved in 1100 ml of toluene in the presence of 11.5 g (0.060 mol) of PTSA. The mixture is brought to reflux for 6 hours while removing the water formed using a Dean-Stark trap. The reaction mixture is brought to room temperature and washed twice with 1500 ml of an aqueous solution containing 5% of NaHCO3. The organic phase is dried over MgSO4 and concentrated under vacuum. The residual oil is used directly in the following step (yield: 99%; NMR analysis)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].C1(C)C=CC=CC=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CN(C)CCCCl
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN(C)C)c(C=O)c1

Procedure:
2-Hydroxy-5-methoxybenzaldehyde (31.2 g) in 170 ml of dimethylformamide is treated first with 10.1 g of 50% sodium hydride, then with 160 ml of a 2 N toluene solution of 3-dimethylaminopropyl chloride, following the procedure described in Example 1A, yielding 34.1 g of the title compound, boiling point 149°-155° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2noc3ccsc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Oc1ccc(-c2noc3ccsc23)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
Treat a stirred solution of 3-(4-methoxyphenyl)thieno[2,3-d]isoxazole (9.10 g, 0.0394 mol) in 1,2-dichloroethane (100 mL) portionwise with aluminum chloride (15.74 g, 0.118 mol). The mixture is stirred at 70° C. for 1.5 hours, cool to room temperature, and decant into a mixture of concentrated hydrochloric acid (50 mL) and ice (160 g). Stir the mixture for 0.5 hour, filter through Celite, separate the phases and extract the filter cake with dichloromethane. Also use the dichloromethane extract to extract the aqueous phase. Combine the organic phases, wash twice with water, dry (Na2SO4), filter and evaporate. Purify the crude material by flash chromatography on silica gel using gradient elution with 1 to 2% methanol in dichloromethane. Concentrate the desired fractions to afford the title compound as a tan solid (7.1 g, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-n2cccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 79.2 %

Procedure:
A charge of 134.6 g (0.500 mol) of 2,5-dichloro-4′-fluorobenzophenone, 50.3 g (0.750 mol) of pyrrole, 76.0 g (0.550 mol) of potassium carbonate and 840 mL of dehydrated N,N′-dimethylacetamide was weighed into a 2-L three-neck flask equipped with a stirrer, a thermometer, a cooling tube and a nitrogen gas introducing tube. The reaction solution was heated under nitrogen atmosphere to 100° C. for 3 hours using an oil bath. After the disappearance of raw materials was confirmed by thin layer chromatography, the reaction solution was left to cool to room temperature. The reaction solution was then gradually added to 3 L of water to coagulate a product, which was filtered. The product obtained by filtration was dissolved in 2.5 L of toluene, which was washed with brine using a separating funnel until an aqueous layer became neutral. After the organic layer was dried over magnesium sulfate, the solvent was removed by an evaporator. A crude yield was 133.3 g. A mixed solvent of hexane and ethyl acetate was used for recrystallization to yield 125.3 g (0.396 mol) of a purified product targeted in 79.3% yield.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:23])[N:19]=[CH:20][C:21]=3[Br:22])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Br:22][C:21]1[CH:20]=[N:19][N:18]([CH3:23])[C:17]=1[C:15]1[CH:14]=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3c(Br)cnn3C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(-c3c(Br)cnn3C)ccc21
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-7-(4-bromo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (37 mg, 0.089 mmol) in methanol (2 mL) was treated with of 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and the solvent evaporated. Flash chromatography (0-15% MeOH in CH2Cl2, silica) resulted in 28 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.50 (s, 1 H), 7.25 (d, J=8 Hz, 1 H), 7.17 (d, J=8 Hz, 1 H), 7.10 (s, 1 H), 3.83 (s, 3 H), 3.17 (m, 1 H), 3.1−2.9 (m, 8 H), 2.80 (dd, J=7, 13 Hz, 1 H), 2.48 (bs, 1 H), 1.40 (d, J=8 Hz, 3 H). MS calculated for C15H18BrN3+H: 320, observed: 320.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:5][CH:4]=1.CN(C=O)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O>[O:14]=[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=2)[CH2:13][CH2:12][N:11]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCCN1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Sodium hydride (60% in oil, 0.40 g, 10.1 mmol) was added to a mixture of 1-(4-pyridyl)-2-imidazolidinone (1.5 g, 9.2 mmol) and DMF (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. Successively, tert-butyl bromoacetate (2.2 g, 11.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (5:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.7 g, 68%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26](O)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)O)cnn4C)ccn3n2)c1
Reactant: C1COCCN1
Product: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCOCC5)cnn4C)ccn3n2)c1

Procedure:
This compound was prepared in the same manner as described in example 75 starting from 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid (Example 75, step e) (1.0 g, 2.55 mmol) and morpholine (245 ul, 2.80 mmol). Off-white solid (937 mg, 80%). LC-MS: m/z=462.6 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15]>C1C=CC=CC=1>[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]1([CH3:18])[CH2:14][O:15][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: CC(CO)(CO)OCc1ccccc1F
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)COC2(CCCCC2)OC1

Procedure:
Using the procedure of Example 51, cyclohexanone and 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol were reacted, using benzene as solvent, to give 3-(2-fluorobenzyloxy)-3-methyl-1,5-dioxaspiro[5.5]undecane, b.p. 170°-174°/0.03 mm, nD25 1.5081. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1.Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=2)=[C:6]([CH3:11])[CH:5]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1Oc1ncc([N+](=O)[O-])cc1C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 1.08 g, 27 mmol) was washed 3× with hexanes then a solution of 4-chloro-2-methylphenol (3.50 g, 24.5 mmol) dissolved in tetrahydrofuran (40 mL) was added. The solution was stirred for 20 minutes then 2-chloro-3-methyl-5-nitropyridine (4.02 g, 23.3 mmol) was added and the reaction mixture was heated to reflux for 3 hours. After cooling, the mixture was concentrated in vacuo then dissolved in ethyl acetate and washed with water, 3× with saturated NaHCO3 and saturated NaCl then dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:28]([O-:30])=[O:29])=[C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].C1N=C[N:33](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[OH:1][C:2]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:28]([O-:30])=[O:29])=[C:16]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([NH2:33])=[O:27])[CH2:23][CH2:24]3)[CH:17]=2)[CH2:9][CH2:10]1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(=O)O)CC3)c2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(N)=O)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid (0.53 g, 1.263 mmol) in DMF (5 mL) was added CDI (0.410 g, 2.53 mmol). The reaction was stirred at RT for 1 hour, and then concentrated aqueous ammonium hydroxide (0.098 mL, 2.53 mmol) was added, and the reaction was stirred overnight. After 16 hours, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with 50-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxamide as an orange powder (0.39 g, 73.8% yield). MS, m/z (C22H34FN4O4): calcd, 418.3. found, 419.1 [M+H].