Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].N1C=CC=CC=1>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCN1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCN2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
p-Toluenesulfonylchloride (1 g) is added portionwise to a solution of 1-(2-hydroxyethyl)pyrrolidin-2-one (500 μL) and pyridine (1.5 mL) in dichloromethane (8 mL) chilled in an ice bath. The mixture is stirred at room temperature for 12 hours and partitioned between 1 M hydrochloric acid and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (ethyl acetate) to give the title compound. Yield: 390 mg; Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].Cl>CS(C)=O.O>[F:13][CH:14]([F:17])[CH2:15][O:16][C:4]1[N:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCC(F)F)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
Powdered potassium hydroxide (712 mg, 12.7 mmol) was added to a mixture of 6-chloronicotinic acid (500 mg, 3.17 mmol) and 2,2-difluoroethanol (520 mg, 6.35 mmol) in DMSO (15 mL) and the mixture was stirred at 120 C for 14 h. An additional two equivalents of 2,2-difluoroethanol and potassium hydroxide were added and the mixture was heated for 24 h. The mixture was cooled to room temperature, diluted with water (5 mL), acidified with 1N aq. HCl (to pH 1) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×25 mL) then brine (50 mL) and concentrated under reduced pressure to provide title compound as a beige solid (620 mg, 96%). Method B HPLC-MS: MH+ requires m/z=204. Found: m/z=204, Rt=1.54 min (90%).
Reaction SMILES: [C:1]1([CH2:7]C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)C=CC1C=CC=CC=1.C1([CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=CC=CC=1>>[C:1]1(/[CH:7]=[CH:27]/[CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Agent: O=CC=Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(/C=C/c1ccccc1)NC(=O)Cc1ccccc1
Yield: 88 %

Procedure:
Compound 46 was prepared from 2-phenylacetamide and cinnamaldehyde using the procedure for compound 44. Yield: 88%. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=7.6 Hz, 2H), 7.21-7.37 (m, 15H), 6.41-6.45 (m, 1H), 6.27-6.32 (m, 1H), 6.04-6.09 (m, 1H), 3.44-3.52 (m, 4H). LCMS (ESI): m/z 385.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([N:18]=[C:19](SC)SC)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:26][CH2:27][C@@:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]3[O:36][C@:28]4([CH2:27][N:26]=3)[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]4)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(OCc3ccccc3)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3nc(NC4=NC[C@@]5(CN6CCC5CC6)O4)sc3n2)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of dimethyl 5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (500 mg, 1.38 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (317 mg, 1.38 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in DMF (7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-20% [9:1 methanol:ammonium hydroxide]-chloroform) to afford (R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (390 mg, 67% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (br. s., 1 H) 7.76 (d, J=8.85 Hz, 1 H) 7.50 (d, J=7.32 Hz, 2 H) 7.41 (t, J=7.32 Hz, 2 H) 7.32-7.37 (m, 1 H) 5.42 (s, 2 H) 4.02 (d, J=9.46 Hz, 1 H) 3.68 (d, J=9.46 Hz, 1 H) 3.37-3.44 (m, 1 H) 2.75-3.06 (m, 5 H) 2.13-2.25 (m, 2 H) 1.73-1.82 (m, 1 H) 1.49-1.70 (m, 3 H). MS (LC/MS) R.T.=1.69; [M+H]+=421.98.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37][C:47](=[O:49])[CH3:48])[CH2:33]5)[C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1
Reactant: N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Yield: 53.7 %

Procedure:
A solution of (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (Example 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and acetic anhydride (0.038 mL, 0.41 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated and washed with aqueous 1N HCl (5 mL), water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure to afford N-((3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl)acetamide (0.076 g, 54%). LCMS APCI (+) m/z 525 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:14])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:14]=[C:10]([O:11][CH2:12][CH3:13])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:26])[CH3:29]
Reactant: CCOC(=N)Cc1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)N=C(Cc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 7.4 mmol) was suspended in hexanes (18.5 mL) and DCM (18.5 mL) at 0° C. 2,4,6-collidine (3.9 mL, 29.6 mmol) and ethyl chloroformate (1.6 g, 14.8 mmol) were added sequentially and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and sonicated for 10 minutes. The solids were removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (3×10 mL). The combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-(4-fluorophenyl)acetimidate (0.99 g, 52.7%) as an amorphous yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, J=8.5, 5.6 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.15 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH:22]=[CH:23][C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:24](=[O:25])[CH:23]=[CH:22][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C(Cl)C=Cc1ccc2ccccc2c1
Product: CCOC(=O)c1cc(C(=O)C=Cc2ccc3ccccc3c2)c(C)[nH]1

Procedure:
5-Methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acid ethyl ester (132) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and-3-naphthalen-2-yl-acryloyl chloride following the procedure described in Example 32. Reaction conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 40%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[N:43]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:42][N:41]=[C:40]2[O:51][CH:52]=[CH:53][C:39]=12.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:37][C:38]1[N:43]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:10](=[O:12])[CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:48][CH:49]=2)[CH2:42][N:41]=[C:40]2[O:51][CH:52]=[CH:53][C:39]=12
Reactant: COc1cccc(CC(=O)O)c1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)Nc2ccc(N3CN=c4occc4=C3N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The carboxylic acid of choice (3-methoxyphenyl acetic acid, 0.055 mmol) and 0.055 mmol of HBTU were dissolved in 0.5 mL amine-free DMF. To this solution was added dropwise a solution of 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) in 0.5 mL DMF. The resulting solution was treated with 0.024 mL of N,N-diisopropylethylamine. The system was stirred at room temperature overnight and then was concentrated to dryness in a Speedvac system, reconstituted in 1 mL DMSO and purified by prep HPLC to give the title compound. MS(ES) m/e 375 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1.O>CCOCC>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:17]2([CH2:30][CH2:31][C:14]([OH:13])([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:15][CH2:16]2)[CH2:18][CH2:19]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1cccnc1)CC2
Reaction time: 0.33 h
Yield: 50 %

Procedure:
3-Bromopyridine (14.9 mmol, 1 equiv.) was dissolved in ether (50 ml) and added dropwise at −78° C. to a solution of n-BuLi (16.5 mmol, 1.17 M solution in ether, 1.1 equiv.). The mixture was stirred for 20 minutes. tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) Amine F-40) (7.49 mmol) was then dissolved in ether (90 ml) and added slowly. The reaction mixture was stirred for a further hour at −78° C. Distilled water was added and the mixture was thawed to 25° C. The phases were separated, and the organic phase was washed with saturated NaCl solution (30 ml), dried over Na2SO4 and concentrated. The crude product was taken up in ethyl acetate (10 ml) and a solid was precipitated with hexane (30 ml). The solid was filtered off and dried under a high vacuum to yield the desired product. Yield: 50%
Reaction SMILES: [N+](=[CH:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N-]>CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh].C(Cl)Cl>[O:23]=[C:4]1[CH2:3][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCCOC(=O)Cc1c(CCC(=O)C=[N+]=[N-])[nH]c2ccccc12
Agent: [Rh]
Solvent: ClCCl
Solvent: CCCCCCCC(=O)O
Product: CCCOC(=O)Cc1c2n(c3ccccc13)CC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Rhodium (II) octanoate dimer (0.1 equiv.) was added to a CH2Cl2 solution (0.02 M) of propyl [2-(4-diazo-3-oxobutyl)-1H-indo1-3-yl]acetate from Step 4. The reaction mixture was stirred overnight at rt and then concentrated. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (2:98 to 10:90) to give the title compound (64%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.P(Br)(Br)([Br:15])=O.CN(C)C=O.C(=O)(O)[O-].[Na+]>>[Br:15][C:3]1[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ncc(C(F)(F)F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C(F)(F)F)cnc1Br
Temperature: 130 °C

Procedure:
A mixture of 3-fluoro-5-(trifluoromethyl)pyridin-2-ol (1.0 g, 5.5 mmol, Matrix) and phosphoric tribromide (1.6 g, 5.5 mmol) in N,N-dimethylformamide (2.9 mL, 38 mmol) was heated to 130° C. for 70 minutes. After cooling to room temperature, the mixture was poured onto a mixture of ice and sodium bicarbonate solution (final pH=8). The product was extracted with diethyl ether. The extract was washed with water (twice), followed by brine, dried and solvent removed in vacuo. Flash chromatography, eluting with a gradient from 0-10% ethyl acetate in hexanes afforded product as a colorless oil (0.59 g, 44%). 1H NMR (400 MHz, CDCl3): δ 8.53-8.50 (m, 1H), 7.66 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH:30][C:10]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]4[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:2]=4[F:1])[O:9][N:8]=3)=[O:12])=[CH:24][NH:25]2)=[CH:21][C:20]=1[CH3:31]
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: Cc1cc2c(CCN)c[nH]c2cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(CCNC(=O)c3cc(Cc4cc(F)ccc4F)on3)c[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
A mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.180 g, 0.752 mmol), 2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine intermediate 142 (0.157 g; 0.752 mmol), HATU (0.286 g; 0.753 mmol) and N,N diisopropylethylamine (0.324 mL; 1.88 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane and eluent 1 to 10% ethyl acetate in dichloromethane) and by preparative HPLC method 2 to yield 0.0051 g (2%) of N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH2:38])[CH:37]=1)(=[O:32])=[O:31]>>[Cl:39][C:35]1[S:34][C:33]([S:30](=[O:32])(=[O:31])[NH:29][CH2:28][CH2:27][OH:26])=[CH:37][C:36]=1[NH:38][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: Nc1cc(S(=O)(=O)NCCO)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)NCCO)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 594.1.2 [(M−H)−]; mp 209° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][CH2:25][NH2:26])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:26][CH2:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCCO[N+](=O)[O-])c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.22 g, 4.1 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.27 g, 1.08 mmol, yield: 41%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccccc1F
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccccc2F)cc1-c1c(Br)cnn1C
Yield: 91.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with 2-fluorophenyl isocyanate (0.018 g, 14.4 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 25 (0.045 g, 0.11 mmol, 91%) as a solid film. LCMS m/z (%)=419 (M+H79Br, 99), 421 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 8.08 (t, J=8.1 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.53-7.59 (m, 1H), 7.40 (s, 1H), 7.12 (d, J=1.5 Hz, 1H), 6.95-7.12 (m, 3H), 6.94 (d, J=5.7 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Ic1ccc2c(c1)CCCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
7-Iodo-2,3,4,5-tetrahydro-1H-2-benzazepine (Preparation 2) (450 mg, 1.648 mmol) was dissolved in DCM (30 ml) and treated with BOC2O (0.459 ml, 1.977 mmol) followed by triethylamine (0.459 ml, 3.30 mmol). The reaction mixture was stirred at RT for 30 minutes. LC/MS showed one major product. The reaction was washed with 0.5M HCl (20 ml), sat NaHCO3 (20 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (650 mg) as a colourless oil. MS (ES) C15H20INO2 requires 373; found 318 (M+H−56)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:14](=[O:28])[N:13]2[CH3:29])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:14](=[O:28])[N:13]2[CH3:29])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of 4-[3-(4-methoxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one (3.51 g, 8.63 mmol) in dry CH2Cl2 (60 mL), cooled to −78° C. and then treated dropwise with BBr3 (6.49 g, 25.9 mmol). The reaction was warmed 0° C. and stirred for 2 h under N2. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was dried (MgSO4), and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 2:1 hexanes:acetone to afford 3.01 g (89%) 4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one. 1H NMR. MS (ES30) Calc'd for C21H24N2O2F3 (M+1) 393. Found m/z 393 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]2)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.FC(F)(F)C(O[C:40]1[C:45]([F:46])=[C:44]([F:47])[C:43]([F:48])=[C:42]([F:49])[C:41]=1[F:50])=O>CN(C=O)C>[F:46][C:45]1[C:40]([O:24][C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:22][CH:21]=3)=[O:25])=[C:41]([F:50])[C:42]([F:49])=[C:43]([F:48])[C:44]=1[F:47]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 32 (0.154 g, 0.44 μmol) in DMF (5 mL) in the presence of DIEA (93 ml, 0.53 mmol) was added dropwise pentafluorophenyl trifluoroacetate (92 μl, 0.53 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature overnight. HPLC showed that the reaction was completed. The solvent was then evaporated to dryness, and the residue was carefully washed with ether to give compound 33 in quantitative yield.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][N:16]=1.Cl>O.CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[NH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2ccccc2OC)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1cnc(CCCCCCC(=O)O)[nH]1
Temperature: 40 °C
Yield: 76.3 %

Procedure:
Add a solution of sodium hydroxide (1.85 g, 46 mmol) in water (40 mL) to a solution of 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid methyl ester (5.84 g, 18.5 mmol) in methanol (30 mL) at room temperature under nitrogen and heat the mixture at 40° C. for 4.5 hours. Cool the mixture and treat with 1 N HCl (46 mL) and heat at reflux for 30 minutes. Collect the precipitate, wash with water (3×30 mL), and dry under reduced pressure for 12 hours. Triturate the solid with methylene chloride (50 mL) at reflux for 40 min and collect by filtration to provide 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid (4.27 g, 77%). APCI mass spectrum m/z 301 [C17H22N2O3—H]−.