Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[K+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:22]=[C:21](/[CH:23]=[CH:24]/[CH:25]([C:30]2[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=2)[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1.[Cu]I>[I:1][C:14]1[CH:22]=[C:21](/[CH:23]=[CH:24]/[CH:25]([C:30]2[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=2)[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: [I-]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1I
Temperature: 100 °C

Procedure:
Per Buchwald, et al.; JACS, 2002, 124, 14844-14845, potassium iodide (KI, 273 mg, 1.64 mmol), CuI (31 mg, 0.16 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (catalytic amount) were added to a solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) in 1,4-dioxane (8 mL). The mixture in an Ace pressure tube was heated at 100° C. for 3 h. The reaction mixture was brought to ambient temperature and filtered through a Celite® pad. The filtrate was concentrated and residue was diluted with EtOAc and washed with 1N HCl followed by brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 25% EtOAc in petroleum ether to afford the title compound as brown semi solid (240 mg, 55%): 1H NMR (400 MHz, DMSO-d6) δ 13.3 (bs, 1H), 8.21 (s, 1H), 7.91 (s, 2H), 7.71-7.64 (m, 2H), 7.01 (dd, J=15.6, 9.2 Hz, 1H), 6.75 (d, J=15.6 Hz, 1H), 4.85-4.81 (m, 1H); ESIMS m/z 532.8 ([M−H]−); IR (thinfilm) 3436, 1699, 1113, 750 cm−1.
Reaction SMILES: FC(F)(F)C(O)=O.O.[C:9]([C:13]1[CH:64]=[CH:63][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH:22]3[CH2:25][CH:24]([N:26]([CH2:31][C@@H:32]4[C@H:36]5[O:37]C(C)(C)[O:39][C@H:35]5[C@H:34]([N:42]5[C:46]6[N:47]=[CH:48][N:49]=[C:50]([NH:51]CC7C=CC(OC)=CC=7OC)[C:45]=6[CH:44]=[CH:43]5)[CH2:33]4)[CH:27]4[CH2:30][CH2:29][CH2:28]4)[CH2:23]3)=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:51][C:50]1[C:45]2[CH:44]=[CH:43][N:42]([C@@H:34]3[CH2:33][C@H:32]([CH2:31][N:26]([CH:24]4[CH2:23][CH:22]([CH2:21][CH2:20][C:18]5[NH:17][C:16]6[CH:63]=[CH:64][C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][C:15]=6[N:19]=5)[CH2:25]4)[CH:27]4[CH2:28][CH2:29][CH2:30]4)[C@@H:36]([OH:37])[C@H:35]3[OH:39])[C:46]=2[N:47]=[CH:48][N:49]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C3CCC3)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc2[nH]c(CCC3CC(N(C[C@H]4C[C@@H](n5ccc6c(N)ncnc65)[C@H](O)[C@@H]4O)C4CCC4)C3)nc2c1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Trifluoroacetic Acid (10 ml, 200 mmol) added to a mixture of Water (1 ml, 80 mmol) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.61 g, 0.80 mmol) at RT. The reaction was stirred o/n at RT and was quenched by the addition of Triethylsilane (0.26 ml, 1.6 mmol). The volatiles were removed in vacuo and resulting and the residue was taken up in MeOH (15 mls),500 mg K2CO3 and 8 drops of water were added and the reaction was stirred at RT for 1 hour. The mixture was filtered and the filter cake was washed with MeOH (10 ml). The filtrate was concentrated and the resulting residue purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to give the desired product (0.13 g) as a colorless foam. MS (EST+) for C33H45N7O2 m/z 572.2 [M+H]+; MS (ESI−) for C33H45N7O2 m/z 570.2 [M−H]−; HPLC purity >90% (ret. time, 2.850 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.083 (s, 1H), 7.492 (s, 1H), 7.412-7.392 (m, 1H), 7.309-7.286 (m, 1H), 7.220-7.205 (m, 1H), 6.620-6.610 (d, J=4.0 Hz, 1H), 4.321-4.283 (m, 1H), 3.888-3.848 (m, 1H), 3.505-3.417 (m, 0.5H (methine of trans isomer)), 3.231-3.147 (m, 0.5H) (methine of cis isomer)), 3.051-2.953 (m, 1H), 2.871-2.732 (m, 3H), 2.583-2.501 (m, 1H), 2.441-2.368 (m, 1H), 2.244-2.205 (m, 3H), 2.170-1.833 (m, 9H), 1.695-1.560 (m, 4H), 1.384 (s, 9H).
Reaction SMILES: Br[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14](B(O)O)=[CH:13][CH:12]=1>>[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: CC1(C)CC(=O)C=C(Br)C1
Product: CC1(C)CC(=O)C=C(c2cccc3c2oc2ccccc23)C1
Yield: 96 %

Procedure:
Synthesized from 3-bromo-5,5-dimethylcyclohex-2-enon and dibenzofuran-4-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography yielded the product (192 mg, 96%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.93 (dd, J=7.4, 1.1 Hz, 1H), 7.92 (ddd, J=7.7, 0.8, 0.6 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.51-7.43 (m, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 6.91 (t, J=1.4 Hz, 1H), 2.85 (d, J=1.4 Hz, 2H), 2.42 (s, 2H), 1.19 (s, 6H). 13C (75 MHz, CDCl3): δ 200.3, 156.0, 153.9, 153.4, 127.7, 127.6, 125.6, 125.3, 124.3, 123.6, 123.2, 123.0, 122.0, 120.7, 112.0, 51.3, 43.0, 34.2, 28.7. HRMS (LCT Electrospray): mass calcd for (C20H18O2+Na) m/z 313.1204; measured [M+Na]+: m/z 313.1201.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[Na].[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[I-].[Na+]>C(COC)OC>[CH3:1][S:2][CH2:3][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: CSCCl
Reactant: COC(=O)c1ccc(CO)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: COCCOC
Product: COC(=O)c1ccc(COCSC)cc1
Yield: 75 %

Procedure:
4-(Methyloxycarbonyl)benzyl methylthiomethyl ether was prepared by the reaction of chloromethyl methyl sulphide with the sodium salt of methyl 4-hydroxymethylbenzoate (see G. D. Brindell, L. D. Lillwitz, J. P. Wuskell and A. P. Dunlop, Ind. Eng. Chem. Prod. Res. Dev. 15, 83(1976) in dimethoxyethane in the presence of sodium iodide as described for analogous reactions in E. J. Corey and M. C. Bock, Tetrahedron Letters 38 3269 (1975); yield 75%, b.p. 110°-120° C./0.01 mmHg. 1H NMR (CDCl3): δ2.17 (SMe) 3.92 (OMe), 4.67 (CH2), 4.70 (CH2), 7.2-8.2 (Ph).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[C:2]#[CH:3].[BH4-].[Na+]>C(O)C>[OH:9][CH:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:14])[N:4]1[CH2:1][C:2]#[CH:3]
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN1C(=O)c2ccccc2C1O

Procedure:
A mixture of 10 g of N-propargylphthalimide and 2 g of sodium borohydride in 100 ml of ethanol was heated on the steam bath for 15 minutes with stirring. The resulting solution was concentrated under reduced pressure to one third of the volume and the product was crystallized by addition of ice and saturated sodium bicarbonate solution. The precipitated crystals of the title compound were collected by filtration, washed with water and sucked dry. After drying in vacuum they had m.p. 157°-159° C.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.CCOCC>C(O)C>[O:1]([CH2:8][CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(O)COc1ccccc1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
Phenoxy-2-propanone (3.4 mL, 25 mmol) was dissolved in ethanol (30 mL) and cooled to 0° C. Sodium borohydride (0.95 g; 25 mmol; 1 equiv.) was added. The mixture was stirred and allowed to warm to room temperature overnight. All of the starting material was gone according to tlc analysis, so the mixture was poured into water (30 mL) and ether (30 mL). The layers were separated and the aqueous layer was extracted with ether (2×20 mL). The organic layers were combined and concentrated. The resulting aqueous residue was poured into ether (25 mL). The organic layer was removed, dried (MgSO4), and concentrated to provide 1e (3.2 g; 85%). 1H nmr (300 MHz, CDCl3): 7.332-7.261 (3H, m); 6.995-6.904 (2H, m); 4.15-4.24 (1H, m); 3.972-3.768 (2H, m); 1.559 (1H, s); 1.290 (3H, d, J=6.38 Hz). IR (neat film, cm-1): 3350 (b, s); 2900 (s); 1590 (m). EIMS (m/e): 152 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C([O-])([O-])=O.[K+].[K+].Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][N:24]=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][N:24]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: O=C(c1ccccc1F)N1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1F)N1CCN(c2ncc([N+](=O)[O-])c3ccccc23)CC1
Reaction time: 24 h
Yield: 75.8 %

Procedure:
Add (2-fluoro-phenyl)-piperazin-1-yl-methanone (3.16 g, 12.9 mmol) and K2CO3 (8.9 g, 64.5 mmol) to 1-chloro-4-nitroisoquinoline (2.85 g, 13.7 mmol) in acetonitrile (100 mL) and stir for 24 hours. Filter the insoluble solid and wash the cake with AcOEt. Evaporate the solvent under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 20-90% to give 3.72 g of (2-fluoro-phenyl)-[4-(4-nitro-isoquinolin-1-yl)-piperazin-1-yl]-methanone as a solid. LCMS ES+(m/z) 381.2 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[Cl:19])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cc(F)ccc2Cl)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 93.6 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate and 0.19 g of 2-chloro-5-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined and washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.30 g of 4-(2-butynyloxy)-6-(2-chloro-5-fluorophenoxy)pyrimidine (the present compound (156)).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si](C)(C)[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:38])[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(C)(C)C>>[OH:38][C:31]1([C:28]2[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=2)[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(O)CCC(=O)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CCC(O)(c2ccc(O)cc2)CC1

Procedure:
The title compound was prepared as a white solid by TBAF de-protection of 4-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-hydroxy-cyclohexanone using the procedure described in Step D of Example 40.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][O:20]C(=O)C)[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:25]([F:28])([F:26])[F:27])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[C:14]1=[O:24]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCOC(C)=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCO)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Part B: Acetic acid 2-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-ethyl ester (1.26 g, 3.17 mmol) was dissolved in methanol (100 mL) and water (5 mL). Potassium carbonate (1.31 g, 9.52 mmol) was added, and the reaction was stirred overnight at rt. The reaction was concentrated, quenched with water (250 mL), extracted with ethyl acetate (3×250 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography with 0–100% ethyl acetate/hexanes gradient as eluent to afford the title compound (1.01 g, 90%): 1HNMR(CDCl3) δ 7.45 (d, j=9.2 Hz, 2H), 6.96 (d, j=8.7 Hz, 2H), 3.84 (s, 3H), 3.82–3.77 (m, 4H), 3.66 (t, j=5.1 Hz, 2H), 3.03 (t, j=6.8 Hz, 2H) ppm; Mass Spec 356.3(M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:20][C:21]1[CH:22]=[CH:23][C:24]2[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([CH3:33])[S:26][C:25]=2[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][O:18][C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([CH3:33])[S:26][C:25]=4[CH:34]=3)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Yield: 42.9 %

Procedure:
Example 11(b) was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (417 mg, 1.40 mmole) with methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (417 mg, 2.11 mmole) and Cs2CO3 (2.29 g, 7.02 mmole) in a manner as previously described for example 1 to give 290 mg (43%) of a yellow solid. 1H NMR (DMSO-d6): δ8.58 (1H, d, J=5.4 Hz), 8.39 (1H, d, J=9.0 Hz), 8.07 (1H, s), 8.02 (1H, d, J=2.3 Hz), 7.42 (1H, dd, J=2.3, 9.0 Hz), 6.79 (1H, d, J=5.4 Hz), 4.08–3.99 (3H, m), 3.87–3.86 (2H, m), 3.91 (3H, s), 3.64–3.59 (2H, m), 3.27, 3.24 (3H, s), 2.82 (3H, s).
Reaction SMILES: Br[C:2]1[CH2:6][O:5][C:4](=[O:7])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:17]1[C:22]2([CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:21][CH2:20][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18]1>C1COCC1>[O:7]=[C:4]1[O:5][CH2:6][C:2]([N:24]2[CH2:25][CH2:26][CH2:27][C:22]3([CH2:17][CH2:18][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21]3)[CH2:23]2)=[CH:3]1
Reactant: O=C1C=C(Br)CO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C3=CC(=O)OC3)C2)CC1
Temperature: 76 °C
Reaction time: 8 h

Procedure:
To commercially available 4-bromofuran-2(5H)-one (128 mg, 0.786 mmol) in THF (4 mL) was added Hunig's Base (275 μL, 1.57 mmol) and tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate (200 mg, 0.786 mmol). The reaction mixture was stirred at 76° C. overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound. LC/MS: [(M+1)]+=337
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][C@@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15]2=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][C@@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15]2=[O:21])=[CH:11][CH:10]=1
Reactant: CC1(C)OC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)[C@H](Cc2ccc(O)cc2)O1
Reaction time: 3 h
Yield: 105 %

Procedure:
(S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (1.0 g, 3.2 mmol) was combined with 10% Pd/C (0.75 g) in EtOAc (40 mL) and purged with N2 then H2 and then stirred under a hydrogen balloon for 3 hours. Sodium sulfate was added, and the mixture was filtered through Celite. The solvent was removed in vacuo to afford the title compound (0.747 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, 2H, J=8.31 Hz), 6.76 (d, 2H, J=8.31 Hz), 4.93 (bs, 1H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.11 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.98 (dd, 1H, J=14.67 Hz, J=5.86 Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES−) m/z mass calc'd for C12H14O4 (M−1) 221. Found m/z 221.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]Br>CC(O)=O>[Br:11][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1Br
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) was added liquid Br2 (60 g, 0.38 mol) dropwise at 5° C. The mixture was stirred for 30 min at that temperature. The insoluble solid was collected by filtration and poured into EtOAc (200 mL). The mixture was basified with saturated aqueous NaHCO3 to pH 7. The organic layer was separated. The aqueous phase was extracted with EtOAc (300 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give 2-bromo-4-nitroaniline (56 g, 72%), which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4]
Reactant: OB(O)c1ccccc1
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2ccccc2)cc1F
Yield: 81.4 %

Procedure:
The title compound (0.401 g) was prepared from 2,6-difluoro-4-bromo aniline (0.5 g, 2.4 mmol) and phenylboronic acid (0.38 g, 3.12 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.60 (d, J 7.4, 2H), 7.38 (t, J 7.5, 2H), 7.30-7.25 (m, 3H), 5.33 (s, 2H).
Reaction SMILES: O=S(Cl)Cl.Cl.[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([F:19])=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1.[CH3:20]O>>[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([F:19])=[C:13]([C:16]([O:18][CH3:20])=[O:17])[CH:14]=2)[CH2:9][CH2:8]1
Reactant: N[C@@H]1CCc2cc(F)c(C(=O)O)cc21
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(cc1F)CC[C@H]2N
Temperature: 25 °C
Reaction time: 14 h
Yield: 89 %

Procedure:
SOCl2 (0.75 ml, 10.365 mmol, 2.4 eq) was added dropwise at 0° C., with stirring, to a suspension of (R)-3-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylic acid hydrochloride (commercially available from NetChem (Order No. 573243)) (1 g, 4.319 mmol, 1 eq) in methanol (20 ml). The reaction mixture was stirred for 14 h at room temperature. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out and the residue was diluted with saturated sodium hydrogen carbonate solution (50 ml) and extracted with 10% methanol/dichloromethane (100 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The desired product was in the form of a light-green solid. Yield: 89% (800 mg, 3.827 mmol)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)[C:12](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:8]([C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1)(=[O:10])[C:12]1[CH:11]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
To 15 g of 6 -methyl-2-pyridylcarboxylic acid (122 mmol) in 200 ml benzene is added dropwise 19.1 g (150 mmol) oxalyl chloride (dissolved in 30 ml benzene) with ice bath cooling. After 1 hr, solvent and excess chloride are removed. Concentrate is taken up in 100 ml benzene, cooled to ~10° & 175 mmol AlCl3 added. The solution is heated to 25° for 1 hour, then heated to reflux for 2 hours, and finally cooled and stirred overnight. The mixture is poured onto ice/conc. HCl, then washed with ether. Fifty Percent (50%) sodium hydroxide is added until the precipitate is dissolved. The solution is extracted with CHCl3, washed with water, dried and stripped, leaving 6-benzoyl-2-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][N:42]([CH3:47])[C:43](=[O:46])[CH:44]=[CH2:45]>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([CH2:45][CH2:44][C:43]([N:42]([CH3:47])[CH3:41])=[O:46])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C=CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(CCC(=O)N(C)C)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol) and N,N-dimethyl-acrylamide (28 mg, 0.283 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. N,N-dimethylacrylamide (28 mg, 0.283 mmol) was added every 2 hour three times. The organic solvent was removed. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28–30% solution) (80:20:0.05) mixture as the mobile phase to give the title compound. 1H NMR (DMSO, d6) δ 1.39 (m, 1H), 1.51(m, 1H), 1.70 (m, 1H), 1.81 (m, 1H), 1.98 (m, 2H), 2.48 (m, 2H), 2.58 (m, 2H), 2.76 (m, 1H), 2.81 (s, 3H), 2.91 (m, 1H), 2.99 (s, 3H), 3.91 (s, 3H), 3.99 (m 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.18 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.60 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.16 (d, 1H), 8.59 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a): MH+=654.1, Rt=2.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:9]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of 1-(2-chloro-phenyl)-5-[4-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (630 mg, 1.13 mmol) prepared in Example 9 in dichloromethane (6 mL), was slowly added trifluoroacetic acid (867.0 uL, 11.33 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 680.0 mg of the titled compound as a yellow liquid.