Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.OC1C2N=NNC=2C=CC=1.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([C:49](O)=[O:50])=[CH:43]2>C(Cl)Cl>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([C:49]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:50])=[CH:43]2
Reactant: O=C(O)c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1
Reactant: C1CCNCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a solution of EDC (370 mg, 1.9 mmol), piperidine (0.24 mL, 0.21 g, 2.4 mmol), DIEA (0.33 mL, 0.25 g, 1.9 mmol) and hydroxybenzotriazole (257 mg, 1.9 mmol) in DCM (15 mL) was added 5-(benzothiazol-2-yloxy)-1H-indole-2-carboxylic acid (500 mg, 1.6 mmol) and the reaction mixture was stirred (rt, 48 h). The reaction mixture was partitioned between saturated NaHCO3 (10 mL) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-70%) to provide the title compound as a colorless solid (374 mg, 63%). MS (ESI): mass calcd. for C21H19N3O2S, 377.1; m/z found, 378.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.77 (5, 1H), 7.74 (d, J=7.6, 1H), 7.67-7.59 (m, 2H), 7.48 (d, J=8.8, 1H), 7.37 (t, J=7.1, 1H), 7.27-7.20 (m, 2H), 6.78 (d, J=1.3, 1H), 3.99-3.74 (m, 4H), 1.90-1.64 (m, J=11.3, 5.8, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Al+3].[Cl-].[Cl-].[Cl-].Br[CH2:17][C:18](Br)=O.[NH2:21][C:22]([NH2:24])=[S:23]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:6]([C:17]3[N:21]=[C:22]([NH2:24])[S:23][CH:18]=3)=[CH:7][NH:8][C:9]2=[N:10][CH:11]=1
Reactant: COc1cnc2[nH]ccc2c1
Reactant: O=C(Br)CBr
Reactant: NC(N)=S
Agent: [Al+3]
Agent: [Cl-]
Product: Nc1nc(-c2c[nH]c3ncc(O)cc23)cs1

Procedure:
The title compound was synthesized in 2 steps in a manner similar to that described above using 5-methoxy-7-azaindole (0.37 g, 2.48 mmol), AlCl3 (1 g, 7.54 mmol), bromoacetylbromide (0.2 mL, 3 mmol) and thiourea (0.14 g, 1.88 mmol) (0.21 g, 39%, 2 steps) as a brown solid. Mass Spec.; MS 233 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.37 (s,1H), 9.10(s,1H), 7.86(d,1H), 7.70(d,1H), 7.61(d,1H), 6.88(s,2H), 6.67(s,1H).
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:28]([CH:31]([CH3:33])[CH3:32])=[C:29]=[O:30]>CN(C=O)C>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:29](=[O:30])[NH:28][CH:31]([CH3:33])[CH3:32])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8]([NH:9][CH3:10])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)N=C=O
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CN)c2)o1)C1CCCCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CNC(=O)NC(C)C)c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3-aminomethyl-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (20 mg, 0.05 mmol) in DMF (0.5 mL) is added 2-isocyanato-propane (5.8 μL, 0.06 mmol). After 2 h stirring at room temperature, the mixture evaporated in vacuo and purified on reverse phase HPLC. The product is obtained as a pale yellow solid, 16 mg, 63%, LC/MS ESI m/z (M+H)+=455.5.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]([O:28]C)=[O:27])[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]([OH:28])=[O:27])[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cnc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 60 °C
Yield: 63.4 %

Procedure:
A mixture of methyl 3-chloro-4-[(2,4-difluorobenzyl)oxy]-5′,6-dimethyl-2-oxo-2H-1,4′-bipyridine-2′-carboxylate (0.13 g, 0.3 mmol) and 1.5 N NaOH (0.25 mL, 0.375 mmol) in dioxane (0.25 mL) was heated at 60° C. for 1 h and stirred at room temperature for an additional hr. The reaction mixture was acidified with acetic acid, and extracted with ethyl acetate (2×15 mL). The combined organic extract were washed with water and concentrated under reduced pressure to give the title compound as a white powder (0.08 g) which was used without purification in the next step. ES-MS, m/z=421 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].O>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: COc1nc(Br)ccc1I
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(Br)ccc1C(C)=O
Temperature: -40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 6-bromo-3-iodo-2-methoxypyridine (500 mg) in diethyl ether (15 mL) was cooled to −80° C. in a nitrogen atmosphere, and n-butyllithium (2.6 M, 0.735 mL) were added dropwise. After stirring at the same temperature for one hour, N,N-dimethylacetamide (0.37 mL) was added dropwise. The mixture was warmed to −40° C. over 1.5 hours to complete the reaction. Water and ethyl acetate was added to the reaction system. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give the title compound as a colorless powder (284 mg, 78%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.S(Cl)([Cl:24])=O>>[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1
Reactant: CN1CCC(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: O=S(Cl)Cl
Product: CN1CCC(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Product: Cl

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 7), except that 4-(1-methylpiperidin-4-ylmethyl)-3-trifluoromethylbenzoic acid obtained in the step 2 was used, and that treatment after the reaction was that thionyl chloride was distilled off under reduced pressure, and then the operation of adding of toluene to the residue, followed by azeotropic removal of thionyl chloride was repeated twice.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[OH-].[Na+].Cl>CO>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:18])=[O:2])=[O:17]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a solution of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline methyl ester (5.06 g) in methanol (40 ml) was added dropwise a 2N sodium hydroxide solution (12 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 3N hydrochloric acid under ice-cooling to adjust the mixture to pH 5. The reaction mixture was concentrated to dryness, suspended in chloroform and filtered. The filtrate was concentrated to give 4.28 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH3:36]>ClCCl>[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:46])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH3:36]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CCCCOc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of 1-butoxy-4-isocyanato-benzene (49.0 mg, 0.26 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol 3-yl]-piperidine-1-carboxylic acid (4-butoxy-phenyl)-amide as a white solid. (Yield 0.05 g, 41.7%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:16])=O.CN(C=O)C>ClCCl>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:16])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
A mixture of trans-4-trifluoromethyl-cyclohexyl-carboxylic acid (10.7 g, 54.3 mmol) and thionylchloride (10 mL, 138 mmol) in 100 mL dichloromethane with 200 μL DMF was refluxed for 2 h. The mixture was concentrated i.vac. and triturated with dichloromethane. The residue was reacted without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH:17]=[CH2:18]>>[Br-:15].[CH2:18]([N+:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=C(c1ccccc1)c1cccnc1
Product: C=CC[n+]1cccc(C(=O)c2ccccc2)c1
Product: [Br-]

Procedure:
3-Benzoyl pyridine was reacted with 1-bromo-2-propene according to the procedure of Part a) of Example 4 to give 1-(2-propenyl)-3-benzoyl pyridinium bromide as a tan coloured crystalline solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](SC2C=CC(N)=CC=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1C=CC(SC2C=C[C:35]([N+:38]([O-])=O)=[CH:34]C=2)=CC=1)CCC.[NH2:41]C1C=CC=CC=1.FC(F)(F)C1C=C(C=CC=1SC1C=CN=CC=1)N>CCOC(C)=O>[CH3:4][C:3]1[CH:2]=[C:1]([O:5][C:6]2[CH:7]=[CH:8][C:9]([NH2:41])=[CH:10][CH:11]=2)[CH:34]=[CH:35][N:38]=1
Reactant: CCCCOc1ccc(Sc2ccc(N)cc2)cc1
Reactant: CCCCOc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1
Reactant: Nc1ccccc1
Agent: Nc1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
4-(4-Butoxyphenyl)thioaniline: 4-(4-Butoxyphenyl)thio-1-nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3-(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method B3b, Step 2): TLC (33% EtOAc/77% hexane) Rf 0.38. A16. General Method for Synthesis of Substituted Anilines by the Acylation of Diaminoarenes
Reaction SMILES: C(C1C=C[C:9]([NH:12][NH:13][C:14]([NH2:16])=[S:15])=CC=1)(OCC)=O.[CH:17]([O-:22])([O-])[O:18][CH2:19][CH3:20].C(O)(=O)C.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:17]([C:29]1[CH:28]=[CH:27][C:32]([N:16]2[CH:9]=[N:12][N:13]=[C:14]2[SH:15])=[CH:31][CH:30]=1)([O:18][CH2:19][CH3:20])=[O:22]
Reactant: CCOC(=O)c1ccc(NNC(N)=S)cc1
Reactant: CCCCCC
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-n2cnnc2S)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A mixture of 13.2 g of (4-carboethoxyphenyl)thiosemicarbazide, 52.8 ml of ethyl orthoformate, and 3.3 g of acetic acid was stirred for 2 hours at 120° C. After cooling the mixture to room temperature, hexane was added to the mixture and crystals thus formed were collected by filtration and recrystallized from ethanol to provide 10.4 g of 1-(4-carboethoxyphenyl)-2-mercapto-1,3,4-triazole. The yield was 75.9% and the melting point was 194°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH:19](O)[CH3:20])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:34]([CH:19]([C:10]1[C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[CH3:20])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(3,5-difluorophenyl)quinolin-7-yl]ethanol (0.048 g, 0.17 mmol) in methylene chloride (1 mL) was added triethylamine (0.0352 mL, 0.252 mmol), followed by methanesulfonyl chloride (0.0163 mL, 0.210 mmol). After stirred at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (0.5 mL) and treated with sodium azide (0.0547 g, 0.841 mmol) at room temperature overnight. After diluted with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. The crude product was used in next step (40 mg, 76%). LCMS calculated for C17H13F2N4(M+H)+: m/z=311.1; found: 311.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(C(C)C)c(C)cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C(C)C)cc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
1-(2-Hydroxy-5-isopropyl-4-methyl-phenyl)-ethanone (13 mg), 4-chloro-6,7-dimethoxyquinoline (30 mg), and 4-dimethylaminopyridine (25 mg) were suspended in o-dichlorobenzene (3 ml) to prepare a suspension which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (2 mg, yield 7%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[C:8]([F:25])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[C:8]([F:25])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Temperature: 80 °C
Yield: 103.1 %

Procedure:
To a solution of 139 (33.0 mg; 0.084 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous sodium hydroxide (7.5 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether. The aqueous layer was separated and acidified with aqueous hydrochloric acid (5 mL; 2N) then extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as a brown solid (32 mg).
Reaction SMILES: Cl.Cl.NC[CH:5]1[CH2:16][N:15]2[C:7]([C:8]3[NH:9][C:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:11][C:12]=3[N:13]([CH2:18][CH2:19][CH3:20])[C:14]2=[O:17])=[N:6]1.CO[CH:28]1[CH2:32][CH2:31][CH:30](OC)O1.[CH3:35][N:36](C)C=O>>[CH:21]1([C:10]2[NH:9][C:8]3[C:7]4=[N:6][CH:5]([CH2:30][C:31]5[NH:36][CH:35]=[CH:28][CH:32]=5)[CH2:16][N:15]4[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC1CCC(OC)O1
Reactant: CN(C)C=O
Reactant: CCCN1C(=O)N2CC(CN)N=C2c2[nH]c(C3CCCC3)nc21
Agent: Cl
Product: CCCN1C(=O)N2CC(Cc3ccc[nH]3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Compound 20 (100 mg, 0.26 mmol) obtained in Example 20 and 2,5-dimethoxytetrahydrofuran (67 μL, 0.51 mmol, 2.0 equivalents) were dissolved in N,N-dimethylformamide (2 mL) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was partitioned with ethyl acetate and water, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (56 mg, 60%) as a light yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][CH:18]1[O:23]C(C)OC(C)O1.[Cl-:26].[Ca+2].[Cl-]>>[Cl:26][CH:18]([O:23][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:17]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CC1OC(C)OC(C)O1
Agent: [Ca+2]
Product: CCCCCCCCCCCCCC(=O)OC(C)Cl
Yield: 496 %

Procedure:
Tetradecanoyl chloride (40 gms, 0.16 mol), dry paraldehyde (21 gm, 0.16 mol) and anhydrous calcium chloride (2 gms) were refluxed in a 500 ml one-necked flask (protected from atmospheric moisture with a drying guard tube) for 24 hours. The reaction mixture was cooled and chromatographed through a column of Florisil using chloroform as the eluent to give a semisolid product (26 gm, 56%). 1H n.m.r.(CDCl3): δ0.90(3H, t, J=4 Hz, CH3 --), 1.26(22H, s, broad, --[CH2 ]11 --), 1.78(3H, d, J=6 Hz, --CHCH3 --), 2.33(2H, d, J=6 Hz, --COCH2 --), 6.55(1H, q, J=6 Hz, --CHCH3 --).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:21][C:20]([F:23])([F:22])[C:16]1[N:15]=[C:14]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCc2cc(Oc3cccc(C(F)(F)F)n3)ccc21
Temperature: 120 °C
Yield: 61.3 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 30.8 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (5.87 g, 32.3 mmol) in ACN (100 mL) was added potassium carbonate (6.39 g, 46.2 mmol), and the reaction was heated at 120° C. in a sealed vessel overnight. The reaction was cooled, diluted with water (100 mL), and extracted with EtOAc (100 mL×3). Organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10-80% EtOAc/hexanes) gave 5.8 g (61%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.13-2.20 (2H, m), 2.67 (2H, t, J=6.2 Hz), 2.97 (2H, t, J=6.0 Hz), 7.07-7.14 (2H, m), 7.45 (1H, d, J=7.4 Hz), 7.89 (1H, t, J=8.0 Hz), 8.09 (1H, d, J=8.3 Hz). [M+H] calc'd for C16H12F3NO2, 308. Found 308.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)(=O)=O)=CC=1.[F-:35].C([N+](CCCC)(CCCC)CCCC)CCC>O>[F:35][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[CH2:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OC(COc2ncnc3ccccc23)c2ccc(C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(C)(C)c1ccc(C(F)COc2ncnc3ccccc23)cc1

Procedure:
A 15 ml round bottom flask is charged with 4-(2-p-toluenesulfonyloxy-2-(4-tert-butylphenyl) ethoxy) quinazoline (0.3 g, 0.84 mmol). Tetrabutylammonium fluoride solution (1M in THF, 4.2 ml, 4.2 mmol) is then added to it and the solution is heated at reflux for 60 minutes. The mixture is then cooled and water is added to it. It is then extracted with dichloromethane, washed with water and dried. The crude obtained after concentration is purified by silica gel flash chromatography (ethyl acetate/hexanes) to obtain the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2O.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[Cl:20]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
1-(6-bromo-4-hydroxyquinolin-3-yl)butan-1-one (3.73 g, 12.7 mmol) was added to phosphoryl chloride (37 mL) and the reaction was stirred at 75° C. for 2 h. After this time the reaction mixture was cooled to room temperature and slowly poured into a solution of satd. aq. sodium carbonate that was cooled to 0° C. The resultant mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica, ethyl acetate) afforded the desired product (3.90 g, 98%) as an off-white solid. ESI MS m/z 312 [C13H13BrClNO+H]+