Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[N+:12]([CH2:13][CH2:14][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[CH:8]=3.[OH-].[Na+].[CH3:21][C:22]([CH3:24])=[O:23]>>[CH2:21]([CH:11]1[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[CH:8]=[C:7]2[N:12]1[CH2:13][CH2:14][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=12)[C:22]([CH3:24])=[O:23]
Reactant: c1ccc2c(c1)CC[n+]1cc3ccccc3cc1-2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC1c2ccccc2C=C2c3ccccc3CCN21

Procedure:
In the first step of the reaction scheme, 5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (II) is reacted with acetone in the presence of a base such as sodium hydroxide to give 8-acetonyl-5,6-dihydrodibenzo[a,g]quinolizine compound of the formula (III).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:12]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]2)=[O:24])=[CH:7][CH:6]=1)#[N:11]
Reactant: N#CC#Cc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C#CC#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of 143 mg of (p-hydroxyphenyl)propiolonitrile, 218 mg of trans-4-pentylcyclohexanecarboxylic acid, 227 mg of N,N'-dicyclohexylcarbodiimide and 12.2 mg of 4-(dimethylamino)pyridine in 15 ml of methylene chloride was stirred at room temperature for 105 minutes in a round flask under argon gasification. The yellow heterogeneous mixture was subsequently poured into 30 ml of water and extracted twice with 30 ml of methylene chloride each time. The organic phases were washed in sequence twice with 30 ml of water each time, twice with 30 ml of 5% acetic acid each time and twice with 30 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue (383 mg) on silica gel with 3% ethyl acetate/petroleum ether gave 270 mg (84%) of trans-4-pentylcyclohexanecarboxylic acid p-(2-cyanoethynyl)phenyl ester as colourless crystals. A single crystallization from hexane yielded 219 mg of the ester as colourless platelets (purity 99.7%); m.p. (C-N) 76.8° C., cl.p. (N-I) 153.2° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 86.9 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.6 g.), 2 N aqueous solution of sodium hydroxide (100.2 ml.), methanol (100 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 22.4 g.), mp 176° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31]Cl)[CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][O:19][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:21])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=3)=[O:20])[CH:23]=1
Reactant: ClCCCCc1cccnc1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2nc3ccc(C(=O)OCCCCc4cccnc4)cn3c(=O)c2c1
Temperature: 50 °C
Yield: 44.6 %

Procedure:
A suspension of 0.70 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 0.50 g of 4-(3-pyridinyl)butylchloride, 0.40 g of potassium iodide and 0.39 g of potassium carbonate in 12 ml of dimethylformamide was stirred over night at a bath temperature of 50° C. The reaction mixture was diluted with ethylacetate, washed with water, dried (potassium carbonate) and concentrated. The residue was chromatographed on 75 g of silica gel eluting with ethyl acetate to give 0.46 g of a yellow solid which was recrystallized from ethyl acetate-hexane to give 0.33 g (32%), mp 95°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:18]([CH3:19])[CH3:17])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-3-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 12a was obtained in 72% yield (4.00 g, 16.2 mmol).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].C1S(=O)(=O)CCC1.[O:16]1[CH2:18][C:17]21[CH2:24][O:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH2:19]2>>[N+:7]([C:27]1[CH:26]=[CH:25][C:22]2[O:23][CH2:24][C:17]3([CH2:19][O:20][C:21]=2[CH:28]=1)[CH2:18][O:16]3)([O-:8])=[O:6]
Reactant: c1ccc2c(c1)OCC1(CO2)CO1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc2c(c1)OCC1(CO2)CO1
Temperature: 35 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.11 mole of nitronium tetrafluoroborate and 60 g. tetramethylene sulfone is stirred at 10° C. and 0.1 mole of 3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-2'-oxirane, prepared as described in Example 57, Step A, added during 30 minutes. The cooling bath then is removed and the mixture stirred an additional 20 minutes at 35° C., poured into ice and water, the product extracted with ether, the ether solution dried over magnesium sulfate and evaporated. The product obtained following crystallization from a mixture of chloroform and petroleum ether is 7-nitro-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-2'-oxirane.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13].O.CN(C)[CH:24]=[O:25]>>[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18]([OH:19])=[C:17]([CH:24]=[O:25])[C:16]([CH3:20])=[N:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Temperature: 100 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice-cooled, stirred suspension of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one (8.70 g, 43.0 mmol) in dimethylformamide (18.0 mL) at such a rate as to maintain the temperature below 20° C. After the addition, the mixture was heated at 100° C. for 2 h, then cooled, poured into iced water (200 mL). The resulting mixture was stirred for 18 h, then filtered. The solid was washed with water and dried to give the title compound (7.83 g, 79%) as a cream-coloured powder. MS (ES) m/e 231 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:12][N:11]=[N:10][N:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nnn[nH]1
Reaction time: 5 h
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 5.96 g (0.050 mole) of orthocyanophenol, 9.76 g (0.150 mole) of sodium azide, 20.65 g (0.150 mole) of triethylamine hydrochloride and 60 ml of toluene. The mixture wasreacted for 5 hours in the same manner as in Example 1, giving 7.95 g (0.049 mole) of 5-(2-hydroxyphenyl)-1H-tetrazole (yield 98.0% based on orthocyanophenol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C)C=O>[CH2:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:18]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of 3,4-difluoro-phenol (10 g, 77 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (20 g, 145 mmol) and iodoethane (50 g, 320 mmol, Aldrich). The reaction mixture was heated at refluxing for 48 h. The crude was cooled to room temperature and filtered through a short pad of celite. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:8) to give 4-ethoxy-1,2-difluoro-benzene as colorless oil (Yield 11 g, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](Cl)=[O:18]>O>[CH3:15][O:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:18]
Reactant: NCCCCCCO
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)NCCCCCCO
Yield: 91 %

Procedure:
To a stirred solution of 6-aminohexanol in 50 ml of water basified with 11 g of K2CO3, was added 4.03 g of methylchloroformate at room temperature. After one night the resulting aqueous solution was extracted with 3×50 ml of dichloromethane. The organic phases were combined, evaporated to dryness and the residue was filtered over silica gel. This furnished 1.36 g (yield 91%) of N-methoxycarbonyl-6-aminohexanol as a white solid. Then, to a solution of N-methoxycarbonyl-6-aminohexanol (200 mg) in dichloromethane (5 ml) was added 361 mg of triphenylphosphine and 832 mg of tetrabromomethane.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][C:40]([NH:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:39][C:38]=2[CH:66]([CH3:68])[CH3:67])=[O:35])[C:6]1=[O:69])[CH2:2][CH2:3][CH3:4].Cl.N>CC(C)=O.CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:16]=2)=[C:7]([NH:33][C:34]([NH:36][C:37]2[C:38]([CH:66]([CH3:68])[CH3:67])=[CH:39][C:40]([NH2:46])=[CH:41][C:42]=2[CH:43]([CH3:45])[CH3:44])=[O:35])[C:6]1=[O:69])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2C(C)C)c(-c2cccc(OCCCOCc3ccccc3)c2)c2cccnc21
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)c(-c2cccc(OCCCO)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.8 %

Procedure:
To a solution of N-[1-butyl-4-[3-[3-(benzyloxy)propoxy]phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-tritylaminophenyl]urea (1.60 g, 1.74 mmol) in a mixture of acetone (20 ml) and methanol (20 ml) is added conc. hydrochloric acid (1 ml, 12 mmol) under ice-cooling, and the mixture is stirred at room temperature for 14 hours. The reaction solution is made basic by adding thereto aqueous ammonia under ice-cooling, and extracted with ethyl acetate. The organic layer is washed twice with aqueous sodium hydrogen carbonate solution, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound (1.07 g, 1.58 mmol).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([CH2:15][O:16]C(=O)C)=[N:12][C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([CH2:15][OH:16])=[N:12][C:11]=3[CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCc1nc2cc(-c3ccccc3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1nc2cc(-c3ccccc3)ccc2o1
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Acetic acid (5-phenyl-benzoxazol-2-yl)methyl ester 50 (409 mg, 1.53 mmol) was dissolved in 10 ml of methanol. Finely ground K2CO3 (53 mg, 0.38 mmol) was added. After 3 hrs, the mixture was concentrated then diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried, filtered and concentrated to yield about 251 mg of (5-phenyl-benzoxazole-2-yl)methanol 51.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:23][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: NCCc1ccccc1
Reactant: CC(C)CCc1cccc(C(=O)O)c1
Product: CC(C)CCc1cccc(C(=O)NCCc2ccccc2)c1
Yield: 74.5 %

Procedure:
Using preparation method 1, 96B (288 mg, 1.5 mmol) was reacted with phenethyl amine (276 μL, 266 mg, 2.2 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals (330 mg, 74%). NMR 1H (ppm, CDCl3): 7.52 (s, 1H), 7.44-7.41 (m, 1H), 7.34-7.22 (m, 7H), 6.09 (br. s, 1H), 3.74-3.67 (m, 2H), 2.92 (t, J3=6.9 Hz, 2H), 2.64-2.59 (m, 2H), 1.63-1.40 (m, 3H), 0.92 (d, J3=6.3 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:12][SH:13])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH:8]([CH2:12][S:13][C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CC(CS)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
To a stirring solution of the compound of example 25 (8.10 g; 36.77 mmoles) in dry THF (25 mL) at room temperature, was transferred dropwise a solution of triphenylmethyl chloride (12.30 g; 44.13 mmoles) in dry THF (25 mL). The mixture was stirred at room temperature for 24 hours. The solvent was then evaporated under vacuum and the residue was directly subjected to flash chromatography (SiO2, gradient of 15% ethyl acetate in hexanes to 50% ethyl acetate in hexanes) to give 3.50 g (20.6% yield) of the pure desired protected compound: 1H NMR (CDCl3, 400 MHz) 7.50 (d, 6H), 7.29 (m, 9H), 2.58 (m, 5H), 1.45 (S, 9H); 13C NMR (CDCl3, 100 MHz) □ 179.31, 170.32, 144.34, 129.47, 127.93, 127.81, 126.75, 81.03, 66.93, 40.73, 36.13, 32.66, 27.90.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14](=[O:25])[N:15]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=3)[S:10][C:3]=12.[F:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[OH:36].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[O:36][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14](=[O:25])[N:15]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: O=c1ncc(-c2cc3nccc(Cl)c3s2)cn1CCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1ncc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1CCN1CCOCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of the pyridone 414 (236 mg, 0.63 mmol) in Ph2O (1.3 mL) was added 2-fluoro-4-nitrophenol (197 mg, 1.26 mmol) and K2CO3 (173 mg, 1.26 mmol). The mixture was stirred at 100° C. for 1 h, then at 180° C. for 2 h, cooled and evaporated under reduced pressure. The residue was purified by flash chromatography with a gradient of methanol (2-10%) in dichloromethane to give title compound 415 (81 mg, 26% yield). MS (m/z): 498.0 (M+H). 1H NMR (DMSO-d6) δ (ppm): 9.16 (d, J=3.3 Hz, 1H), 8.66 (d, J=3.3 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 8.47 (dd, J=10, 2.5 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 7.69 (t, J=8.6 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 4.02 (t, J=5.5 Hz, 2H), 3.58-3.43 (m, 4H), 2.59 (t, J=5.5 Hz, 2H), 2.50-2.41 (m, 4H).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][CH2:5][S:4][CH2:1][C:2]#[CH:3])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCSCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CCSCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-[2-(prop-2-ynylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(prop-2-ynylthio)propionic acid and 3-t-butyl-3-hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([Cl:13])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:18][O:19][CH2:20]Cl.O>C1COCC1>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([Cl:13])[C:5]([O:12][CH2:18][O:19][CH3:20])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCl
Reactant: COC(=O)c1cc(Br)c(OC)c(Cl)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1c(C(=O)OC)cc(Br)c(OC)c1Cl
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of methyl 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoate (5.00 g) in THF (120 mL) was added sodium hydride (1.01 g) under ice-cooling, and the mixture was stirred for 1 hr under nitrogen atmosphere. To this reaction mixture was added dropwise chloromethyl methyl ether (1.63 g), and the mixture was stirred at 20° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.08 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:12][S:13]([O:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:15])=[O:14]
Reactant: OC1CCc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
2-tetralinol (0.86 g) in pyridine (5 ml) was stirred with cooling to 0°. Methylsulphonyl chloride (0.8 g) was added dropwise while maintaining the temperature at 0°. The mixture was then allowed to warm to room temperature and was stirred for 0.5 hour. The mixture was then poured on to ice and immediately a white precipitate formed; the mixture was allowed to stand overnight. The precipitate was then filtered off, washed with water and air-dried to give 2-methylsulphonyloxytetralin (0.72 g), m.p. 60°-62°.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Br:17]Br>CO>[Br:17][CH2:9][C:8](=[O:10])[CH2:7][CH2:6][N:5]1[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]2[C:1]1=[O:16]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 130 g (0.6 mole) of 4-phthalimido butan-2-one (7a) in 1000 ml of absolute methanol is added 96 g (0.6 mole) of bromine and the reaction mixture is stirred for 24 hours at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:14])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3×250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97% yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1.FC(F)(F)C([O-])=O.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)=[O:33].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:24][C:25]1[C:29]([Cl:30])=[C:28]([CH3:31])[NH:27][C:26]=1[C:32]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=2)[CH2:37][CH2:36]1)=[O:33]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2ccccc2n1
Yield: 47.7 %

Procedure:
As described for the synthesis of Example 264, ethyl 4-chloroquinazoline-2-carboxylate (690 mg), 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 1.7 g), and K2CO3 (1.7 g) in 20 ml tert-butanol were combined to yield 662 mg grey solid.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[O:24][C:25](=O)[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>C(O)(=O)C>[CH3:22][C:23]1[N:21]([C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)[C:25](=[O:24])[C:26]2[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:28]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Nc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1

Procedure:
A solution of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-amine (Example 89A, 27mg, 0.089 mmol) and 2-methyl-4H-benzo[d][1,3]oxazin-4-one (Example 89B, 14.39 mg, 0.089 mmol) in acetic acid (1 mL) was heated in a microwave reactor to 160° C. for 20 minutes. The mixture was concentrated under reduced pressure and chromatographed on silica gel column eluting with 2% (9:1 methanol:concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.45-1.53 (m, 2H), 1.58-1.70 (m, 4H), 1.98-2.12 (m, 1H), 2.26-2.30 (m, J=1.36 Hz, 3H), 2.29-2.37 (m, 1H), 2.42-2.58 (m, 4H), 2.94-3.10 (m, J=8.48 Hz, 1H), 3.39-3.51 (m, 1H), 3.52-3.64 (m, 1H), 3.71-3.94 (m, 2H), 7.14 (dd, 1H), 7.43-7.51 (m, 2H), 7.66-7.72 (m, 2H), 7.74-7.81 (m, 1H), 8.24-8.31 (m, 1H); MS (DCI/NH3) m/z 387 (M+H)+.