Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)C=O>O>[ClH:1].[OH:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:7][CH:8]=1
Reactant: OCc1ccc(OCCCCl)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: OCc1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(3-chloropropoxy)benzyl alcohol (11.1 g), potassium carbonate (23.0 g), piperidine (6.57 mL) and N,N-dimethylformamide (130 mL) is heated at a temperature close to 100° C. for 5 h30, then cooled back to room temperature. Water (130 mL) is added and organics are extracted with dichloromethane. The combined extracts are pooled, dried over magnesium sulphate, purified by chromatography over silica gel (eluent: dichloromethane/methanol with trace amount of ammonia from 90/10 to 80/20) to give 5.62 g of 1-[3-(4-hydroxymethylphenoxy)-propyl]piperidine, hydrochloride as a white solid used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:23]C(C)([O-])C.[K+].FC(F)(F)S(OC)(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:23])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: CC(C)(C)[O-]
Agent: COS(=O)(=O)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reaction time: 0.17 h

Procedure:
Codeinone (300 mg) was added to a stirred suspension of potassium tert-butoxide (153 mg) in N,N-dimethylformamide (5 ml) at room temperature. After 10 minutes, methyl trifluoromethanesulphonate (164 mg) was added dropwise to the suspension. The solution was stirred for 5 minutes, diluted with ethyl acetate (30 ml), and then poured into water (50 ml). The aqueous phase was removed, and the organic phase was dried with sodium sulphate and evaporated, producing an orange solid. Analysis by HPLC against pure thebaine gave a thebaine content of 10%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A suspension of 4-chloro-3-nitro[1,5]naphthyridine (10.0 g, 47.7 mmol) and ethyl 4-aminobutyrate hydrochloride (9.6 g, 57 mmol) in dichloromethane (200 mL) was cooled to 5° C. Triethylamine (16.6 mL, 119 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred for two hours. The mixture was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2×150 mL). The combined aqueous fractions were extracted with dichloromethane (100 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 14.5 g of ethyl 4-(3-nitro[1,5]naphthyridin-4-ylamino)butanoate as a yellow solid.
Reaction SMILES: [CH2:1]1[O:6][CH:2]1[CH2:3][CH2:4][CH3:5].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]>>[CH2:13]([NH:14][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5]
Reactant: NCCCCCCN
Reactant: CCCC1CO1
Product: CCCC(O)CNCCCCCCNCC(O)CCC

Procedure:
Condensation of 1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxypentylamine] (I: R = CH3 (CH2)2, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH3:6])[CH3:2].C([Li])CCC.[C:15]([C:17]1[C:21]([CH:22]=[O:23])=[CH:20][N:19]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[Cl:35])[N:18]=1)#[N:16].O>O1CCCC1.CCOCC>[C:15]([C:17]1[C:21]([CH:22]([OH:23])[C:6]#[C:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[CH:20][N:19]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:32])([F:34])[F:33])=[CH:26][C:25]=2[Cl:35])[N:18]=1)#[N:16]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reactant: CCOC(CC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(C#CC(O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N)OCC
Reaction time: 0.17 h

Procedure:
To a solution of propionaldehyde diethyl acetal (0.0192 g) in anhydrous tetrahydrofuran (2 ml) cooled to -78° C. under an atmosphere of nitrogen was added dropwise n-butyl lithium (621 μl, 2.5M in hexanes) and the mixture was stirred for 10 minutes. 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.05 g) was added and stirring continued for 30 minutes. The reaction mixture was poured into water (5 ml) and ether (5 ml). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (5 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][NH2:11]>C(O)C>[C:4]1([CH2:1][CH:2]=[N+:10]=[N-:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: CC(=O)c1ccccc1
Solvent: CCO
Product: [N-]=[N+]=CCc1ccccc1
Reaction time: 2 h
Yield: 68.8 %

Procedure:
Acetopheneone hydrazone: acetophenone (2.0 g, 16 mmol) is diluted in 16 ml of absolute ethanol and then hydrazine (2.3 ml, 48 mmol) is added. The mixture is heated to reflux temperature. After 2 h, the solvent is evaporated and the residue is taken up in ether (150 ml). The medium is washed with water (100 ml). After drying over Na2SO4, the ether is evaporated off. A pale yellow oil (1.5 g, 11 mmol, 69%) is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52](O)=[O:53])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1.[CH3:55][NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:55][N:56]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C:52]([C@@H:48]1[CH2:49][CH2:50][CH2:51][N:47]1[CH2:46][CH2:45][N:2]([CH3:1])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1)=[O:53]
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: CN(CCN1CCC[C@H]1C(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a mixture of (S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidine-2-carboxylic acid (0.035 mmol, 25.7 mg), tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate 135c (0.042 mmol, 12.4 mg) and DIEA (0.212 mmol, 27 mg) in DMF (0.15 mL) was added HATU (0.042 mmol, 16 mg). The mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried and concentrated. 23% of the residue was purified by prep. HPLC to give a yellow solid (4 mg, 37%). MS (ES, m/z): 1002.36 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>ClCCl>[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCCN
Reactant: COc1cc(Cl)nc2ccccc12
Solvent: ClCCl
Product: COc1cc(NCCCCN)nc2ccccc12
Yield: 46.7 %

Procedure:
2-Chloro-4-methoxyquinoline (prepared as for 2-chloro-4-ethoxyquinoline but using methanol as solvent; 3.873 g, 20 mmol) and 1,4-diaminobutane (12.3 g, 140 mmol) were heated at 60° C. for 50 h. The solution was then reduced in volume in vacuo, and diluted with dichloromethane. The solid was filtered off and washed with dichloromethane. The filtrate was evaporated to dryness and purified by flash chromatography, eluting with 0-10% ‘10% ammonia in methanol’ in dichloromethane, to give 2-(4-aminobut-1-ylamino)-4-methoxyquinoline as a white solid (2.29 g, 47%). This material (2.142 g, 8.73 mmol) in concentrated hydrochloric acid (80 ml) was gently refluxed for 15 h, and then evaporated to dryness to give the title compound as a white foam (2.65 g, 99%); δH (CD3OD) 1.8-1.9 (4H, m), 2.95-3.05 (2H, m), 3.5-3.6 (2H, m), 6.36 (1H, s), 7.46 (1H, t), 7.7-7.9 (2H, m), 8.45(1H, d): MS (ES+) 232 (100%, MH+).
Reaction SMILES: [CH:1]12[CH2:13][CH:4]([C:5]3[C:6]([OH:12])=[CH:7][CH:8]=[C:9]([OH:11])[C:10]=31)[CH2:3][CH2:2]2.B(F)(F)F.CCOCC.[Cl:23][CH2:24][CH2:25][C:26]([CH3:30])(O)[CH:27]=[CH2:28].O>O1CCOCC1>[Cl:23][CH2:24][CH2:25][C:26]1([CH3:30])[CH2:27][CH2:28][C:7]2[C:6](=[C:5]3[CH:4]4[CH2:13][CH:1]([CH2:2][CH2:3]4)[C:10]3=[C:9]([OH:11])[CH:8]=2)[O:12]1
Reactant: C=CC(C)(O)CCCl
Reactant: Oc1ccc(O)c2c1C1CCC2C1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC1(CCCl)CCc2cc(O)c3c(c2O1)C1CCC3C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of, 1,2,3,4-tetrahydro-1,4-methano-naphthalene-5,8-diol (1.34 g, 794 mmol), 1.0 ml (3.97 mmol) of BF3.Et2O and 25 ml of dioxane was heated up to 110° C. under a nitrogen atmosphere. A solution of 5-chloro-3-methyl-pent-1-en-3-ol (1.12g, 8.6 mmol) in 24 ml of dioxane was added slowly to the mixture. The addition was completed after two hours and the mixture was continued to reflux for an additional 3 hours. After cooling down to room temperature, the mixture was poured to water, extracted with ethyl acetate, washed with water and dried over MgSO4. After the removal of solvents, the residue was mixed with methanol/HCl and let stirred overnight at room temperature. After the removal of the solvents the residue was purified via flash column chromatography on silica gel (1:3 EtOAc/Hex) twice to give 1.30 g of 2-(2-chloro-ethyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-6-ol. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.39 (s, 1H), 4.27 (s, 1H), 3.63-3.47 (m, 4H), 2.73-2.70 (m, 2H), 2.00-1.47 (m, 8H), 1.43-1.15 (m, 4H); MS: 307 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30](OC)=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:35]([O:34][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][O:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:10][CH2:9]1)(=[O:37])[CH3:36]
Reactant: COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 2) (200 mg) in dichloromethane (5 ml) were added acetyl chloride (0.06 ml), triethylamine (0.19 ml) and the mixture was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give the titled compound (190 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:16])[C:11]([O:13]CC)=O)=[CH:5][CH:4]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH:10]([CH3:16])[C:11]2=[O:13])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Cc1ccc(OC)cc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(C)C2
Temperature: 50 °C

Procedure:
Ethyl β-(p-methoxyphenyl)-α-methylpropionate is added to 56 g of polyphosphoric acid with stirring at 50°C. The mixture is then heated to 83°-90°C for 2 hours. The cooled reaction mixture is poured slowly into a mixture of water and crushed ice with stirring and extracted with 3 × 300 ml of ether. The etheral solution is washed with 10% sodium bicarbonate solution followed by cold water to neutral, then with saturated sodium chloride solution and dried over magnesium sulfate for 1.5 hours and filtered. The solvent is removed on an evaporator and the residue distilled to obtain 6-methoxy-2-methylindanone.
Reaction SMILES: CO.C(Cl)Cl.[CH2:6]([O:8][C:9](=[O:37])[C@@H:10]([NH:29]C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[N:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[CH3:7]>C(OC(O)C)C>[C:19]1([NH:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH2:29])[C:9]([O:8][CH2:6][CH3:7])=[O:37])=[CH:17][CH:16]=2)[C:28]2[C:23](=[CH:24][CH:25]=[N:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(C)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nccc3ccncc23)cc1

Procedure:
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and Intermediate 3 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl) amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-colored solid (420 mg, 60% over two steps). δH (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[C:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:37]([OH:41])[C:38]([OH:40])=[O:39].CI>C1COCC1.CN1C(=O)N(C)CCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:29]([O:28][C:27]1[C:22]([O:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[C:23]([CH:37]([OH:41])[C:38]([OH:40])=[O:39])[CH:24]=[CH:25][CH:26]=1)[CH3:1]
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(Oc1cccc(C(O)C(=O)O)c1OCc1ccccc1Cl)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred solution of diisopropylamine (170 μL, 1.21 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (483 μL, 2.5 M in hexanes, 1.21 mmol). After 15 min, the reaction mixture was cooled to −78° C. and a solution of Example 1 Part B compound (248 mg, 0.537 mmol) in THF (1 mL) was then added over 2 min. After an additional 15 min, DMPU was added (2 mL) and then methyl iodide (42 μL, 0.68 mmol). The reaction mixture was stirred for 2 h and then warmed to −40° C. After 14 h, the reaction was quenched with sodium hydroxide solution (1 M), warmed to room temperature and stirred for 1 h. The reaction mixture was acidified with 5% potassium hydrogen sulfate, extracted with CH2Cl2, dried (MgSO4) and evaporated. Purification by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−0.1% TFA gradient) provided the title compound, a colorless oil, as a 1:1 mixture of diastereomers, 75 mg (31% yield). LC/MS gave the correct molecular ion [(M+H)+=447] for the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-:31].[K+].C(O)(C)C.Cl.[OH2:38]>>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]([OH:38])=[O:31])=[CH:17][N:16]=3)=[CH:23][CH:24]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(Oc3ccc(C#N)cn3)cc2)ccc(C(C)=O)c1O
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Product: CCCc1c(OCc2ccc(Oc3ccc(C(=O)O)cn3)cc2)ccc(C(C)=O)c1O
Temperature: 130 °C
Yield: 17 %

Procedure:
Mix 6-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenoxy]-nicotinonitrile (,0.14 g, 0.34 mmol), powdered potassium hydroxide (0.69 g, 12.20 mmol), isopropyl alcohol (1.5 mL) and water (1.5 mL). Heat to 130° C. for 8 hrs. Allow to cool to ambient temperature. Pour into water (20 mL) and acidify to pH 1 with hydrochloric acid (37% in water, 1 mL). Extract with ethyl acetate (3×30 mL). Combine the organic extracts, dry over magnesium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purification using 5% isopropyl alcohol/chloroformchloroform to 10% isopropyl alcohol/chloroformchloroform as gradient eluent gives the title compound (0.02 g, 17%): MS (m/z): 420.1 (M−1). 1H NMR (acetone-d6) 12.94 (s, 1H), 8.77 (s, 1H), 8.40 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.79 (d, J=9.2 Hz, 1H), 5.34 (s, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.63 (s, 3H), 1.66-1.56 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1([CH:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=[CH:18][N:17]=[N:16]1.[OH-].[Na+].O.[CH3:23][N:24](C)C=O>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5]([CH:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)([CH2:7][N:17]1[CH:18]=[N:24][CH:23]=[N:16]1)[OH:6]
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Reactant: CC1(C)OCC(C2(C(C)(C)C)CO2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)OCC(C(O)(Cn2cncn2)C(C)(C)C)O1
Temperature: 100 °C
Reaction time: 10 h
Yield: 26 %

Procedure:
12.4 g (0.062 mol) of 2-t-butyl-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxirane, 5.1 g (0.074 mol) of triazole and 3 g (0.074 mol) of sodium hydroxide are dissolved in 60 ml of dimethylformamide and the mixture is stirred at 100° C. for 10 hours. For working up, the cooled reaction mixture is introduced into water and extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate and concentrated in vacuo and the residue is purified by column chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 3:1). 4.4 g (26% of theory) of 2,2-dimethyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-(1,2,4-triazol-1-yl-methyl)-propan-1-ol are obtained as an oil of refractive index nD20 1.4890;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:26]=[CH:25][C:24]2[O:23][CH2:22][O:21][C:20]=2[CH:19]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:17][C:18]3[CH:26]=[CH:25][C:24]4[O:23][CH2:22][O:21][C:20]=4[CH:19]=3)[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1
Reactant: CS(=O)(=O)c1nc2cc(Cl)ccc2[nH]1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(Cl)ccc2n1Cc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2.3 g of the 6-chloro-2-methanesulfonylbenzimidazole was dissolved in 30 ml of dimethylformamide, followed by the addition of 480 mg of 60% sodium hydride and 2.04 g of piperonyl chloride under cooling with ice. The obtained mixture was maintained at 80° C. by heating for 4 hours, allowed to stand overnight and filtered to remove insolubles. The filtrate was concentrated in a vacuum and subjected to silica gel column chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:18]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cnc2ccccc2n1
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1cnc2ccccc2n1
Temperature: 68 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-Methylquinoxaline (8.94 g) was combined with 50 ml CCl4 and 6.5 g Na2CO3 in a 125 ml beaker. This was heated to 68° C. and then Cl2 was introduced via an inverted funnel so that the Cl2 was bubbled very slowly. This was continued for 1 hour and then the reaction mixture was cooled to 20° C. in an ice bath and partitioned between ether and saturated NaHCO3 solution. The ether was separated, dried over MgSO4, and concentrated to dryness. The residue was immediately flashed down a column packed with 20 cm of 32-63 micron silica gel (the column having a diameter of 8 cm) using 1:1 ether:hexane as eluant. After a 1 liter forerun, 250 ml fractions were collected. Fractions 3-5 were combined and concentrated to yield 2.58 g (23%) of title product as a yellow solid; tlc (3:7 ethyl acetate:CH2Cl2) Rf 0.65.