Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH:9]1[CH2:18][CH:17]([OH:19])[CH:16]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:10]1[CH2:11]2.CCN(C(C)C)C(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC(OC)(C)C>[OH:28][CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][CH:16]1[CH:10]2[CH2:11][C:12]3[C:7]([CH2:8][CH:9]2[CH2:18][CH:17]1[O:19][C:42]([CH:39]1[CH2:41][CH2:40]1)=[O:43])=[C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:29])[CH:15]=[CH:14][CH:13]=3
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)OC)CC21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCCC(O)CCC1C(OC(=O)C2CC2)CC2Cc3c(cccc3OCC(=O)OC)CC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
A solution of [2-Hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-acetic acid methyl ester (32 mg, 0.06 mmol), DIPEA (31 μl, 0.18 mmol) and DMAP (1 crystal) in DCM (2 ml) was treated with cyclopropanecarbonyl chloride (8 μl, 0.08 mmol) and stirred for 24 hr at RT under nitrogen. The reaction mixture was diluted with MTBE and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography. This resulting material was dissolved in MeOH/THE (4 ml), treated with Amberlite IR120H and stirred 24 hr. The reaction mixture was filtered and concentrated to yield cyclopropanecarboxylic acid 1-(3-hydroxy-octyl)-5-methoxycarbonylmethoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl ester (32 mg) as an oil. 1HNMR: (400 MHz, DMSO-d6) δ 7.06 (d, 1H, J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.8); 4.78 (s, 2H); 4.1-4.2 (m, 1H); 4.05-4.50 (m, 1H); 3.68 (s, 3H); 2.6-2.8 (m, 2H); 2.4-2.5 (m, 2H); 2.20-2.35 (m, 1H); 2.10-2.20 (m, 1H); 1.8-1.95 (m, 1H); 1.10-1.16 (m, 15H); 0.95-1.10 (m, 1H); 0.70-0.90 (m, 7H); MS: m/z 495 [M+Na]+
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:20]1[N:15]([CH2:14][CH2:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Yield: 78 %

Procedure:
10.0 g (25 mmol) of DTPA was dispersed in 20 ml of pyridine. 18 g (0.18 mol) of acetic anhydride was added to the dispersion, and a reaction was allowed to take place at 65□ for 24 hrs with stirring. After the reaction was completed, the reaction mixture was filtered to recover generated material. The recovered compound was washed with acetic anhydride and diethyl ether several times, and dried under pressure for 24 hrs, thereby obtaining a DTPA anhydride at a yield of 78%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](F)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:17]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O>CN(C)C=O.O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@H:18]2[O:19][CH2:20][CH2:21][NH:16][CH2:17]2)=[CH:24][C:25]=1[C:30]([F:32])([F:33])[F:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(F)c(C(F)(F)F)c2)C1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F
Temperature: 105 °C
Reaction time: 6 h

Procedure:
To a suspension of sodium hydride (43 mg, 1.08 mmol) in N,N-dimethyl formamide (3 mL) at 0° C. was added 2,2,2-trifluroethanol (108 mg, 1.08 mmol), and the resultant mixture stirred for 5 mins. N-Boc-(R)-2-(4-fluoro-3-trifluoromethylbenzyl)morpholine, example 2, intermediate (b) (98 mg, 0.27 mmol) was added in one portion as a solution in N,N-dimethyl formamide (1.5 mL) and the reaction mixture warmed to 105° C. and stirred at that temperature for 6 hrs. The reaction was cooled to room temperature and poured into water (20 ml). The suspension was extracted with ethyl acetate (20 mL×2). Combined organic extracts were washed with water (25 mL×2) and brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; 20% ethyl acetate/isohexane) to yield the desired product as a colorless oil (87 mg) and used directly in the next reaction. The crude material was deprotected using TFA (20% v/v in dichloromethane, 2 mL) over 3 hrs, poured onto an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and dichloromethane: methanol (1:1, 2 mL×2). The column was then washed with ammonia (2N solution in methanol, 2 mL×3) and the ammonia washes were concentrated in vacuo to yield the desired morpholine example 37 a colorless oil (59 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CO.C(Cl)Cl>[NH2:17][C:18]1[C:19]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[O:5])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: Nc1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180° C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which 100 ml of hot toluene was added. On cooling to 50° C., 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending in methylene chloride. The weight of crude solid produced was 22.5 g. The solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal the second time, to give 14 g (28%) solid which was red-orange in color; m.p. 121.5°-122.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[C:37](=[O:41])[C:38]#[C:39][CH3:40]>>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37](=[O:41])[C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[F:28]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC#CC(=O)c1cc(F)c(F)cc1F
Product: C/C(=C/C(=O)c1cc(F)c(F)cc1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 677 mg (1.85 mmol) of Intermediate 45 and 366 mg (1.85 mmol) of Intermediate 38 to yield 482 mg (46% yield) of Example 16. TLC (DCM/MeOH (4:1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.39 (d, 1H, J=8.9), 7.86 (m, 2H), 7.69-7.59 (m, 1H), 7.54-7.40 (m, 4H), 7.10 (d, 2H, J=8.5), 6.79 (d, 2H, J=8.5), 5.3 (s, 1H), 4.12 (t, 2H, J=6.5), 4.1 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.76 (dd, 1H, J=13.7, 8.9), 2.3 (s, 3H), 1.64 (s, 3H): low resolution MS (ES+)m/e 565.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1F)[CH3:2].[S-2:14].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[SH:14])[CH3:2]
Reactant: CCOC(=O)c1cccc(F)c1F
Reactant: [S-2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(F)c1S
Reaction time: 10 h

Procedure:
A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9.
Reaction SMILES: [ClH:1].[C:2]([C:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:5]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=O)([CH3:7])[CH3:6])#[N:3].S(=O)(=O)(O)[OH:34]>O>[ClH:1].[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][CH2:19][C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:5]([CH3:7])([CH3:6])[CH2:8][C:9](=[O:11])[NH:3][C:2]1=[O:34]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C(C#N)(CCCN(C)C)c1cccc(OC)c1
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: O
Product: COc1cccc(C2(CCCN(C)C)C(=O)NC(=O)CC2(C)C)c1
Temperature: 25 °C

Procedure:
A reaction vessel is charged with 11.24 kg of diethyl 2-[2-cyano-5-(dimethylamino)-2-(3-methoxyphenyl)-1,1-dimethylpentyl]propanedioate, monohydrochloride (9), and a solution of 11.46 kg of sulfuric acid (96% w/w) in 90 L of water is added. The reaction mixture is refluxed for about 54 h. When the reaction is complete as indicated by thin layer chromatography, the solution is cooled to 25° C. The aqueous solution is washed with 20 L of methylene chloride. The aqueous phase is mixed with 40 L of methylene chloride and basified with 19 L of aqueous ammonium hydroxide (29% w/w) while maintaining the temperature at less than 30° C. After separation of the layers, the aqueous phase is extracted twice with 20-L portions of methylene chloride. The combined organic phase is washed twice with 20-L portions of water and filtered through a layer of diatomaceous earth.
Reaction SMILES: CO[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]3[C:15]4[S:21][CH:20]=[CH:19][C:16]=4[NH:17][N:18]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:22]1([Mg]Br)[CH2:24][CH2:23]1.O1[CH2:31][CH2:30][CH2:29]C1>>[CH:22]1([C:3]([CH:29]2[CH2:30][CH2:31]2)([C:5]2[CH:13]=[C:12]3[C:8]([CH:9]=[C:10]([C:14]4[C:15]5[S:21][CH:20]=[CH:19][C:16]=5[NH:17][N:18]=4)[NH:11]3)=[CH:7][CH:6]=2)[OH:4])[CH2:24][CH2:23]1
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2cc(-c3n[nH]c4ccsc34)[nH]c2c1
Product: OC(c1ccc2cc(-c3n[nH]c4ccsc34)[nH]c2c1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(1H-Thieno[3,2-c]pyrazol-3-yl)-1H-indole-6-carboxylic acid methyl ester (180 mg, 0.605 mmol, Example 43) in anhydrous tetrahydrofuran (8 mL) is added cyclopropylmagnesium bromide (6.0 mL, 0.5 M in tetrahydrofuran) at 0° C. The ice bath is removed and the reaction mixture stirred at room temperature for 4 hours. To it is added an additional cyclopropylmagnesium bromide (6 mL, 0.5 M in tetrahydrofuran) and stirred at room temperature overnight. The reaction is not completed (TLC) and added cyclopropylmagnesium bromide (6.0 mL). The solublized reaction mixture is then stirred overnight. The reaction is quenched at 0° C. by the addition of saturated ammonium chloride. The reaction mixture is partitioned between diethyl ether and water. The diethyl ether layer is washed with brined and dried over magnesium sulfate. The crude is chromatographed on 10 g silica gel cartridge (30-50% ethyl acetate gradient in heptane) to afford product (120 mg). The product is recrystallized as follows: In a Smith vial, a mixture of solid (120 mg) and ethyl acetate (2 mL) is heated at 70° C. using microwave (Personal chemistry optimizer) for 240 seconds at normal absorption. Upon cooling dicyclopropyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yl]-methanol crystallized as a white solid. mp 110-112° C.; 1H NMR [(CD3)2SO)]: δ 13.189 (1H, s), 11.440 (1H, s), 7.747 (1H, d, J=5.1 Hz), 7.631 (1H, s), 7.467 (1H, d, J=8.4 Hz), 7.249 (2H, m), 6.579 (1H, s), 4.304 (1H, s), 1.225 (2H), 0.581 (2H, m), 0.387 (4H, m), 0.195 (2H, m); LC/MS: 350 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[C:15](OCC)(OCC)(OCC)[CH3:16]>>[Cl:1][C:2]1[C:11]2[N:10]([C:15]([CH3:16])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Product: Cc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture consisting of 20 g. (0.087 mole) of 2,6-dichloro-3-hydrazinoquinoxaline and 160 ml. (0.87 mole) of triethyl orthoacetate was heated with mechanical stirring under a dry nitrogen atmosphere in a preheated oil bath at 100° C. for a period of 20 hours to give a yellow suspension. The resulting mixture was cooled to room temperature and filtered, and the recovered solid product was subsequently washed with ethanol and air-dried to constant weight to ultimately afford 10.2 g. (46%) of pure 4,8-dichloro-1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >280° C. Mass Spectrum: m/e, 254/252 (P+).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NCC1CCN([NH:27][C:28](=[O:41])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=2)CC1>>[CH2:39]([O:38][C:36](=[O:37])[C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]2[CH2:7][CH2:6][CH:18]([CH2:10][NH:11][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:17][CH2:16]2)=[O:41])=[CH:35][CH:34]=1)[CH3:40]
Reactant: CCOC(=O)c1ccc(NC(=O)NN2CCC(CN)CC2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CCOC(=O)c1ccc(NC(=O)N2CCC(CNC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 46.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.150 g, 0.63 mmol) and 3-(4-aminomethyl-1-piperidinyl)-1-(4-ethoxycarbonylphenyl) urea (0.305 g, 1.0 mmol) according to the procedure used in example 2 to give 0.080 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)ccc(OC)c2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
To a mixture of methyl 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylate (82.9 mg, 0.279 mmol) in THF (0.3 mL) and MeOH (0.3 mL) was added 1.0 M aq. NaOH (1.39 mL, 1.39 mmol). The reaction mixture was stirred at room temperature for 40 min., neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove the solvents. The residue was dissolved in THF, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a white powder (53.4 mg, 68%). LCMS calc. for C13H9F3NO3 (M+H)+: m/z=284.1. Found: 284.2.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][CH3:38].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[NH:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CNc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3 mmol), K2CO3 (1.4 g, 10.3 mmol), 1-[4(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3 mmol), KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux under nitrogen for 23 hours. The reaction was cooled to ambient temperature, poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate yield 4.8 g of a damp, brown solid. The compound was isolated by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g. Recrystallization from ethanol gave 2.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone as a beige solid, m.p.=151°-153° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([O:14][CH2:13][CH2:12][CH:10]2[CH2:9][CH:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:11]2)=[CH:37][CH:36]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCC1CC(OC2CCCCO2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCC2CC(OC3CCCCO3)C2)cc1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
2-[3-(Tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethanol (1.08 g, 5.39 mmol) was dissolved in tetrahydrofuran (20 mL) and was cooled in an ice bath. Triphenylphosphine (2.12 g, 8.09 mmol) and 4-bromo-phenol (1.12 g, 6.47 mmol) were added and the reaction was stirred until dissolved. Diethylazodicarboxylate (1.45 g, 8.09 mmol) was added dropwise to the reaction and the reaction was then warmed to room temperature and stirred for 48 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a clear oil. Purification on silica gel with heptane-ethyl acetate (15% ethyl acetate) gave 2-({3-[2-(4-bromophenoxy)ethyl]cyclobutyl}oxy)tetrahydro-2H-pyran (622 mg, 32.4%) as a clear oil. Partial 1H NMR indicated a −4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.08 (m, 0.80H), 4.38 (m, 0.20H), 6.74 (d, J=8.98, 2H), 7.34 (d, J=9.18, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C(=O)OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1
Temperature: 60 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of compound 13 (1.08 g) in trifluoroacetic acid (17 mL) was stirred at 60° C. for 5 hrs. The solution was then cooled down at 0° C., water was added, and the mixture was extracted with EtOAc. Organics were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (DCM/MeOH) to yield compound 14 as a white powder in 97% yield. MS (ESI, EI+) m/z=482 (MH+).
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N+:10]([O-:20])[CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CC)(OC)c1cccnc1C
Solvent: ClCCl
Product: CCC(CC)(OC)c1ccc[n+]([O-])c1C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.176 g, 0.911 mmol) in CH2Cl2 (10 mL) was added 3-chloroperoxybenzoic acid (0.473 g, 2.75 mmol). The mixture was stirred for 16 h and concentrated by evaporation under vacuum. The residue was purified by flash chromatography on a silica gel column (6:1 EtOAc/MeOH), affording 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine 1-oxide as a white solid (0.188 g, 98%). 1H NMR (CDCl3) δ 0.74 (t, 6H, J=7.5 Hz), 1.94 (q, 4H, J=7.5 Hz), 2.80 (s, 3H), 3.01 (s, 3H), 7.07-7.10 (m, 1H), 7.21 (d, 1H, J=8.1 Hz), 8.27 (d, 1H, J=6.3 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:18][CH:17]([C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]4[CH:33]=[CH:34][N:35]=[C:29]4[CH:28]=3)=[O:24])=[CH:21][CH:20]=2)[CH2:16]1.[H-].[Na+].[CH3:40][CH:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>O1CCCC1>[N:35]1[CH:34]=[CH:33][N:30]2[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([CH:17]4[CH2:18][N:15]([S:43]([CH:41]([CH3:42])[CH3:40])(=[O:45])=[O:44])[CH2:16]4)=[CH:37][CH:36]=3)=[CH:28][C:29]=12
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)N1CC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1
Reaction time: 1 h

Procedure:
In a 4 mL vial was mixed 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide bis(2,2,2-trifluoroacetate) (60 mg, 0.112 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature. To this mixture was added in portions 60% sodium hydride in mineral oil (22.45 mg, 0.561 mmol). This heterogeneous mixture was stirred 1 hour. To this was added propane-2-sulfonyl chloride (0.015 mL, 0.135 mmol) at and reaction mixture was stirred for 3 hours. The mixture was quenched with water, and product was extracted with 10% methanol/dichloromethane. The organic layers were combined, concentrated and purified by normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (m, 1H), 8.47 (d, J=7.0 Hz, 1H), 7.90 (m, 3H), 7.48 (m, 3H), 7.37 (s, 1H), 6.84 (m, 1H), 4.50 (d, J=5.9 Hz, 2H), 4.22 (m, 2H), 3.93 (m, 3H), 3.48 (m, 1H), 1.25 (d, J=5.9 Hz, 6H); MS (ESI(+)) m/e 413 (M+H)+.