Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+].Cl.[OH-].[Na+]>C1COCC1.COC(C)(C)C.ClCCl>[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([CH:21]([NH2:22])[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1
Reactant: N#CC1CCC2(CC1)OCCO2
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(N)C2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C

Procedure:
Under argon, 4-methoxy-phenylmagnesium bromide (0.5M in THF, 24 mL, 12 mmol) was added to a solution of 1,4-dioxa-spiro[4.5]decane-8-carbonitrile (1.0 g, 6 mmol) in THF (100 mL). The mixture was stirred under reflux for 16 hours. The reaction mixture was then cooled to 0° C. Saturated sodium sulphate solution was added dropwise until no more precipitate formed. The precipitate was removed by filtration and washed with THF. The combined organic phases were stirred with sodium borohydride (452 mg, 12 mmol) overnight at 25° C. The reaction mixture was then diluted with t-butyl methyl ether (100 mL) and treated with 0.05M aqueous hydrochloric acid (three times with 100 mL). The combined aqueous phases were adjusted to alkaline pH with a 6M aqueous sodium hydroxide solution with cooling, before extraction with dichloromethane gave a solution of the desired product which was used directly in the next stage. Rt=0.74 min (Method 5). Detected mass: 278.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3.[N-:21]=[N+:22]=[N-:23].[Na+]>C(O)(C)C.O.[Cl-].[Zn+2].[Cl-]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]1[NH:23][N:22]=[N:21][N:19]=1)=[CH:6]3
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(-c4nnn[nH]4)cn1c23
Temperature: 110 °C
Yield: 60.2 %

Procedure:
To a mixture of nitrile 5 (40 mg, 0.14 mmol) in isopropanol and water (1:1 v/v, 15 ml) were added 20 mg of sodium azide (0.29 mmole) and 22 mg of zinc chloride (0.29 mmole). The mixture was heated to 110° C. for 18 h. The precipitates were collected by filtration and washed with water. The solid was dried under vacuum to give 27 mg (60% yield) of 13. This title compound was used without further purification in the next step.
Reaction SMILES: [Na].C[O-].[Na+].CS[C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:13])[N:8]=1.Cl.[NH2:15][OH:16]>CO>[OH:16][NH:15][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:13])[N:8]=1
Reactant: CSc1cn[nH]c(=O)n1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1nc(NO)cn[nH]1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Metallic sodium (0.55 g) was dissolved in methanol (40 ml) to prepare a methanolic solution of sodium methoxide. 5-Methylthio-2,3-dihydro-1,2,4-triazin-3-one (2.86 g) and hydroxylamine hydrochloride (1.67 g) were added thereto, and the resultant mixture was heated with reflux for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The concentrated residue was recrystallized from 30% aqueous ethanol to give 5-hydroxyamino-3-oxo-2,3-dihydro-1,2,4-triazine (Ic) (2.32 g) as pale yellow crystals. Yield, 90.6%. M.P., 270° C.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:12][S:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34](O)[CH:35]1[CH2:37][CH:36]1[C:38]#[N:39]>ClCCl>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]([C:22]1[C:21]2[C:25](=[C:17]([CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH:18]=[CH:19][CH:20]=2)[NH:24][CH:23]=1)[CH:35]1[CH2:37][CH:36]1[C:38]#[N:39]
Reactant: N#CC1CC1C(O)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
116 mg (0.53 mmol) of indium(III) chloride and 0.07 ml (0.86 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A and 120 mg (0.57 mmol) of the compound from Example 162A under argon in 5 ml of dichloromethane, and the mixture was stirred under reflux for 1 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 29.0 mg (15% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[OH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[CH:11]2.[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:17][CH2:18][C:19]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[CH:11]2)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: O=c1ccc2cccc(O)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)Oc1cccc2ccc(=O)[nH]c12

Procedure:
20 g of aluminum chloride was added to 5.0 g of 8-hydroxycarbostyril (VII) and the resulting mixture was thoroughly mixed. 10 g of chloroacetyl chloride was gradually added to the mixture while ice-cooling. The mixture was allowed to react by heating at 40° to 45° C. for 2 hours to form 8-chloroacetoxycarbostyril (V) followed by stirring at 70° C. for 3 hours. After cooling, the precipitated crystals were collected by filtration, and the crystals were washed with 300 ml of water followed by recrystallization from methanol to obtain 2.6 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) having a melting point of 285°-287° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:13](=[O:35])[NH:14][C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=[CH:19][C:18]([C:31]([F:34])([F:33])[F:32])=[CH:17][CH:16]=3)=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>C1COCC1.O>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:31]([F:32])([F:33])[F:34])[CH:19]=3)[NH:14][C:13](=[O:35])[C:12]=2[S:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=2)[CH:27]=1
Reactant: CCOC(=O)c1ccc(Sc2c(-c3cc(Cl)ccc3OC)c3cc(C(F)(F)F)ccc3[nH]c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1-c1c(Sc2ccc(C(=O)O)cc2)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of 0.50 g (0.95 mmol) of 4-[4-(5-Chloro-2-methoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-quinolin-3-ylsulfanyl]-benzoic acid ethyl ester in 5 mL of THF and 5 mL of water was added 5.0 mL (5.0 mmol) of 1N NaOH in water. The mixture was stirred for 4 hr, neutralized with 1 N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to dryness to afford 0.48 g (100% yield) of the title compound. 1H NMR 400 MHz (DMSOd6) 3.61 (3H, s), 7.19 (4H, m), 7.37 (1H, d, J=2.7 Hz), 7.54 (1H, dd, J=8.8, 2.7 Hz), 7.58 (1H, d, J=8.6 Hz), 7.76 (2H, d, J=8.6 Hz), 7.92 (1H, dd, J=8.8, 1.7 Hz). MS m/z 506 (M+H). HPLC retention time 2.02 min (0% B to 100% B over 2 min at 5 mL/min.; Solvent A=10% MeOH/90% H2O/0.1% TFA, Solvent B=90% MeOH/10% H2O/0.1% TFA; EXTERRA C18 S5 4.6×50 mm column; UV detector at 220 nM).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])=[C:14]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.[CH2:31](Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOCC.CCOC(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[C:19]([O:21][CH3:31])=[O:20])=[C:14]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: ClCCCl
Reactant: O=C(O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2-oxo-2H-quinolizine-7-carboxylic acid (Example 53, 21 mg) in THF/MeOH (1/1) was added EDC (20 mg) and HOBt (10 mg) at room temperature. After stirring for 2 h, the mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (methylene chloride/methanol=20/1) to give the title compound (12 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2N(C)C)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[N:36]1([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][C:45]=2[CH3:51])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2[C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:42][CH2:41][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:45]([CH3:51])[CH:46]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1cc(Br)ccc1OCCN1CCCC1
Reactant: Cc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Product: Cc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 59 %

Procedure:
The title compound was prepared from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 124, Part C) and 4-bromo-2-methylphenyl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 59% yield after PrepLC (SiO2; gradient of 85:10:5 to 75:20:5 hexanes-THF-TEA) by essentially following the procedure detailed in Example 123, Part A.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C1Cc2ccccc2N1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1c2ccccc2CC1C(C)(C)C
Reaction time: 2 h

Procedure:
2-t-Butylindoline (20.3 g, 116 mmol) (can be made according to the procedures described in J. Chem Soc. Chem. Commum. 1974, 677-678) and 4-dimethylaminopyridine (10 mg) are dissolved in pyridine (100 ml). Acetic anhydride (11.5 ml, 122 mmol) is added and the solution stirred for 2 hours. The mixture is poured into water (1 L) and the solid filtered and dried in vacuo. The title compound is obtained as white crystals (22.2 g, 88%): mp 75° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH:16](Br)([CH3:18])[CH3:17]>CC(C)CC(=O)C>[CH:16]([N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1])([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(C)N(C)Cc1ccccc1

Procedure:
A flask containing N-methylbenzylamine (3.87 ml, 3.63 g, 0.03 moles), potassium carbonate (8.29 g, 0.06 moles) and 4-methyl-2-pentanone (100 ml) was treated with isopropyl bromide (2.69 ml, 0.03 moles) then heated under reflux for 18 hours. The reaction was checked by thin layer chromatography (tlc) to ensure the starting materials had been consumed. The reaction mixture was gravity filtered hot to remove the potassium salts and the filtrate was concentrated to an oil under reduced pressure on the rotovap. The oil was purified by flash chromatography (davisil 633, 20% ethyl acetate/hexane). The appropriate fractions were pooled and concentrated to an oil which was dissolved in anhydrous diethyl ether. The ether solution was treated with gaseous HCl. The ether was removed under reduced pressure. The residue was dissolved in absolute ethanol, treated with activated carbon, filtered, and cooled. The liquid was concentrated with acetone to remove traces of water. The solid was collected by vacuum filtration. m.p. 127.5°-128.5° C. Proton NMR (CDC13 +TMS) 1.36 doublet J= 6.66 Hz 3 H ipr methyl, 1.51 doublet J=6.66 Hz 3 H ipr methyl, 1.88 ppm NH+, 2.62 doublet J=5.04 Hz 3 H N-Methyl, 3.47 septette 1 H tertiary, 4.15 doublet J=6.05 Hz 2 H benzylic CH2 --, 7.28-7.42 5 H aromatic; C-13 (DMSO) ref:39.5, 131.16(11.88), 130.53(8.72), 129.12(5.74), 128.56 (10.92), 55.99(2.06), 55.11(7.14), 39.51(1.48), 34.36(6.93), 1845(3.11), 16.89(6.18), 15 19(5.20). EI Mass spec. M/e-(int) M+163(6.3), 148(40.7), 120(1.2), 92(8.0), 91(100), 90(1.5), 89(3.1), 78(2.2), 77(4.1), 65(18.8), 57(1.6), 56(8.1), 51(3.5), 44(6.0), 43(3.5) 42(11.8), 41(5.2).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1.[Cu]Br.O>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:22]
Reactant: BrCCC1OCCO1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCC2OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (45 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 51.2 g of magnesium chloride, in 1300 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature for 15 minutes, cooled to 0° C. and, after the addition of 49.6 g of copper(I) bromide, stirred at 5° C. for 15 minutes. After cooling to -70° C. 50.0 g of p-anisoyl chloride dissolved in 150 ml of absolute tetrahydrofuran were added dropwise within 20 minutes. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 800 ml of saturated ammonium chloride solution while cooling at a maximum 30° C. After the addition of 500 ml of water the mixture was extracted three times with 700 ml of ethyl acetate each time. The combined organic extracts were washed with 1000 ml of saturated sodium chloride solution, dried over MgSO4 and freed from solvent. 82.4 g of dark brown oil were chromatographed on 2000 g of silica gel with ethyl acetate/hexane (1:1) as the eluent. 48.8 g (71%) of 3-(1,3-dioxolan-2-yl)-4'-methoxypropiophenone were isolated as a yellow-orange oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8](=[CH2:13])[C:9](OC)=[O:10].[Na]>>[OH:10][C:9]1[CH:8]=[CH:13][NH:1][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=C(Cl)C(=O)OC
Reactant: COC(=O)CN
Agent: [Na]
Product: COC(=O)c1[nH]ccc1O

Procedure:
Prepared by the method described in Example 101 from methyl glycinate (22 g, 0.25 moles), methyl α-chloroacrylate (29.8 g, 0.25 moles), and sodium (17 g, 0.74 moles). Following filtration through silica gel and evaporation of the filtrate, the product is obtained pure and crystalline (18.6 g ; mp 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=3[N:14]=2)[CH:5]=1.[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][Br:21])[C:13]=3[N:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc3c(C)cccc3o2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2nc3c(CBr)cccc3o2)c1

Procedure:
A solution of 3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester (1.2 mmol), N-bromo succinimide (1.5 mmol) and AIBN (0.3 mmol) in CCl4 are heated in microwave at 100° C. for 30 minutes (1 mL). The mixture is filtered and concentrated to yield the crude 3-(4-bromomethyl-benzooxazol-2-yl)-benzoic acid methyl ester. LC/MS (ES+): (M+) 346.1, 348.1, (M−Br) 266.1, 268.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Li])[CH2:23][CH2:24]C.C(I)CC>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][C:15]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCc2coc(-c3ccccc3)n2)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1oc(-c2ccccc2)nc1CCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
4-(2-Benzyloxyethyl)-2-phenyloxazole (670 mg, 239 mmol) was dissolved in THF (10 mL) and cooled to −78° C. before adding n-butyllithium (1.15 mL of a 2.5 M solution in hexanes). The resulting orange solution was warmed to −65° C., stirred 45 min, and then propyl iodide (1.22 g, 7.17 mmol, 0.70 mL) was added via syringe. The solution was warmed to ambient temperature and stirred 90 min. The mixture was concentrated and the product purified by flash chromatography (100 mL SiO2, hexanes to 20% EtOAc/hexanes) and obtained as a colorless oil (340 mg, 44%): Rf=0.49 in 20% EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.00-7.96 (m, 2H), 7.42-7.26 (m, 8H), 4.54 (s, 2H), 3.76 (t, J=7.0 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H) 1.68 (sextet, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].[K+].[Br-]>CS(C)=O.O.C(N(CC)CC)C>[CH2:7]([NH:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24])[C:8]#[CH:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCNc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a suspension of potassium carbonate (20.0 g) in DMSO (7 ml) was added triethylamine (3 ml) and 2-propyn-1-amine(7.92 g, 1.44×10-1 mole). The reaction mixture was cooled in an ice bath while 1-fluoro-4-nitro-2-trifluoromethylbenzene (30.13 g, 1.44×10-1 mole) was added gradually with stirring. The mixture was gradually allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was poured into excess water and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a silica column, eluting with benzene, and recrystallized from benzene to afford yellow crystals; m.p. 71°-72° C. Yield: 24.24 g (69%). I.R. (KBr): 3450 (NH), 3290 (CH), 1588 (Ar-NO2) and 1300 cm-1 (CF3).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[NH:11][CH:10]=[N:9][C:8]=2[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[NH:4][N:3]=1.[C:18](Cl)(Cl)=[O:19].C1(C)C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[N:6]=[C:5]2[N:4]([C:18](=[O:19])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]3[N:9]=[CH:10][NH:11][C:7]=32)[N:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCn1c(=O)n2nc(C)nc2c2[nH]cnc21
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 5-(3-methyl-1H-1,2,4-triazol-5-yl)-N-pentyl-1H-imidazol-4-amine (45 mg, 0.19 mmol) in THF (10 mL) at 0° C. was added phosgene in toluene (0.3 mL, 1.0 mmol). The reaction mixture was slowly warmed to room temperature while stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative LCMS (method A) to provide the desired product (25 mg, 50% yield) as a white powder. LCMS calculated for C12H17N6O (M+H): 261.1. found: 261.1.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[N:15]([CH3:16])[C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:8]=1.[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:15]([CH3:16])[C:14]([CH2:17][C:18]([O:20][CH2:23][CH:22]=[CH2:21])=[O:19])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Reactant: C=CCBr
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The sodium salt of tolmetin (15.0 g, 47.6 mmol) and allyl bromide (4.3 ml, 49.9 mmol) were dissolved in DMF (50 ml) and the mixture was stirred at room temperature until the esterification was complete (~30 h). The solvent was removed in vacuo and the residue was partitioned between ether and water. The organic layer was separated, washed with water, 1M sodium hydroxide, and brine, and dried over sodium sulfate. Evaporation gave allyl 5-(4-methylbenzoyl)-1-methylpyrrole-2-acetate (11.97 g, 85%) as a solid. ##STR26##
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][N+:5]=1[O-:28]
Reactant: Cc1cnc(N2C(=O)c3ccccc3C2=O)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3ccccc3C2=O)[n+]([O-])cc1C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione (1.7 g, 0.01 mol) in CH2Cl2 (50 mL) was added m-CPBA (3.5 g, 0.02 mol) at the room temperature. The mixture was stirred overnight, then quenched by addition of a saturated solution of Na2S2O3 (100 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-(1,3-dioxoisoindolin-2-yl)-4,5-dimethylpyridine 1-oxide (1.5 g, 83%), which was used directly in the next step.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16])[CH3:13].CC1(C)CCCC(C)(C)N1.[CH3:36][Si:37](Cl)([CH3:39])[CH3:38]>C1COCC1>[CH2:12]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[Si:37]([CH3:39])([CH3:38])[CH3:36])=[O:16])[CH3:13]
Reactant: CCNC(=O)n1ccc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)n1c([Si](C)(C)C)cc2ccccc21
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (8.97 mL, 11.66 mmol) was added dropwise to a -78° C. cooled solution of N-(ethylaminocarbonyl)indole (1.0 g, 5.3 mmol) and 2,2,6,6-tetramethylpiperidine (0.75 g, 5.3 mmol) in THF (50 mL). After 30 min, TMSCl (0.9 g, 8 mmol) was added in a single portion, then the cold bath was removed to allow the reaction to warm over 1 h. This mixture was quenched with 25% citric acid in water (50 mL) and extracted with ethyl acetate (3 X). The organic extracts were combined, dried (MgSO4), concentrated, and recrystallized from ether/hexanes to afford 1.1 g of desired compound as a white solid, an 80% yield. m.p. 96-99° C.