Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:10][CH2:9]1)=O)C.C(OC(N1CCNCC1)=O)C.ClC1C=C(CCBr)C=CC=1>O.C1(C)C=CC=CC=1.C(O)C>[Cl:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)N1CCN(CCc2cccc(Cl)c2)CC1
Agent: CCOC(=O)N1CCNCC1
Agent: Clc1cccc(CCBr)c1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1cccc(CCN2CCNCC2)c1

Procedure:
50 ml of ethanol, 50 g of potassium hydroxide and 8.8 ml of water are added to 39.8 g of 1-ethoxycarbonyl-4-[2-(3-chlorophenyl)-ethyl]-piperazine, obtainable by reacting 17.7 g of 1-ethoxycarbonylpiperazine and 24.6 g of 2-(3-chlorophenyl)-ethyl bromide while heating at 120°-125° under nitrogen, and the whole is heated under reflux for 3 hours. The whole is then allowed to cool, is diluted with 300 ml of water and 300 ml of toluene and shaken thoroughly, and then the organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-[2-(3-chlorophenyl)-ethyl]piperazine is obtained and can be purified via the hydrochloride (m.p. 260°) from which it can then be freed again by treatment with sodium hydroxide solution, separation with diethyl ether and evaporation of the latter.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])(=O)=O>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(CO)Oc1ccc(Br)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(Br)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-(4-bromophenoxy)-2-methylpropan-1-ol (25.4 g) and 2,6-lutidine (30.2 mL) in dichloromethane (300 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (28.6 mL) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (37.1 g, 100%).
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (trans)-benzyl 3-azido-4-fluoropyrrolidine-1-carboxylate (30 g, 0.114 mol) in THF (0.3 L) was added PPh3 (33 g, 0.126 mol) portion wise at 0-5° C. The resulting mixture was then warmed to rt and stirred for 2 hr. 30 mL of water was then added and the resulting mixture was heated to reflux overnight. The reaction mixture was concentrated and the residue diluted with EtOAc (0.2 L) and extracted with sat. citric acid (4×100 mL). The combined aqueous extracts were washed with EtOAc (3×50 mL), then adjusted pH to 8 with sat. aq. K2CO3, and extracted with DCM (4×100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, concentrated, then dried in vacuo to give the title compound as light yellow oil that solidified on standing to afford an off-white solid (16 g, 59% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)[CH2:3]1.Cl.[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C([BH3-])#N.[Na+].C#N>CO>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:17][CH:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]3)[CH2:16][CH2:15]2)=[CH:29][CH:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1CCCC(CCCC2CCC(N)CC2)C1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: C#N
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC1CCCC(CCCC2CCC(NCc3ccc(C(C)(C)C)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 11.9 g (0.05 mole) of 4-[3-(3-methylcyclohexyl)-propyl]cyclohexylamine in 50 ml of anhydrous methanol is acidified to pH 5-6 with a methanolic HCl solution, after which 8.1 g (0.05 mole) of 4-tert-butylbenzaldehyde and 15 g of dry molecular sieve (3 Å, Grace type 0564) are added and the mixture is cooled to 0° C. 1.6 g (0.025 mole) of sodium cyanoborohydride are added a little at a time to the stirred mixture, the latter is heated to room temperature and stirring is continued for 24 hours. Thereafter, the mixture is acidified with concentrated HCl, hydrogen cyanide formed is expelled by means of nitrogen, and the mixture is filtered and rendered alkaline with dilute NaOH. It is extracted several times with dichloromethane, the organic phase is dried over MgSO4 and evaporated down, and the residue is distilled to give 9.5 g (56% of theory) of a yellow oil of boiling point 236°- 242° C./0.4 mm (compound no. 65).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].[Br:7][C:8]1S[CH:10]=[CH:11][CH:12]=1.C([Li])CCC.BrCCCCBr>>[Br:7][CH2:8][CH2:12][CH2:11][CH2:10][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]c1cccs1
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: BrCCCCBr
Product: BrCCCCc1cccs1

Procedure:
2-Thienyl lithium can be generated from 2-bromothiophene (Aldrich Chemical Co.) and n-butyl lithium (Aeros Organics, Pittsburgh, Pa.). 2-Thienyl lithium is allowed to react with 1.5 equivalents of 1,4-dibromobutane (Aeros Organics, Pittsburgh, Pa.) to give bromobutyl thiophene. The bromine is then replaced by an azide ion. The thienyl butyl azide thus obtained is reduced by sodium borohydride to yield the amine, 2-thienyl butyl amine (Scheme 5). The 2-thienyl butyl amine dissolved in water is added dropwise to a solution of thiophosgene in dichloromethane. In another dropping funnel a solution of 10% sodium hydroxide is introduced slowly to maintained alkalinity of the reaction mixture. The reaction is allowed to stand at room temperature for an additional hour with stirring. The organic layer is separated and washed with water, saturated sodium chloride solution, water, and dried over anhydrous magnesium sulfate. The solvent is removed in vacuo and the product, 2-TBITC, obtained by vacuum distillation.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([CH2:23][CH2:22][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=3[CH:13]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCc1ccccc1
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CC1=Cc2cc(OCCCc3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: A solution of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (5.0 g, 28.4 mmol) in 100 ml of DMF is treated with potassium carbonate (7.85 g, 56.8 mmol) and 1-bromo-3-phenylpropane (6.22 g, 31.2 mmol). The reaction mixture is stirred for 2 days at room temperature. This is partitioned between water and dichloromethane and the aqueous layer is extracted twice with dichloromethane. The combined organic layer is dried (MgSO4), and evaporated. The residue is chromatographed (silica gel, 20% ethyl acetate/hexane) to afford 6-(3-phenylpropyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 71°-73° C., as an oil which crystallizes on standing. The aldehyde is converted to 3-(N-hydroxyaminomethyl)-6-(3-phenylpropyloxy)-2H-1-benzopyran as described above.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH3:5].[OH-].[Na+]>>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:16])=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)c1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Quinolin-6-yl-propionic acid methyl ester containing 10% 2-methyl-2-quinolin-6-yl-propionic acid methyl ester (7.7 g, 35.8 mmol) and 2 N aq. NaOH (27 ml) was heated to reflux for 4 hours until the reaction mixture became clear. After cooling to room temperature the mixture was extracted with dichloromethane and the aqueous layer was acidified with concentrated hydrochloric acid to pH 4-5. Ethyl acetate (30 ml) was added and stirred for 10 min, the resulting solid was filtered off to obtain product, which was re-crystallized twice from methanol to return the title compound (5.3 g, 73.7%): 1H NMR 300 MHz (DMSO-d6) δ12.43 (s, 1H), 8.86 (d, 1H), 8.33 (d, 1H), 7.99-7.86 (m, 2H), 7.72-7.49 (m, 2H), 3.92 (q, 1H), 1.48 (d, 3H). ES− MS m/z: 200 [M−H+]−, 400 (dimer).
Reaction SMILES: [Mg].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:13]([CH:3]([C:4]([CH3:6])=[O:5])[C:2]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
5 ml of tetrachloromethane were added to 24.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 177.7 g (1 mol) of tert-butyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of benzoyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure tert-butyl 2-benzoylacetoacetate were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[F:23][CH:24]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C@@H:24]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:25][N:8]1[CH2:12][CH2:11][C@H:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)CCc2ccccc2)cc1
Reactant: O=S(=O)(c1ccc(O)cc1)[C@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)[C@H]1CCN(C[C@@H](F)CCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=378.3 (M+H+) was prepared from (S)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and (RS)-toluene-4-sulfonic acid 2-fluoro-4-phenyl-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:41]=[C:42]([N+:44]([O-])=O)[CH:43]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:40])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:39])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O.NC1C=C(C=C(N)C=1)C(OCCCCCCOC1C=CC(/C=C/C(OC)=O)=CC=1OC)=O>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:41]=[C:42]([NH2:44])[CH:43]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:40])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:39])[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:32][CH:33]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: COCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OCCCCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2)cc1
Agent: COC(=O)/C=C/c1ccc(OCCCCCCOC(=O)c2cc(N)cc(N)c2)c(OC)c1
Product: COCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OCCCCCCOC(=O)c3cc(N)cc(N)c3)cc2)cc1

Procedure:
6-{[(2E)-3-(4-{[4-(2-methoxyethoxy)benzoyl]oxy}phenyl)prop-2-enoyl]oxy}hexyl 3,5-diaminobenzoate is prepared from 6-{[(2E)-3-(4-{[4-(2-methoxyethoxy)benzoyl]oxy}phenyl)prop-2-enoyl]oxy}hexyl 3,5-dinitrobenzoate analogous to 6-{2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenoxy}hexyl 3,5-diaminobenzoate (Example 1)
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[C:25]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:48]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([CH3:34])[C:25]=1[C:35]1[CH:40]=[C:39]([CH:41]([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[O:44][CH3:45])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)cc(C)c2-c2cc(C(C)C)ccc2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1c(C)cc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (20 mg) is dissolved in ethanol (2 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (21 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 1N-aqueous sodium hydroxide solution (28 μl) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (19 mg). MS (m/z): 742 [M−Na]−
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=O)C.O.[NH2:16][NH2:17]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[CH2:5][C:4](=[O:3])[NH:17][N:16]=2)[CH:9]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1cccnc1
Solvent: O
Product: O=C1CC(c2cccnc2)=NN1
Yield: 49.5 %

Procedure:
The starting material was prepared using an analogous procedure to that described in Example 9. Ethyl-2-(3-pyridylcarbonyl)acetate (1 g, 5.18 mmol) was treated with hydrazine hydrate (251 μl, 5.2 mmol) to give 3-(3-pyridyl)-4,5-dihydro-1H-pyrazol-5-one (413 mg, 50%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH3:12][C:4]1[CH:3]=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1C
Temperature: 100 °C
Yield: 88.7 %

Procedure:
In a pressure vessel was added methyl 4-bromo-2-methylbenzoate (500 mg, 2.18 mmol), Dioxane (5.0 mL), Cs2CO3 (1.4 g, 4.36 mmol), and Xantphos (92.0 mg, 0.16 mmol). The mixture was stirred and nitrogen was bubbled into the reaction for 5 min before adding in Palladium(II) acetate (58 mg, 0.08 mmol), and commercially available N-methyl piperazine (0.26 mL, 2.62 mmol). The vessel was then sealed and heated to 100° C. overnight. The reaction was cooled and filtered through celite. The supernatant was then concentrated and column purified (5:95 EtOAc:Hexanes) to give methyl 2-methyl-4-(4-methylpiperazin-1-yl)benzoate (480 mg, 89% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]3[CH2:18][CH2:17][CH2:16][CH:15]4[CH:13]3[O:14]4)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[CH:24]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.O1CCOCC1.C1(C)C=CC=CC=1.BrC1CC2C(C2)OC1>C1COCC1>[CH:30]1[C:26]2[CH2:27][CH2:28][C:29]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH:24]([N:34]3[CH2:35][CH2:36][N:37]([CH:15]4[CH2:16][CH2:17][CH2:18][CH:12]([O:11][C:10]5[C:4]6[S:3][C:2]([CH3:1])=[N:6][C:5]=6[CH:7]=[CH:8][CH:9]=5)[CH:13]4[OH:14])[CH2:38][CH2:39]3)[C:25]=2[CH:33]=[CH:32][CH:31]=1.[CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]3[CH2:18][CH2:17][CH2:16][CH:15]4[CH:13]3[O:14]4)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Agent: BrC1COC2CC2C1
Agent: Cc1nc2cccc(OC3CCCC4OC34)c2s1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(OC3CCCC(N4CCN(C5c6ccccc6CCc6ccccc65)CC4)C3O)c2s1

Procedure:
The title compound was prepared according to Method A from 2-methyl-7-(7-oxa-bicyclo[4.1.0]hept-2-yloxy)-benzothiazole and 1-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)piperazine with dioxane/toluene (2:1) as the solvent. mp 207° C. (decomposition); LSIMS m/z 540. The 2-methyl-7-(7-oxa-bicyclo[4.1.0]hept-2-yloxy)-benzothiazole was prepared according to Method IV using THF as the solvent and 4-bromo-2-oxa-bicyclo[4.1.0]heptane as the alkylating agent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][C:25](=[O:27])[NH:24][CH2:23]4)=[O:21])=[C:16]([C:28]([F:31])([F:30])[F:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:33])([F:35])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][C:25](=[O:27])[N:24]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:23]4)=[O:21])=[C:16]([C:28]([F:31])([F:30])[F:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CC(F)(F)F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)imidazolidin-4-one (300 mg, 0.56 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), sodium hydride (26 mg, 1.08 mmol, 2.00 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (260 mg, 1.12 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 20° C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 58.8 mg (17%) of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as a off-white solid. (ES, m/z): [M−H]− 620; 1H NMR (300 MHz, CDCl3) δ: 8.01-8.03 (m, 2H), 7.53 (s, 3H), 7.47 (s, 1H), 5.20 (s, 1H), 4.65 (s, 1H), 4.32 (s, 1H), 4.17 (s, 1H), 4.02-4.11 (m, 2H), 3.73-3.84 (m, 2H)
Reaction SMILES: [Na].[CH3:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][N:10]=2)[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH:16]([O:19]C(C)C)(C)C.[NH4+].[Cl-]>CO.[Cu]I.CN(C=O)C>[CH3:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([O:19][CH3:16])=[CH:11][N:10]=2)[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CC(C)OC(C)C
Reactant: Cc1ccc(C)n1-c1ccc(I)cn1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-n2c(C)ccc2C)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Sodium (3.0 equiv., 735 mmol, 16.9 g) was dissolved in dry methanol (240 ml). DMF (160 ml), CuI (0.15 equiv., 37 mmol, 7.0 g) and N-protected 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-pyridine (I17) (1.0 equiv., 245 mmol, 73.0 g) were added. The reaction mixture was heated to 80° C. for 3 h. After the mixture had been allowed to cool to room temperature, isopropylether and an aqueous NH4Cl solution (5%) were added, the mixture was stirred overnight. The solids were filtered off over Celite and the filtrate was extracted several times with dichloromethane. The combined organic phases were washed with a 10% aqueous NH4OH solution, dried with MgSO4 and concentrated in vacuo. After drying in high vacuum, 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methoxy-pyridine (I18) (50 g, yield=100%) was pure enough to be used as such in the next step. 1H NMR (δ, CDCl3): 2.08 (6H, s), 3.91 (3H, s), 5.87 (2H, s), 7.15 (1H, d, J=8.7 Hz), 7.32 (1H, dd, J=8.7, 3.0 Hz), 8.27 (1H, d, J=3.0 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH2:16][CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCOCCBr
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
In DMF (120 ml) was dissolved 4-bromobenzyl alcohol (15 g). To the mixture was added under ice-cooling 65% sodium hydride (3.0 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise at room temperature 2-bromoethylethyl ether (11.4 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-[(2-ethoxyethoxy)methyl]benzene (9.0 g). In THF (104 ml) was dissolved 1-bromo-4-[2-ethoxyethoxy)methyl)]benzene (8.7 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (23 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise trimethyl borate (8.7 g), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 5% sulfuric acid (35 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=1/2) to give 4-[(2-ethoxyethoxy)methyl]phenyl borate (2.1 g).