Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=[C:5]([CH2:11][CH2:12][CH2:13]C(=O)C=C)[CH:6]=[CH:7][C:8]=1[O:9]C.C[O:19]C1C=C(CCCC(=O)CCN(CC)CC)C=CC=1OC>[OH-].[K+]>[CH2:12]([CH:11]1[C:5](=[O:19])[CH2:6][CH2:7][C:8]1=[O:9])[CH3:13]
Reactant: C=CC(=O)CCCc1ccc(OC)c(OC)c1
Reactant: CCN(CC)CCC(=O)CCCc1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux 6-(3,4-dimethoxyphenyl)hex-1-en-3-one, containing a small amount of 6-(3,4-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolic potassium hydroxide (10 cc) for 10 hours. Remove most of the methanol under reduced pressure, add benzene (25 cc) and ether (25 cc) and wash the solution with water, dilute aqueous potassium hydroxide, dilute hydrochloric acid and water. Dry and evaporate the solvent to give the triketone adduct 2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione; infrared absorption (gum) 5.80, 6.25 μ (split peak).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22](SC)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[C:34]([N:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]2=[O:42])[CH:33]=[C:32]([F:43])[CH:31]=1)[CH:16]=[CH2:17]>>[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[C:34]([N:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]2=[O:42])[CH:33]=[C:32]([F:43])[CH:31]=1)[CH:16]=[CH2:17]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cc(F)cc(-n2ccccc2=O)c1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cc(F)cc(-n2ccccc2=O)c1

Procedure:
The entitled compound was obtained as a yellow solid (68.4 mg) in the same manner as in Production Example 12-2, for which, however, 4-(4-methylpiperazin-1-yl)aniline was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 2-allyl-1-[3-fluoro-5-(2-oxopyridin-1(2H)-yl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [Si]([N:8]1[CH:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[CH2:10][C:9]1=[O:29])(C(C)(C)C)(C)C.Cl.P([O-])([O-])(O)=O.[K+].[K+]>CO>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15]([CH2:14][C:13](=[O:28])[CH2:12][CH:11]2[NH:8][C:9](=[O:29])[CH2:10]2)=[O:16])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Product: O=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)CC1CC(=O)N1
Reaction time: 3.33 h
Yield: 90.8 %

Procedure:
A solution of N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (5.17 g, 12.3 mMol) in methanol (55 ml) is treated with 1N hydrochloric acid (6.2 ml) and then kept at room temperature for 200 mins. The solution is treated with 1M dipotassium hydrogenphosphate (6.2 ml) and concentrated under vacuum. The residue is taken up in ethyl acetate (100 ml), washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. Triturating the resulting oil with diethyl ether yields 4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-azetidin-2-one (3.42 g, 91%) as an off-white powder: mp 50°-52°; IR (CH2Cl2) 3416, 1767, 1723, 1528, and 1352 cm-1 ; NMR (CDCl3) α2.60 (ddd,1,J=1,2.7, and 15.1,H3β), 2.77 (dd,1,J=8.4 and 18.2, CHCH2CO), 3.13 (dd,1,J=5.1 and 18.2, CHCH2CO), 3.20 (ddd,1,J=2.4, 5.0, and 15.1, H3α), 3.57 (s,2,COCH2CO2), 3.98 (m,1,H4); 5.27 (s,2,CH2Ar), 6.28 (br s,1,NH), 7.53 and 8.23 (two d's,4,J=8.5, ArH); mass spectrum m/e 306(M+), 264(M+-42), 237, 153, 125, 111, and 136.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]3[C:24](=[O:55])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:56]1(=[O:62])[O:61][C:59](=[O:60])[CH2:58][CH2:57]1>C(#N)C>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:32]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:24]([C@H:19]2[N:18]([C:16]([O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[O:17])[CH2:22][C@H:21]([O:23][C:56](=[O:62])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH2:20]2)=[O:55])=[CH:44][CH:43]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(C(OCCOCCNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC#N
Product: COc1ccc(C(OCCOCCNC(=O)[C@@H]2C[C@@H](OC(=O)CCC(=O)O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
(2S,4R)-2-(2-{2-[Bis-(4-methoxy-phenyl)-phenyl-methoxy]-ethoxy}-ethylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound 73) (1.00 g, 1.35 mmol), succinic anhydride (192 mg, 2.02 mmol) and N,N-dimethylaminopyridine (246 mg, 2.02 mmol) were dissolved in acetonitrile (3.0 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was purified by reverse-phase silica (0.1% ammonium acetate, H2O, CH3OH, gradient) to afford the title compound (Compound 74) (349 mg, 31%) as a colorless amorphous.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH:10]([CH3:11])[CH3:16])=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), isopropyl aldehyde (0.04 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (70 mg, 43.9% yield) as white crystals.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:17]1[CH:22]=[C:21]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CON(C)C(=O)c1cc2ccccc2[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
Activated molecular sieves (13 g) 4 Å were placed in an oven dried round bottom flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N-methyl-1H-indole-2-carboxamide (0.97 g, 4.7 mmol), (3-fluorophenyl)-boronic acid (1.5 g, 11 mmol), cupric acetate (1.3 g, 7.3 mmol), methylene chloride (130 mL) and then pyridine (1.5 mL, 19 mmol). The reaction mixture was stirred at room temperature over the weekend. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-30% EtOAc/hexane) to give the title compound (0.52 g, 37%). LCMS calculated for C17H16FN2O2(M+H)+: m/z=299.1. Found: 299.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])=[C:2]=[O:3].C[Si](C)(C)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][Si](C)(C)C)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:10])=[C:2]=[O:3]
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(O[Si](C)(C)C)cc2)cc1
Reactant: O=C=NCCCCCC(=O)Cl
Product: O=C=NCCCCCC(=O)Oc1ccc(-c2ccc(OC(=O)CCCCCN=C=O)cc2)cc1

Procedure:
From 35 g (0.2 mol) of 6-isocyanatohexanoic acid chloride and 23 g (0.07 mol) of 4,4'-bis(trimethylsiloxy)biphenyl.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:3]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Yield: 85.2 %

Procedure:
To a solution of methyl 3-hydroxybenzoate (1.00 g, 6.57 mmol) in N,N-dimethylformamide (60 mL) add tert-butyl bromoacetate (1.10 mL, 7.44 mmol) followed by potassium carbonate (4.0 g, 29 mmol) of. Heat the mixture at 70° C. for 5 hours, Cool to room temperature and pour over ice. Allow the mixture to sit until all of the ice melts during which time a solid precipitates from solution. Collect the white solid by filtration, wash with water and dry on the filter pad to provide 1.49 g of 3-tert-butoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (58% yield). m.p. 164-166° C. 1H NMR (300 MHz, CDCl3) δ 8.07, 7.96, 7.69, 7.54, 7.02, 4.07-3.35, 1.52, 0.79-0.68, 0.48-0.43, 0.14-0.08. MS (ES+) m/z 482.1 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][C:16](Cl)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][C:16]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:17][CH:18]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 47 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 369 mg, 2.08 mmol), 5-bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 38, 500 mg, 1.73 mmol), and DIEA (468 mg, 3.8 mmol). Anhydrous n-BuOH (5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (320 mg, 47%). LC-MS, 393 (M+1). 1H NMR δ 12.02 (s, 1H), 8.82 (s, 2H), 7.94 (s, 1H), 7.48 (s, 0.55H), 5.90 (s, 0.41H), 5.09 (s, 1H), 2.19 (m, 3H), 1.49 (m, 3H).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3]1.[CH3:10]O>>[C:7]([C:5]1[CH:6]=[N:2][NH:3][CH:4]=1)([O:9][CH3:10])=[O:8]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cn[nH]c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To an ice cold saturated solution of HCl in methanol (500 ml), pyrazole-4-carboxylic acid (4) (19.2 g, 0.17 m) was added and the solution stirred at 0° C. for 3 hours and at ambient temperature overnight. The solvent was distilled off and the brown residue was dissolved in water. The aqueous solution was neutralized with NaHCO3 and the product was repeatedly extracted with ether (25×100 ml). The ether extract was dried over Mg SO4 and concentrated to give the methyl ester (5) as a pale yellow solid (13.59 g, 79.6%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[C:24]([CH:36]=1)[C:25]([N:27]([CH3:35])[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26]>>[Cl:19][C:20]1[C:21]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[N:22][CH:23]=[C:24]([CH:36]=1)[C:25]([N:27]([CH3:35])[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26]
Reactant: CN(CCN1CCCC1)C(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Product: CN(CCN1CCCC1)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol and 5,6-dichloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)nicotinamide, and in the same manner as in Example 65 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (99 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:19])([CH3:18])[CH3:17]>>[CH:16]([NH:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C
Yield: 79.9 %

Procedure:
4-Chloro-3,5-dinitro-o-xylene (10.0 grams, 0.043 mole) and isopropylamine (10.1 grams, 0.17 mole) are mixed and refluxed for 12 hours using an efficient reflux condenser. The mixture is then cooled and poured into 100 ml. of 5% hydrochloric acid and extracted with diethyl ether. The ether extract is dried over magnesium sulfate. Removal of the drying agent and solvent leaves an orange oil which readily solidifies. The product is recrystallized from methanol to give 8.7 grams (80%) of an orange solid with melting point 69° C. to 70° C.
Reaction SMILES: [CH:1](O)=[O:2].[CH2:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:4]([N:6]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:1]=[O:2])[CH3:5]
Reactant: O=CO
Reactant: CCNCCOc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCN(C=O)CCOc1ccccc1

Procedure:
To a solution of formic acid (3.3 ml) and N-ethyl-N-β-phenoxyethylamine (14.5 g) in methylene chloride (100 ml) at 0°-5°C was added N,N'-dicyclohexylcarbodiimide (19.7 g) with stirring. The mixture was stirred for 18 hours at room temperature and filtered. The filtrate was evaporated in vacuo to leave an oil which was taken up in either (100 ml) and extracted with 0.4 N hydrochloric acid (2 × 25 ml) and water (2 × 25 ml). After drying, the ether was removed in vacuo to leave the above compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:19]([O:25][CH2:26]Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CC(C)=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([C:12]([O:14][CH2:26][O:25][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1c(Cl)cccc1Nc1ncccc1C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1Nc1ncccc1C(=O)OCOC(=O)C(C)(C)C
Yield: 77.4 %

Procedure:
To a stirred mixture of 2-(3'-chloro-2'-methylanilino)-pyridine-3-carboxylic acid (26.3 g) in 400 ml of acetone, triethylamine (20.5 ml) was added. Thereafter pivaloyloxymethyl chloride (15 ml) was poured into the mixture and then it was refluxed 4 hours. Subsequently, the reaction mixture was cooled to 15°-20° C. poured into previously cooled distilled water (3000 ml) and maintained at 5°-7° C. for 4 hours. The cake was filtered by suction and the formed compound dried at 25°-35° C. under vacuum to obtain a yield of 77.4% (29.2 g) of pivaloyloxymethyl 2-(3'-chloro-2'-methylanilino)-pyridine-3-carboxylate, m.p.: 91° C.-92° C.
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])OCC.Cl.C(OCC)C>C(O)C>[CH2:17]([O:16][CH:9]([O:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(OCC)c1ccccc1
Yield: 82 %

Procedure:
A solution of benzaldehyde (6.82 mmol), triethyl orthoformate (3.3 g, 22.5 mmol), and conc. HCl (10 μL, 90 μmol) was refluxed in 3.7 mL of ethanol for 24 hrs. Diethyl ether was added and the organic layer was extracted with 3×2 M NaOH. The organic layer was dried over anhydrous Na2SO4. After removal of diethyl ether under reduced pressure, the crude mixture was distilled under vacuum (55-65° C./0.5 mmHg) to give pure benzaldehyde diethylacetal (82-91% yield). All acetals were characterized by 1H-NMR and used without further purification.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11]>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:3]1[O:4][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:6]
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: CC(Cl)c1nc2ccccc2c(=O)o1
Temperature: 65 °C

Procedure:
17.47 ml of 2-chloropropionic acid chloride were added with stirring at room temperature to a solution of 10.3 g of 2-amino-benzoic acid in 20 ml of toluene and the mixture was progressively heated to 65° C. during which a mass was formed and gas disengaged and the mixture fluidized. The mixture was held at reflux for 90 minutes and was evaporated to dryness under reduced pressure. The residue was empasted with petroleum ether (b.p.=60° to 80° C.), was iced and vacuum filtered. The product was washed and dried under reduced pressure at 50° C. to obtain 14.45 g of 2-(1-chloroethyl)-4H-3,1-benzoxazine-4-one melting at 90° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:17]=1[C:18]#[N:19].[OH-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]2[C:17]=1[C:18]([NH2:19])=[C:2]1[C:1]([CH2:6][CH2:5][CH2:4][CH2:3]1)=[N:15]2
Reactant: O=C1CCCCC1
Reactant: N#Cc1c(N)cccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c2c(nc3cccc(F)c13)CCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
To a stirred solution of cyclohexanone (1.0 g, 10.0 mmole) in methylene chloride (10 ml) at -20° C., a 1M solution of titanium (IV) chloride in methylene chloride (20 ml) was added. The reaction mixture became yellow in color and to it a mixture of triethylamine (2.0 g, 20 mmole) and 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmole) in methylene chloride (30 ml) were added. The reaction mixture immediately became dark in color and was allowed to warm to room temperature (about 25° C.) and stirred further for 15 hours. At the end of this period, the reaction mixture was treated with 12% aqueous NaOH (100 ml), and methylene chloride (100 ml). The reaction mixture was then filtered through a 2 inch diatomaceous earth pad (Celite (trademark)) which was washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated, washed with water (1×30 ml) and dried (anhydrous MgSO 4). The methylene chloride was removed under vacuum to afford an oil which was triturated with ether to give the title compound as a white solid (218 mg, 10%, m.p. 175° C.). 1H-NMR (CDCl3, 300 MHz,δ): 4H, m, 2.0 ppm; 2H, t, 2.59 ppm (J=7.0 Hz); 2H, t, 3.06 ppm (J=7.0 Hz); 2H, bs, 5.37 ppm; 1H, dd, 7.0 ppm (J=7.5, 14 Hz); 1H, dd, 7.46 ppm (J=8, 16 Hz); 1H d, 7.72 ppm (J=8.5 Hz). HRMS: Calculated--216.1053; Found--216.1039.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.P(Br)(Br)[Br:19].[OH-].[Na+]>C1C=CC=CC=1>[Br:19][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(CO)c(OCc2ccccc2)c1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(CBr)c(OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
A solution of crude 4-methyl-2-phenylmethoxy-benzenemethanol (20 g, 87.6 mmol) in dry benzene (100 ml) was treated with 9.1 ml (96 mmol) PBr3 at room temperature and after being stirred for 10 min the mixture was treated with 50 ml 2N NaOH solution. The organic layer was separated and dried (Na2SO4) to give 1-bromomethyl-4-methyl-2-phenylmethoxybenzene (23.7 g, 93% crude yield) as an oil.
Reaction SMILES: [CH:1]1[C:23]2=[C:24]3[C:4]4[C:5]([CH:17]=[CH:18][C:19]3=[C:20](S([O-])(=O)=O)[CH:21]=[C:22]2[OH:25])=[C:6](S([O-])(=O)=O)[CH:7]=[C:8](S([O-])(=O)=O)[C:3]=4[CH:2]=1.[Na+:30].[Na+].[Na+].[OH:33][S:34](O)(=[O:36])=[O:35]>O>[OH:25][C:22]1[CH:21]=[CH:20][C:19]2[C:24]3=[C:4]4[C:5]([CH:6]=[CH:7][CH:8]=[C:3]4[C:2]([S:34]([O-:36])(=[O:35])=[O:33])=[CH:1][C:23]=13)=[CH:17][CH:18]=2.[Na+:30]
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])c1cc2c(O)ccc3ccc4cccc1c4c32
Temperature: 150 °C

Procedure:
Referring to Scheme 6, a 50-mL round bottom flask equipped with a magnetic stirring bar was charged with HPTS (9.5 mmols, 5 g) and 30% H2SO4 (35 mL). The mixture was heated at 150° C. for 20 min and then allowed to cool at ambient temp for 10 min. The solution was poured into 100 g of crushed ice and diluted to 200 mL with water. The mixture was extracted with isopropyl acetate (200 mL×4) and concentrated in vacuo. The residue was mixed with silica gel (3 g) and crushed into a fine powder and dry loaded onto a Biotage 40 M cartridge. The residue was purified via gradient elution using 5% MeOH: (5% NEt3:CH2Cl2) to 15% MeOH:(5% NEt3:CH2Cl2) to give the triethylamine salt of 1 (0.281 g). The salt was treated with 1 M HCl and extracted with isopropyl acetate and the isopropyl acetate layer dried over MgSO4 and concentrated in vacuo to give 1 as a brown/green foam. Synthesis of 1 was reported previously by E. Tietze and O. Bayer 1939 Ann 540:189-210. TLC (MeOH: CH2Cl2:NEt3, 2:7:1) Rf=0.23. 1H NMR (500 MHz, CD3OD) δ 7.94 (t, J=7.6 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 8.02 (d, J=9.2 Hz, 1H), 8.11 (t, J=7.7 Hz, 2H), 8.25 (s, 1H), 8.39 (d, J=9.1 Hz, 1H), 8.98 (d, J=9.3 Hz, 1H).