Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][N:7]1[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1Cc2ccccc2CN1C(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of (±)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester (6.26 g, 30.5 mmol) and 3-phenoxybenzoic acid (7.19 g, 33.6 mmol) in chloroform (150 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.43 g, 33.5 mmol). The reaction was allowed to proceed overnight and then washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and concentrated. The crude product was purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 12.07 g (99%) of product as a colorless gum. In chloroform-d solvent, the proton NMR spectra of this compound appears as a 55:45 mixture of rotamers: 1H NMR (CDCl3) δ 7.46-6.90 (m, 13H), 5.46 (t, J=5.6 Hz, 0.55H), 5.18 (d, J=17.6 Hz, 0.45H), 4.80-4.73 (m, 0.45H), 4.68-4.50 (m, 1.55H), 4.22-4.07 (m, 1.10H), 4.05-3.92 (m, 0.90H), 3.34-3.19 (m, 1.55H), 3.16-3.06 (m, 0.45H), 1.19 (t, J=7.1 Hz, 1.65H), 1.04 (t, J=7.1 Hz, 1.35H) ppm.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C:20]([OH:31])([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.C(OC1C=CC(OCCBr)=CC=1)C1C=CC=CC=1.Cl.CC1C=CC(CC2(O)CCNCC2)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.CO.CCOCC>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][C:20]([OH:31])([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: BrCCOc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
1-[2-(4-Benzyloxyphenoxy)ethyl]-4-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride. A mixture of 2-(4-benzyloxyphenoxy)ethyl bromide (368 mg, 1.2 mmol), 4-(4-methylbenzyl)-4-hydroxypiperidine hydrochloride (290 mg, 1.2 mmol), potassium carbonate (414 mg, 3 mmol) in 30 mL of acetonitrile was allowed to reflux for 12 h. The inorganic salt was removed through a short column of silica gel and washed with ethyl acetate (3×25 mL). The combined flitrate was evaporated in vacuo to give a crude mixture, which was purified by flash chromatography (5% methanol in ethyl acetate), giving a pale yellow oil, which was disolved into methanol (10 mL), to which was added 4 mL of 1 M HCl in methanol. The resulting solution was allowed to stir at rt for 10 min, and methanol was evaporated in vacuo to give a residue, to which 50 mL of ether was added. The resulting mixture was stirred overnight. A white solid was collected by filtration and dried in vacuo, giving 420 mg (75%) of the title product: mp 179-181° C. 1H NMR (CDCl3) 1.605 (s, 2 H), 1.725 (d, J=14.1 Hz, 2 H), 2.332 (s, 3 H), 2.453 (m, 2 H), 2.809 (s, 2 H), 3.221 (m, 2 H), 3.361 (s, 1 H), 3.464 (d, J=8.4 Hz, 2 H), 4.488 (s, 2 H), 5.005 (s, 2 H), 6.820 (d, J=9.0 Hz, 2 H), 6.904 (d, J=9.0 Hz, 2 H), 7.077 (d, J=7.5 Hz, 2 H), 7.166 (d, J=7.5 Hz, 2 H), 7.376 (m, 5 H), 12.4 (bs, 1 H).
Reaction SMILES: CO.O1CCOCC1.[OH:9][C:10]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH2:43][CH2:44][CH2:45][O:46]C(=O)C)[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][CH2:11]1.[OH-].[Na+]>O>[OH:9][C:10]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH2:43][CH2:44][CH2:45][OH:46])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:12][CH2:11]1
Reactant: CC(=O)OCCCOc1ccccc1C1(O)CCN(CCC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2OCCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
In a liquid mixture of 5 mL of methanol and 5 mL of dioxane was dissolved 180 mg (0.32 mmol) of 4-(4-hydroxy-4-(2-(3-acetoxypropoxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide. To the resulting solution, 5 mL of a 1N aqueous solution of sodium hydroxide was added. The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform, washing with water and drying. The residue obtained by distilling off the solvent was purified by chromatography on a silica gel column, whereby 150 mg (yield: 89.8%) of 4-(4-hydroxy-4-(2-(3-hydroxypropoxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 25) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1)[CH2:18][CH3:19]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([N:20]1[C:24]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:23][CH:22]=[N:21]1)[CH2:18][CH3:19]
Reactant: COC(=O)c1cc(Br)cs1
Reactant: CCCn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCn1nccc1-c1csc(C(=O)OC)c1
Temperature: 70 °C
Yield: 70.3 %

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (221 mg, 1.0 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (414 mg, 3.0 mmol), tetrakistriphenylphosphine Pd(0) (60 mg, 0.05 mmol), and 1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (404 mg, 1.5 mmol). The reaction mixture was heated to 70° C. in a sealed tube for 2 h. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-40%) to give the title compound (176 mg, 70%) as a white solid: LC-MS (ES) m/z 251 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1[C:14]([CH:15]2[C:21](=[O:22])[CH:20]3[CH2:23][CH:17]([CH2:18][CH2:19]3)[C:16]2=[O:24])=[C:13]([CH3:25])[CH:12]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:24][C:16]1[CH:17]2[CH2:23][CH:20]([C:21](=[O:22])[C:15]=1[C:14]1[C:9]([CH3:8])=[CH:10][C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:12][C:13]=1[CH3:25])[CH2:19][CH2:18]2)=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2CCC(C2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pivaloyl chloride (248 μl, 2 mmol) is added to a solution of 3-(3,5-dimethylbiphen-4-yl)bicyclo[3.2.1]octane-2,4-dione (148 mg, 0.46 mmol) in dichloromethane (10 ml) and triethylamine (280 μl, 2 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight. The reaction mixture is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to afford 3-(3,5-dimethylbiphen-4-yl)-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl 2,2-dimethylpropionate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]([O:20]C(=O)C)[CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:20][CH:14]1[C:15](=[O:19])[NH:16][C:17](=[O:18])[CH:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH2:13]1
Reactant: CC(=O)OC1CC(N2C(=O)c3ccccc3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1NC(=O)C(N2C(=O)c3ccccc3C2=O)CC1O
Yield: 60 %

Procedure:
This example illustrates the preparation of 2-(5-hydroxy-2,dioxo-piperidin-3(2H)-dione) having a molecular weight of about 274.2. A mixture of about 1.0 g (about 3.2 mmol) of acetic acid 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxo-piperidin-3-yl-ester (single diastereomer) prepared according to Teubert, U. et al., Arch. Pharm. Pharm. Med. Chem., 1998, 331, 7 (incorporated herein by reference) and about 0.3 g (about 1.6 mmol) of p-toluenesulfonic acid was refluxed in about 30 ml of methanol for about 5 hours. The solution was allowed to cool to about room temperature. After cooling, the precipitated product was filtered and recrystallized from acetone/petroleum ether (having a boiling point of about 60° to about 80° C.). Alternatively, the precipitated, filtered product was recrystallized from acetonitrile. A yield of about 0.52 g (about a 60% yield) of 2-(5-hydroxy-2,6-dioxo-piperidin-3-yl)-1H-isoindole-1,3[2H]-dione having a melting point of about 195° to about 230° C. resulted.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:5]=1.COC(=O)C1C=CN=C(I)C=1.C[Si](C#C)(C)C.C([O-])([O-])=O.[K+].[K+].C1C(=O)N(Cl)C(=O)C1.C(=NO)C.[C:52]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])(=[O:54])[CH3:53].[Li]>CO.C(Cl)(Cl)Cl.N1C=CC=CC=1.CCN(CC)CC>[C:56]([O:55][C:52](=[O:54])[CH2:53][C:3]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:5]=1)=[O:16])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccnc(-c2cc(C)no2)c1
Agent: C#C[Si](C)(C)C
Agent: COC(=O)c1ccnc(I)c1
Agent: O=C([O-])[O-]
Solvent: CC=NO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)on1

Procedure:
The title compound was prepared from 2-(3-methyl-isoxazol-5-yl)-isonicotinic acid methyl ester [prepared by i.) reaction of 2-iodo-isonicotinic acid methyl ester [CAS-No. 134579-47-8] with trimethylsilylacetylene according to general procedure H; ii.) desilylation by reaction with cat. K2CO3 in MeOH at 0° C. for 4 h; iii.) cycloadditon with a mixture of NCS, acetaldoxime, Et3N and cat. amount of pyridine in CHCl3 at 50° C. according to Tetrahedron 1984, 40, 2985-2988] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a brown solid (5.17 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1C(F)(F)F

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid in MeOH were added concentrated sulfuric acid at 0° C. The reaction mixture was heated and refluxed for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4, and then concentrated under reduced pressure to obtain methyl 4-fluoro-2-(trifluoromethyl)benzoate as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:33][CH:32]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-[1,2,4]triazol-1-yl-benzoic acid. MS: 431.3 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCCCCCCCCS.Cl.C[CH:23]1[CH2:29][C:28](C)(C)[CH2:27][C:25](=[O:26])[CH2:24]1>>[CH:29]1[CH:28]=[C:27]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:25]([OH:26])=[CH:24][CH:23]=1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: Oc1ccccc1
Agent: CCCCCCCCCCCCS
Agent: Cl
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
7.5 mol (705 g) phenol and 0.15 mol (30.3 g) dodecylthiol are introduced into a 1-liter round-bottomed flask equipped with a stirrer, dropping funnel, thermometer, reflux condenser and gas inlet pipe and saturated with dry HCl gas at 28° to 30° C. A solution of 1.5 mol (210 g) dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) and 1.5 mol (151 g) phenol is added dropwise to the resulting solution over a period of 3 hours, HCl gas continuing to be passed through the reaction solution. After the addition, HCl gas is introduced for another 5 hours. The mixture is then left to react for 8 hours at room temperature. The excess phenol is then removed by steam distillation. The residue is hot-extracted twice with petroleum ether (60-90) and once with methylene chloride and filtered off. Yield: 370 g; Mp: 205°-207° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O>CO.N1CCCCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:3]2[C:4]3[O:8]/[C:7](=[CH:26]\[C:28]4[C:36]5[C:31](=[CH:32][C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:35]=5)[NH:30][CH:29]=4)/[C:6](=[O:9])[C:5]=3[CH:10]=[CH:11][C:2]=2[OH:1])[CH2:18][CH2:17]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 782.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.060 g, 0.017 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with methyl 3-formyl-1H-indole-6-carboxylate (0.040 g, 0.019 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 60° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (93:7)) to obtain methyl (Z)-3-[(7-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-6-hydroxy-3-oxobenzofuran-2(3H)-ylidene)methyl]-1H-indole-6-carboxylate (0.071 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:23].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[N:6]=[C:5]2[Cl:23]
Reactant: COc1ccccc1-c1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Yield: 43.8 %

Procedure:
6-Bromo-2-(2-methoxyphenyl)quinazolin-4(3H)-one (0.31 g, 0.94 mmol), POCl3 (86 μL, 0.94 mmol), and N,N-dimethylaniline (180 μL, 1.4 mmol) were refluxed in dry toluene for 3 h. Additional POCl3 (0.94 mmol) was added, and the reaction was refluxed for one additional hour. The reaction mixture was diluted with EtOAc and water. The aqueous layer was made basic with NaHCO3, and the layers were separated. After the organic phase was washed with water, dried over Na2SO4 and concentrated, purification via silica gel chromatography using 0-50% EtOAc in 1:1 hexanes:CH2Cl2 gave 6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline as a yellow solid (144 mg, 44%). 1H NMR (400 MHz, CDCl3) d 8.45-8.45 (m, 1H), 8.04-7.99 (m, 2H), 7.82 (dd, J=7.6, 1.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.12-7.08 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.90 (s, 3H) ppm; LC/MS: m/z 350.9 (M+H)+ at 3.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)c(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 3,4-dichloroaniline to yield 2-[(3,4-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:38]1[C:42]([NH2:43])=[N:41][CH:40]=[N:39]1.C1COCC1.CC([O-])(C)C.[Li+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:42]1[S:38][N:39]=[CH:40][N:41]=1)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncns1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A flask was charged with perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (INTERMEDIATE LL) (24.8 mg, 0.046 mmol), 1,2,4-thiadiazol-5-amine (5.64 mg, 0.056 mmol), and THF (465 μl) to give a clear, colorless solution. The flask was cooled in an ice-bath for 5 min, then lithium 2-methylpropan-2-olate (1M in hexane) (102 μl, 0.102 mmol) was added dropwise. After 1 h, the mixture was loaded directly onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum, then eluted onto a prequilibrated 12-g silica gel column with 0 to 10% MeOH/DCM to give 5-(1-benzylpyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (12.69 mg, 0.028 mmol, 60.6% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.46-8.33 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J=7.1 Hz, 1H), 7.83 (dd, J=1.9, 8.9 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.34-7.21 (m, 5H), 4.62 (br. s., 1H), 3.91 (d, J=13.0 Hz, 1H), 3.24 (br. s., 4H), 1.97 (d, J=14.1 Hz, 2H), 1.86-1.72 (m, 1H); m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:15]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(Br)nc1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A solution of 6-bromo-3-pyridinecarboxaldehyde (3.06 g, 15.63 mmol) and (carbethoxymethylene)triphenylphosphorane (6.60 g, 17.97 mmol) in toluene (45 mL) was heated at reflux overnight and then cooled to room temperature. After solvent removal at reduced pressure, the residue was chromatographed (16% EtOAc/hexane) to give 3.9 g (97%) of ethyl(E)-3-(6-bromo-3-pyridinyl)-2-propenoate as a pale-yellow solid. Recrystallization from hexane yielded 3.5 g (87%) of pure E-isomer as a white solid, mp 79-80° C. By comparison, the material prepared by the literature method (van den Heuvel, M., et al., J. Org. Chem., 2004, 69, 250-262) had a melting point of 83.6-84.1° C. IR 2979, 1709, 1462, 1179 cm−1; 1H NMR (CDCl3) δ 1.36 (t, J=7.2 Hz, 3H, OCH2CH3), 4.31 (q, J=7.2 Hz, 2H, OCH2CH3), 6.53 (d, J=16.2 Hz, 1H, CH═CHCO), 7.55 (d, J=8.1 Hz, 1H, 5-ArH), 7.68 (d, J=16.2 Hz, 1H, CH═CHCO), 7.72 (dd, J=2.1 Hz, 8.1 Hz, 1H, 4-ArH), 8.52 ppm (d, J=2.1 Hz, 1H, 2-ArH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:21][C:22](OCC)=[O:23])([CH2:15][C:16](OCC)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:15][CH2:16][OH:17])([CH2:21][CH2:22][OH:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1(CC(=O)OCC)CCCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(CCO)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Diethyl 2,2′-(1-benzylazepane-4,4-diyl)diacetate (1.0 g, 2.77 mmol, 1.0 eq.) in THF (10 ml) was added to a suspension of LAH (315 mg, 8.3 mmol, 3.0 eq.) in THF (40 ml) at 0° C. and the mixture was stirred at RT for 20 h. The reaction mixture was then quenched with a mixture of H2O-THF (1:10, 4 ml), stirred for 15 min and filtered through celite. The filtrate was concentrated under reduced pressure and the crude product thus obtained was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:15])=O>>[C:1]([Cl:15])(=[O:12])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC#CCC(=O)O
Product: CCCCCCC#CCC(=O)Cl

Procedure:
The 3-decynoic acid is converted to its corresponding acyl chloride by reaction with thionyl chloride.