Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([CH3:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:29][C:10]1([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[C:18]([CH3:28])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(C)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.4 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.52 g, 1.3 mmol), lithium hydroxide hydrate (0.54 g, 13 mmol), water (1 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 31%) as a white solid: LC/MS m/e calcd for C23H28N2O3 (M+H)+: 381.5, observed: 381.2.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)[C@H:10]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][N:12]([C:20]1[S:21][C:22]([Br:25])=[CH:23][N:24]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=O)C(C)(C)C.[Li+].[B-](CC)(CC)CC>C1COCC1>[C:27]([NH:26][C@H:10]([CH2:11][N:12]([C:20]1[S:21][C:22]([Br:25])=[CH:23][N:24]=1)[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:9]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][CH:35]=1)[CH2:8][OH:7])([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1ncc(Br)s1)[C@@H](COC(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1ncc(Br)s1)[C@@H](CO)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
(2S,3S)-3-(Boc)amino-4-(5-bromothiazol-2-yl(Boc)amino)-2-(4-(trifluoromethyl)phenyl)butyl pivalate (0.66 g, 0.95 mmol) was taken up in 10 mL of THF and chilled to −78° C. Super hydride, 1M in THF (2.4 mL, 2.4 mmol) was added. The mixture was stirred for 5 minutes and then warmed to 0° C. The mixture was stirred for 15 minutes and then quenched with 5 mL of EtOAc. The mixture was diluted with 10 mL of aqueous NH4Cl and partitioned in a separatory funnel. The aqueous portion was extracted twice with 20 mL of EtOAc, and the combined organic layers were washed with 10 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 25% EtOAc/hexanes) afforded (2S,3S)-3-(Boc)amino-4-(5-bromothiazol-2-yl(Boc)amino)-2-(4-(trifluoromethyl)phenyl)butan-1-ol (0.51 g, 88% yield) 82646-5-1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (d, J=8.02 Hz, 2H) 7.35 (d, J=8.02 Hz, 2H) 5.16-5.02 (m, 1H) 4.60-4.51 (m, 1H), 4.33-4.20 (m 1H) 4.09-3.96 (m, 1H), 3.91-3.65 (m, 2H) 3.15-3.05 (m, 1H) 1.52 (s, 9H) 1.37 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=1)(=[O:5])=[O:4].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[CH3:1][NH:2][S:3]([C:6]1[CH:18]=[CH:17][C:9]2[S:10][C:11]3[CH:16]=[CH:15][C:14]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:13][C:12]=3[C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2sc3ccccc3c2c1
Reactant: O=S(=O)(O)Cl
Product: CNS(=O)(=O)c1ccc2sc3ccc(S(=O)(=O)Cl)cc3c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
N-Methyldibenzo[b,d]thiophene-2-sulfonamide (1.56 g) was added to chlorosulfonic acid (3.27 g) and the mixture was stirred at RT for 5 h. The mixture was then treated with ice cold water, the precipitate was filtered off, washed with cold water and dried to give the title compound (1.6 g, 76%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33][CH:34]=[CH2:35])[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([OH:40])=[O:39])[CH2:7][CH2:6]1)C=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:42]([O:41][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:46])([O:4][CH2:1][CH:35]=[CH:34][CH2:33][C@H:31]([CH3:32])[O:30][C:24]2[C:23]([CH2:22][O:21][CH2:20]3)=[CH:28][C:27]([CH3:29])=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)[C:38]([OH:40])=[O:39])([CH3:43])([CH3:45])[CH3:44]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(C)ccc4O[C@@H](C)CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Solvent: ClCCCl
Product: Cc1ccc2c(c1)COCc1cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCC=CC[C@H](C)O2
Temperature: 90 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To a solution of (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((5-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (32.7 mg, 0.052 mmol) in DCE (4 mL) were added Hoveyda-Grubbs catalyst 2nd generation (8.07 mg, 0.013 mmol) and copper(I) iodide (9.81 mg, 0.052 mmol) and the mixture was stirred at 90° C. After 3 h, the mixture was cooled to rt and concentrated. The crude material was purified via preparative HPLC to give (2S)-2-(tert-butoxy)-2-[(20S)-4,15,20,26-tetramethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (2.1 mg, 5.64% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.10 (s, 1H), 7.03 (d, J=6.6 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.52 (s, 1H), 6.08-5.93 (m, 1H), 5.78 (s, 1H), 5.75-5.67 (m, 1H), 4.82 (d, J=12.1 Hz, 1H), 4.71-4.56 (m, 4H), 4.56-4.39 (m, 2H), 4.01-3.79 (m, 2H), 3.73 (t, J=11.2 Hz, 1H), 3.35 (br. s., 1H), 3.17 (br. s., 1H), 2.74-2.59 (m, 1H), 2.45-2.31 (m, 2H), 2.29-2.14 (m, 5H), 1.89 (t, J=12.5 Hz, 2H), 1.68 (td, J=12.8, 4.0 Hz, 1H), 1.56 (td, J=13.0, 4.4 Hz, 1H), 1.26-1.19 (m, 6H), 1.19-1.01 (m, 9H). LCMS (M+H) calcd for C14H20FN3O4S: 607.35. found: 607.4.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1C(OCC)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3>C(O)C.O.Cl>[CH:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]1[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][N:6]12
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1CCCn2c1cc1ccccc12
Yield: 99.8 %

Procedure:
A solution of 1.03 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 20 ml of ethanol, 10 ml of water and 10 ml of concentrated hydrochloric acid was heated at 80° C. for 3 hours. The solvents were evaporated to give 740 mg of 7,8-dihydropyrido[1,2-a]indol-9(6H)-one of melting point 138°-140° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[N:3][C:4]([C:12]([F:15])([F:14])[F:13])=[N:5]4)[CH3:11])[C:26]=3[CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.048 g, 0.21 mmol) and 1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.21 mmol) in DMF (1 mL) were added Hunig's base (0.055 g, 0.42 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (0.090 g, 0.23 mmol). The mixture was stirred at room temperature for 1 hour, and then partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (0.028 g, 0.063 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.43 (s, 4H), 5.60 (q, J=7.1 Hz, 1H), 3.77 (ddd, J=12.6, 7.5, 3.0 Hz, 1H), 3.52 (ddd, J=12.3, 8.3, 3.0 Hz, 1H), 2.84 (tt, J=6.9, 3.3 Hz, 2H), 2.52 (s, 3H), 2.09-1.81 (m, 5H); MS: (ES) m/z calculated for C19H18ClF3N6O [M+H]+ 439.1, found 438.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:40][CH2:39]1)=[O:37].Cl.[CH3:52][N:53]([CH2:55][C:56](Cl)=[O:57])[CH3:54].CCN(C(C)C)C(C)C>ClCCl>[CH2:49]([N:46]([CH2:47][CH3:48])[CH2:45][CH2:44][N:41]1[CH2:40][CH2:39][N:38]([C:36]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:24][CH3:25])=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:6]=[C:7]([F:8])[C:2]=2[NH:1][C:56](=[O:57])[CH2:55][N:53]([CH3:54])[CH3:52])=[O:37])[CH2:43][CH2:42]1)[CH3:50]
Reactant: CN(C)CC(=O)Cl
Reactant: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4c(c3)c(-c3ccccc3OC)cn4S(=O)(=O)c3ccc(C)cc3)cc(F)c2N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCN1CCN(C(=O)c2cc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc(F)c2NC(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.5 %

Procedure:
30 mg (0.04 mmol) of {2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-methanone was combined with 9.0 mg (0.06 mmol) of dimethylaminoacetylchloride hydrochloride and 32 mg (0.11 mmol, 3.31 mmol/gram loading) of PS-DIEA resin (Argonaut Technologies, Inc.) in 1.0 mL dichloromethane. The reaction was shaken gently at room temperature for 48 hours. 22 mg (0.14 mmol) of dimethylaminoacetylchloride hydrochloride and 26 mg (0.09 mmol) more PS-DIEA resin (Argonaut Technologies, Inc.) was added and the reaction was continued to shake at room temperature for 24 more hours. The resin was filtered off and rinsed well with methanol and dichloromethane. The filtrate was concentrated down. The dried residue was dissolved in 0.5 mL methanol and 0.5 mL acetone. 150 μL of a 50% w/v potassium hydroxide (aqueous) solution was added and the reaction was stirred at room temperature for 1 hour. The reaction was neutralized by adding a few drops of acetic acid and concentrated. The residue was dissolved in dimethyl sulfoxide, filtered through a 0.45 μm syringe filter, and purified by reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 1.9 mg (0.003 mmol, 7% yield) of N-{2-[4-(2-diethylamino-ethyl)-piperazine-1-carbonyl]-6-fluoro-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-2-dimethylamino-acetamide as a fluffy white powder. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, 1H), 8.28 (d, 1H), 7.70 (s, 1H), 7.67 (dd, 1H), 7.60 (dd, 1H), 7.46 (s, br., 1H), 7.32 (t, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 3.87 (s, 3H), 3.77 (s, br., 2H), 3.56 (d, 2H), 3.19 (s, 2H), 3.13 (s, br., 2H), 2.71 (t, 2H), 2.64 (t, 2H), 2.59 (d, 2H), 2.41 (s, 6H), 1.26 (t, 6H); MS: m/z 630.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([N:12]1[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:13]1=[O:29])[CH2:6][CH2:5]2.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.CN(CCN(C)C)C.C1(C)C=CC=CC=1.[C:70](OCC)(=[O:72])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:29]=[C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C@H:7]1[CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([CH:70]=[O:72])[CH:11]=[CH:10][C:9]=2[CH2:8]1
Reactant: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@H]1CCc2cc(Br)ccc2C1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)CC[C@H](N1CCc3cc(OC[C@@H]4CCCO4)ccc3C1=O)C2
Temperature: 120 °C

Procedure:
A mixture of 2-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-6-[(S)-1-(tetra-hydrofuran-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one (1.10 g), palladium(II) acetate (16.2 mg), butyldi-1-adamantylphosphine (77 mg), TMEDA (0.27 ml) and toluene (22 ml) was heated to 120° C. in an autoclave under a hydrogen/carbon monoxide atmosphere for 14 hours. The cooled reaction mixture was diluted with ethyl acetate and washed first with dilute hydrochloric acid and then with sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 405.50 (C25H27NO4); MS (ESI): 406 (M+H+).
Reaction SMILES: [C:1]([O-:5])(=O)[CH2:2][CH3:3].[Na+].[CH2:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH3:18])[C:11]=1[OH:19])[CH2:8][CH3:9]>OS(C(F)(F)F)(=O)=O>[CH2:16]([C:12]1[CH:13]=[C:14]([C:1](=[O:5])[CH2:2][CH3:3])[CH:15]=[C:10]([CH2:7][CH2:8][CH3:9])[C:11]=1[OH:19])[CH2:17][CH3:18]
Reactant: CCC(=O)[O-]
Reactant: CCCc1cccc(CCC)c1O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CCCc1cc(C(=O)CC)cc(CCC)c1O

Procedure:
Sodium propanoate (0.88 g, 1.5 eq) and 2,6-dipropylphenol (1.09 g, 1.0 eq) were combined in Triflic Acid (5.0 g) as in Example 13, step 1. The resulting waxy solid was purified by chromatography on silica gel using ethyl acetate:hexanes:acetic acid (10:90:1) to give the titled phenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:28](OC)([O:31]C)[O:29]C.Cl>C1COCC1.CCCCCC.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([B:28]([OH:31])[OH:29])=[C:17]([F:21])[C:16]=2[F:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2ccc(OCc3ccccc3)cc2)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)c(F)c1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
32.0 g (106 mmol) of 4′-benzyloxy-2,3-difluorobiphenyl (CAS No. 305366-70-5) are dissolved in 250 ml of THF, and 75.0 ml (119 mmol) of a 15% solution of n-butyllithium in hexane are added dropwise at −70° C. When the addition is complete, the mixture is stirred for a further 1 h, and a solution of 13.5 ml (119 mmol) of trimethyl borate in 50 ml of THF is added dropwise. After 1 h, the batch is left to thaw, MTB ether is added, and the mixture is acidified using 2 M hydrochloric acid. The org. phase is separated off, washed with sat. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is heated to 70° C. in 200 ml of heptane/toluene (1:1) with stirring and filtered off with suction after cooling, giving 4′-benzyloxy-2,3-difluorobiphenyl-4-boronic acid as a colourless solid, which is employed in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4](I)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OO>CS(C)=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][N:7]2[C:8]([C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=[C:11]12)=[O:21]
Reactant: COC(=O)C(I)CCn1cccc1C(=O)c1ccccc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
As set out in Scheme 1, 2-benzoylpyrrole (II, prepared according to known procedures, e.g., J. Org. Chem. 1977, 42, 4248) is N-alkylated in step 1 with gamma-butyrolactone to provide, after esterification, 4-(2-benzoylpyrrol-1-yl)butyric acid methyl ester (III). 4-(2-Benzoylpyrrol-1-yl)butyric acid methyl ester (III) is then iodinated in step 2 with lithium diisopropylamide and a source of electrophilic iodine, such as iodine, iodine monochloride, or N-iodosuccinimide, to yield 4-(2-benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV). 4-(2-Benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV) is then cyclized in step 3 via a free radical ring closure reaction, for example, with hydrogen peroxide and iron (II) sulfate heptahydrate in dimethylsulfoxide, to yield 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (V). 5-Benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (V) is then hydrolyzed in step 4 to the corresponding acid (I, ketorolac) by known procedures, e.g., U.S. Pat. No. 4,089,969.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)O)=[CH:4][CH:3]=1.[N:26]1[CH:31]=CC=C[CH:27]=1.CS(Cl)(=O)=O.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[N:26]([CH3:31])[CH3:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Reactant: c1ccncc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a mixture of (4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol (141 mg, 0.382 mmol) (synthesized in an analogous way as described in Example 3) in methylene chloride (2.8 mL) was added pyridine (6.0 mL, 74 mmol) and methanesulfonyl chloride (0.148 mL, 1.91 mmol) at 0° C. After the addition, the mixture was warmed to rt and stirred for 30 min and then heated at 60° C. for 20 min. The mixture was cooled in an ice bath and dimethylamine (0.553 mL, 11.5 mmol) in THF was added to the mixture. After the addition, the ice bath was removed and the mixture was stirred at rt for 30 min and then heated at 55° C. for 2 h. The mixture was cooled, concentrated, and the residue was purified by HPLC to afford 1-(4-chlorophenyl)-N,N-dimethyl-1-[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanamine as white powder (115 mg, 76%). LCMS: (AA) ES+ 396.3, 398.1; 1H NMR (400 MHz, d6-DMSO) δ: 14.48-14.27 (m, 1H), 8.71 (s, 1H), 8.57 (dd, J=4.55, 1.62 Hz, 2H), 7.95 (s, 1H), 7.73-7.63 (m, 4H), 7.39-7.30 (m, 2H), 5.53 (s, 1H), 2.13 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[C:18]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[C:18]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][O:16][N:15]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2nocc2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nocc2-c2cccnc2C(F)(F)F)cc(O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)isoxazole (0.79 g, 2 mmol) was taken up in dichloromethane (15 mL) and the yellowish suspension was cooled to −78° C. under argon whereupon boron tribromide (4.5 g, 18 mmol) was added dropwise. The reddish reaction mixture was allowed to warm to room temperature and stirred for 18 hours, then carefully poured into ice-water (100 mL) and allowed to stir for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. Trituration with boiling ethanol gave 3-nitro-5-(4-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-3-yl)benzene-1,2-diol as a yellow solid, 0.47 g (64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:13]=2)[CH:5]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][CH:19]=3)[N:13]=2)[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:5]=1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)c1cccc(CN(c2ccnc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CN(c2ccnc(-c3ccc(OCC4CCCCC4)cc3)n2)C2CCCC2)c1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To an acetone (3 mL) solution of 3-({cyclopentyl-[2-(4-hydroxy-phenyl)-pyrimidin-4-yl]-amino}-methyl)-benzoic acid methyl ester (23 mg, 0.057 mmol) was added (bromomethyl)cyclohexane (11 mg, 0.063 mmol), K2CO3 (36 mg, 0.26 mmol) and tetrabutyammonium bromide (0.4 mg, 0.003 mmol). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature the reaction mixture was filtered, and the residue was washed with acetone (4 mL). The solution was concentrated, and the crude solid was purified by silica gel chromatography eluting with hexanes/ethyl acetate 4:1 then 2:1 to yield 22 mg of 3-({[2-(4-cyclohexylmethoxy-phenyl)-pyrimidin-4-yl]-cyclopentyl-amino}-methyl)-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:19](=O)[CH3:20])[C:11]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].[NH2:22][C:23]([CH2:29][F:30])=[CH:24][C:25]([O:27][CH3:28])=[O:26]>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:19]([CH3:20])[NH:22][C:23]([CH2:29][F:30])=[C:24]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C=C(N)CF
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1CCCC1
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC2CCCC2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of the product of step (a) (5.1 g, 14.3 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (1.9 g, 14.3 mmoles) in dry tert-butanol (25 ml) was heated to 60° (oil bath temperature) for 108 hours. The solution was allowed to cool to room temperature and the solvent removed in vacuo. Chromatography on silica eluting with dichloromethane afforded the title compound as a yellow oil which crystallises on addition of petroleum ether (60°-80° ) to afford the title compound 1.5 g mp 148°-9°. (Identical with the product of Example 3).