Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH3:23]O>S(=O)(=O)(O)O>[CH3:23][O:9][C:8](=[O:10])[CH:7]([C:4]1[CH:3]=[CH:2][C:1]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:5]=1)[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (192.3 mg, 0.653 mmol) in methanol (3.3 mL) was treated slowly with concentrated sulfuric acid (1 drop). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (50 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (191.5 mg, 95%) as a yellow oil: EI-HRMS m/e calcd for C21H24O2 (M+) 308.1776, found 308.1774.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCCCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and piperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:6]=1[CH:7]([C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:16]=[CH:17][CH:18]=1)[O:8]2.[OH-].[Na+]>CO.O.Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:6]=1[CH:7]([C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=[CH:17][CH:18]=1)[O:8]2
Reactant: CCOC(=O)CCCc1cccc(C2Oc3cccc(OC)c3-c3ccc(NS(C)(=O)=O)cc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1cccc(CCCC(=O)O)c1)O2
Yield: 101.6 %

Procedure:
A solution of Example 150 (0.78 g, 1.6 mmol) and NaOH (0.67 g, 16.7 mmol) in MeOH-H2O (3 mL, 1:1) was stirred for 6 hours, diluted with aqueous HCl (50 mL, 1M) and extracted with ethyl acetate (3×35 mL). The combined ethyl acetate was dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (0.76 g, 99%) of the title compound. 1NMR (CDCl3 300 MHz) δ 1.95 (quintet, J=7 Hz, 2H), 2.31 (t, J=7 Hz, 2H), 2.68 (t, J=7 Hz, 2H), 2.95 (s, 3H), 3.94 (s, 3H), 5.93 (s, 1H), 6.55 (d, J=3 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.69 (dd, J=2 Hz, 8 Hz, 1H), 6.89 (s, 1H), 7.15 (t, J=8 Hz, 1H), 7.15-7.24 (m, 3H), 7.25-7.32 (m, 4H), 8.42 (d, J=9 Hz, 1H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].OS(C(F)(F)F)(=O)=O>>[OH:2][C:1]1[C:9]2[C:4]([CH2:6][CH3:7])=[CH:3][C:1](=[O:2])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCc1cc(=O)oc2cc(O)cc(O)c12
Reaction time: 16 h
Yield: 127.8 %

Procedure:
A suspension of phloroglucinol (1.04 g, 8.35 mmol) in ethyl propionyl acetate (1.24 mL, 8.71 mmol) was added over 0.5 h to triflic acid (2 mL). The reaction was mechanically stirred in an ice bath for 16 h. The reaction was quenched by carefully pouring into an ice bath. The solid was filtered and dried yielding a white solid (1.1 g, 83.2%): mp. 248-252° C.; 1H NMR (DMSO-d6) δ1.15 (t, 3H), 2.91 (q, 2H), 5.83 (s, 1H), 6.17 (d, 1H), 6.26 (d, 1H) 10.3 (s, 1H) 10.6 (s, 1H).
Reaction SMILES: [Na].[CH2:2]([SH:6])[CH2:3][CH2:4][CH3:5].[CH3:7][C:8]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][CH2:22]Cl)[C:9]1=[O:24]>C(O)C>[CH3:7][C:8]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][CH2:22][S:6][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]1=[O:24]
Reactant: CC1(C)C(=O)N(CCCCCl)C(=O)c2ccccc21
Reactant: CCCCS
Agent: [Na]
Solvent: CCO
Product: CCCCSCCCCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
1 gm of sodium was dissolved in 100 ml of ethanol, 3.7 gm of n-butylmercaptan were added dropwise to the solution, and a solution of 12 gm of 4,4-dimethyl-2-(4-chloro butyl)-2H,4H-isoquinoline-1,3-dione was slowly added. After refluxing the mixture for 3 hours, the precipitate was filtered off, the filtrate was evaporated, the residue was poured into ice water, and the aqueous mixture was acidified and extracted with chloroform. The chloroform phases were evaporated, whereby an oily crude product was obtained (13.0 gm, 98% of theory), which was purified by chromatography on silicagel (eluant: chloroform).
Reaction SMILES: [CH:1]1([C:11]([O:13]CC)=[O:12])[C:3]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(OCC)=O)C2(CCCCC2)C1>>[CH:1]1([C:11]([OH:13])=[O:12])[C:3]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: CCOC(=O)C1CC12CCCCCCC2
Agent: CCOC(=O)C1CC12CCCCC2
Product: O=C(O)C1CC12CCCCCCC2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 49B for the product from Example 1A.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)(OCC1C=CC=CC=1)=O.OS(O)(=O)=O>C1COCC1.CCOCC>[CH3:18][C:14]1[CH:15]=[C:15]([C@@H:14]2[CH2:18][CH2:19][CH2:20][N:13]2[CH3:3])[O:17][N:13]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 0 °C
Yield: 88 %

Procedure:
To a stirred suspension of sodium borohydride (7.59 g, 200 mmol) in 100 mL of THF cooled to 0° C. was added a solution of 20 g (80.28 mmol) of N-Cbz-L-proline, from step 24a above, in 50 mL of ether. To this solution was added dropwise a solution of 5 mL of H2SO4 in 20 mL of ether, with stirring and while maintaining the temperature below 20° C. The reaction mixture was warmed to room temperature and stirred for 16 hr. The reaction was quenched by the addition of 100 mL of methanol dropwise. The solvents were removed, 30 mL of 4N NaOH was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over Na2SO4 and concentrated to afford the title product, 16.61 g (88% yield).
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[CH2:20]([O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21]
Reactant: COC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1=C(c2ccccc2)C(CCC(=O)OC)OC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A mixture of methyl 3-(4-hydroxy-5-oxo-3-phenyl2,5-dihydro-2-furyl)propionate (262 mg), ethyl iodide (234 mg) and potassium carbonate (207 mg) in dimethylformamide (3 ml) was stirred for 3.5 hours at ambient temperature. The mixture was poured into a mixture of dichloromethane (10 ml) and water (10 ml). The separated organic layer was washed with water three times, dried and evaporated to dryness. The oily residue was purified by column chromatography on silica gel (8 g, elution by benzene) to yield methyl 3-(4- ethoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (0.20 g) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Li].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C.ClCCl>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:49]3[CH2:53][CH2:52][CH2:51][C@H:50]3[CH2:54][N:55]3[CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:14])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CSc1ccc(-c2ccc(C(=O)O)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1
Yield: 71 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 8 mL 37% DMF/dichloromethane using 4-(5-methylsulfanyl-thiophen-2-yl)-benzoic acid, Lithium salt (51 mg, 0.20 mmol), EDC-HCl (57 mg, 0.30 mmol), HOBt (41 mg, 0.30 mmol), DIEA (0.09 mL, 0.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (28 mg, 0.18 mmol) to give the title compound (50 mg, 71% yield). MS (ES+) 387.7 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:26][CH3:27])=[O:19])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1cc(Cl)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(c1)ncn2-c1cc(Cl)ccc1O

Procedure:
A mixture of 4a (170 mg, 0.59 mmol), conc. sulfuric acid (3 mg, 0.029 mmol), and 99% ethanol (10 ml) was refluxed for 1 h. Silica gel was added to the mixture and the solvent was evaporated. The silica gel containing the crude product was put on top of a silica gel column and the product was eluated by methylene chloride/ethanol (9:1). Yield 120 mg, mp>360° C.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[N:6]=1
Reactant: OCCO
Reactant: O=Cc1csc(Br)n1
Solvent: Cc1ccccc1
Product: Brc1nc(C2OCCO2)cs1
Yield: 74.7 %

Procedure:
2-Bromothiazole-4-carbaldehyde (6.56 g,34.17 mmol) [A. T. Ung, S. G. Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407] and ethylene glycol (5.72 ml, 102.5 mmol) were heated under reflux in toluene (50 ml), with a Dean and Stark trap fitted, for 18 hr. The product was concentrated and purified by column chromatography (15% ethyl acetate/hexane) to give the product as a yellow solid (6.03 g); m/z 236,238.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([C:20](OC(C)(C)C)=O)[CH2:15][C:14]=2[C:13]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=2[F:35])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=2[F:35])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C(=O)OC(C)(C)C)C2)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of (S)-tert-butyl 1-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-ylcarbamoyl)-3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (0.92 g, 1.76 mmol) in TFA/DCM (1:1) was stirred at room temperature for 30 min. The reaction mixture was diluted with toluene and evaporated under vacuum. The resulting residue was dissolved in THF, to which formaldehyde (37%, 0.65 mL) and sodium triacetoxyborohydride (424 mg) was added sequentially. After stifling at room temperature for 2 h, THF was evaporated under vacuum. The residue was extracted between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column with a gradient of from 10% to 40% ethanol in MeCN to give (S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-methyl-3-(2,4,5-trifluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide 37 as a solid (412 mg, 49% yield for two steps). 1H NMR (CDCl3) δ 7.86 (d, J=9.4 Hz, 1H), 7.47-7.54 (m, 1H), 6.98-7.04 (m, 1H), 5.85 (br, 1H), 4.11 (d, J=9.4 Hz, 1H), 3.39 (s, 2H), 3.16-3.20 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.73 (t, J=6.2 Hz, 2H), 2.47 (s, 3H), 1.05 (s, 9H). LCMS (+ESI) m/z=438 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: CC(C)CBr
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(Br)nc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
2-Bromo-5-hydroxypyridine (2 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-Bromo-2-methylpropane (1.1 eq.) is added and the reaction solution is stirred 3 days at 100° C. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-isobutoxy-pyridine is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as a yellow oil in a yield of 19%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 54.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0291 g, 0.0630 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.378 mmol) and 2,4-dichlorobenzenesulfonyl chloride (0.0436 g, 0.189 mmol) to obtain 4-(2,4-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0232 g. yield 55%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]=O)=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[C:25]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].[BH3-]C#N.[Na+]>CCO>[C:25]([N:29]1[CH2:34][CH2:33][N:32]([CH2:23][C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][CH2:20][N:21]4[CH:22]=[C:9]([C:8]5[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:12]=3[CH:13]=2)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C=O)ccc1OCC2
Reactant: CC(C)(C)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CN3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carbaldehyde (50 mg, 0.16 mmol) in EtOH (5.0 mL) was added 1-tert-butylpiperazine (46 mg, 0.32 mmol) and Ti(Oi-Pr)4 (88 mg, 0.31 mmol). The mixture was stirred at room temperature for 30 min. NaBH3CN (20 mg, 0.32 mmol) was added and the reaction mixture was further stirred at room temperature for overnight. The solid was filtered, and the filtrate was concentrated and purified by reverse phase combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to give 108 (16 mg, 25% yield). LCMS (ESI): RT=4.92 min, m/z: 450.4 [M+H+]. 1H NMR (500 MHz, CD3OD): δ 8.41 (d, J=2 Hz, 1H), 7.92 (d, J=3 Hz, 1H), 7.20 (dd, J=8.5 Hz, 2.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 5.90-5.85 (m, 1H), 4.43-4.51 (m, 4H), 3.47 (s, 2H), 2.51-2.39 (m, 8H), 1.51-1.46 (m, 6H), 0.98 (s, 9H)
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]3[C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=5)=O)=[CH:40][CH:39]=4)=[CH:36][N:37]=[C:31]3[CH:30]=2)=[CH:25][CH:24]=1.CO>CN(C)P(N(C)C)(N(C)C)=O>[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]3[C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=5)=[S:10])=[CH:40][CH:39]=4)=[CH:36][N:37]=[C:31]3[CH:30]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: FC(F)(F)c1cccc(NC(=S)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Add Lawesson's reagent (0.246 g, 0.61 mmol, 1.2 eq.) to the solution of 2-[4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-acetamide (0.240 g, 0.51 mmol, 1.0 eq.) in hexamethylphosphoramide (2.5 mL). Stir the reaction mixture at 80° C. overnight. Cool the mixture down to room temperature and load onto a Varian MegaElut® SCX cartridge (5 gram cartridge prewashed with methanol). Rinse with methanol to remove impurities then elute crude product with 2 M NH3 in methanol. Concentrate this solution in vacuo then purify HPLC to give a yellow foam (0.078 g, 31%). MS (ES), m/z 489 (M+1).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[CH2:6]1)=[O:4].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br-].[Mg+2].[Br-]>C(#N)C>[CH3:12][O:11][C:7]1([O:9][CH3:10])[CH2:6][CH:5]([C:3]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:4])[CH2:8]1
Reactant: COC(=O)C1CC(OC)(OC)C1
Reactant: C1CCNC1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CC#N
Product: COC1(OC)CC(C(=O)N2CCCC2)C1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirring solution of 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester, (J. Org. Chem. 1988, 53, 3841 and J. Org. Chem. 1996, 61, 2174) (1.0 g, 5.7 mmol) in acetonitrile (200 mL) was added pyrrolidine (951 uL, 11.5 mmol), followed by magnesium bromide (0.53 g, 2.9 mmol). The reaction was then heated to 60 □C (oil bath) for 18 hours. After 18 hours a second portion of pyrrolidine (1.9 mL, 23 mmol) and magnesium bromide (0.8 g, 4.3 mmol were added. The reaction was then heated to 80 □C (oil bath) for 48 hours. TLC and MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and quenched with a saturated solution of NaHCO3, and diluted with CH2Cl2. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 40M Biotage column, eluting with 70% EtOAc/toluene. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (1.0 g, 86% yield) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:15][C:16]1[C:17]([C:14]#[C:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H]3CCCN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (R)-N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 89B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and a catalytic amount of CuI (2 mg) in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-70% EtOAc in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved at 0° C., in 5 mL of a solution of 50% trifluoroacetic acid in CH2Cl2 that contained 0.3 mL of H2O and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after reverse phase column chromatography with 0-90% MeOH in H2O gradient, a silica gel column chromatography with neat THF and a precipitation out of THF with excess of hexanes. (Yield 14 mg, 31%).