Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH3:24])=[N:22][N:23]=3)[C:15]=2[CH:14]=1.CN(C=O)C.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:25][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH3:24])=[N:22][N:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4nnc(C)n43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: NCCN
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4nnc(C)n43)[nH]1)cn2C
Temperature: 85 °C
Yield: 8.4 %

Procedure:
To a round bottom flask was added 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.040 g, 0.086 mmol), DMF (0.865 mL), ethylenediamine (0.088 mL, 2.6 mmol) and TBAF (1.0 M in THF, 0.346 mL, 0.173 mmol). The reaction mixture was heated to about 85° C. for about 4 h. To the reaction mixture was added ethylenediamine (0.088 mL, 2.6 mmol) and TBAF (1.0 M in THF, 0.346 mL, 0.173 mmol). The reaction mixture was heated at about 85° C. for about 2 h. The reaction mixture cooled to room temperature and diluted with water (50 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparatory RP-HPLC (Table 2, Method u). The material was further purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.0024 g, 8.4%). LC/MS (Table 1, Method a) Rt=1.84 min; MS m/z: 333 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)c2ccc(C#N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
4-Cyanobenzoyl chloride (4.50 g) was added to a stirred suspension of methyl 5-amino-2-methylbenzoate (J. Med. Chem., 1991, 34, 2176-2186; 3 g), triethylamine (2.54 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was acidified by the addition of 1N aqueous hydrochloric acid solution and the mixture was stirred at ambient temperature for 30 minutes. The resultant solid was isolated and dried under vacuum at 40° C. to give methyl 5-(4-cyanobenzamido)-2-methylbenzoate (5.32 g); NMR Spectrum: (DMSOd6) 2.47 (s, 3H), 3.83 (s, 3H), 7.31 (d, 1H), 7.88 (d, 1H), 8.0 (d, 2H), 8.1 (d, 2H), 8.27 (s,1H), 10.57 (s, 1H); Mass Spectrum: M+H+ 295.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)n2)CC1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (100 mg) in pyridine (2.5 ml) is added, at 0° C. under argon, POCl3 (0.26 ml). The mixture is stirred at 0° C. and then slowly warmed to room temperature. The mixture is stirred at room temperature overnight. The reaction mixture is subsequently admixed with saturated sodium hydrogencarbonate solution and the aqueous phase is removed. After the aqueous phase has been extracted with tert-butyl methyl ether, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 6-bromo-3′,6′-dihydro-2,4′-bipyridine-1′(2′H)-carboxylate (60 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:3]=12.[F:35][C:36]1[C:37]([CH2:42][OH:43])=[N:38][CH:39]=[CH:40][CH:41]=1>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[C:7]([C:7]2[CH:2]=[C:3]([CH:42]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][N:38]=3)[OH:43])[CH:4]=[N:5][CH:6]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:3]=12
Reactant: OCc1ncccc1F
Reactant: CC1(C)OB(c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccccc2F)c2c(Cl)c(-c3cncc(C(O)c4ncccc4F)c3)cnc21
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 176.1 %

Procedure:
A mixture of 4-chloro-3-(2-fluoro-phenyl)-5-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.2 mmol), 5-bromo-pyridin-3-yl)-(3-fluoro-pyridin-2-yl)-methanol (57 mg, 0.2 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (7 mg, 0.01 mmol) in THF/Acetonitrile/saturated NaHCO3 (5 ml/5 ml/5 ml) was stirred at 120° C. in the microwave for 20 minutes. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (2×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded {5-[4-chloro-3-(fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-pyridin-3-yl}-(3-fluoro-pyridin-2-yl)-methanol (102 mg, 88% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:42](O)=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[OH:15][C@@H:7]([CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])[C@@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:42]([C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:43])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:4])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Yield: 26.8 %

Procedure:
A mixture of 880 mg (2.5 mmol) of (S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 1.99 g (7.5 mmol) of t-butoxycarbonyl-L-phenylalanine. 1.05 ml (7.5 mmol) of triethylamine and 3.32 g (7.5 mmol) of BOP in 100 ml of acetonitrile was stirred at room temperature for 6 days. Thereafter, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. The organic solution was dried over sodium sulfate and evaporated and the residue was triturated twice with hexane. The residue was chromatographed on 100 g of silica gel with a 98:2 mixture of chloroform and methanol. Recrystallization of the thus-obtained crude product from methylene chloride and hexane yielded 400 mg of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4 -isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as a white powder, melting point 82°.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[C:5]([O-:8])([O-])=O.O.O.O.[K+].[K+].[K+].[K+].[N+]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])=[O:26])([O-])=O.[C:36](=[O:39])([O-])[O-].[K+].[K+].[BH4-].[Na+].[CH3:44][CH2:45]OCC>O>[N+:33]([C:28]1[CH:29]=[C:30]([O:39][CH3:36])[C:31]([O:8][CH3:5])=[CH:32][C:27]=1[CH:25]([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:19][CH2:44][CH2:45][C:1]([OH:4])=[O:2])([O-:35])=[O:34]
Reactant: O=C(c1ccccc1[N+](=O)[O-])c1ccccc1[N+](=O)[O-]
Reactant: CCOCC
Reactant: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(O)CCCCCCCCC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Yield: 95 %

Procedure:
To a rapidly stirred solution of 8.33 g potassium carbonate 1.5 hydrate in 330 ml water was added 18.5 g of the nitrophenyl ketone. 2.5 g of potassium carbonate was added to make a clear solution. A solution of 2.36 g sodium borohydride in 50 ml water was added over 5 min. The mixture was heated to 45° for one hour, cooled to room temperature over 2 hours, and shaken with 200 ml ether. The layers were separated and the water layer stirred as a solution of 8% aqueous HCl was added until the solution was a pH of 2-3. An orange solid was collected by filtration, blended in ice water, filtered, washed with water and vacuum oven dried at 60° C. to yield 18 g, 95% yield.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 36 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (42 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (36% yield). M.p. 93-95° C., LCMS: m/z=553.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.75-1.85 (m, 5H), 1.87-2.04 (m, 2H), 2.22-2.33 (m, 1H), 2.88-3.08 (m, 2H), 3.28-3.33 (m, 2H), 3.52-3.58 (m, 2H), 3.82-3.90 (m, 1H), 4.53 (s, 1H), 4.90 (bs, 1H), 6.96-7.02 (m, 1H), 7.17 (s, 1H), 7.18-7.20 (m, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.75 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:19]1([CH2:18][CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C(C=Cc1ccccc1OCc1ccccc1)=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCCCc1ccccc1
Yield: 94.4 %

Procedure:
The whole of this 1-(2-benzyloxyphenyl)-4-phenylbutadiene was mixed with 300 ml of ethanol, and the mixture was stirred at 60° C. for 5 hours in an atmosphere of hydrogen and in the presence of 1 g of 5% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.34 g (yield 94.4%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[O:19])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)O)nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCc2cn(COC(=O)C(C)(C)C)nn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanoic acid (1.63 g, 6.05 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.212 g, 6.05 mmol) in DMF (10 mL) was added Huenig's Base (3.17 mL, 18.16 mmol) followed by T3P® 50% in DMF (7.07 mL, 12.11 mmol) at RT. The reaction mixture was allowed to stir at RT for 20 hours. The DMF was removed under reduced pressure and the residue dissolved in EtOAc and washed with a saturated solution of sodium bicarbonate, a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(Cl)Cl.CO>ClCCl.CS(Cl)(=O)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCc2ccccc2)co1
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To an ice/salt cooled suspension of 5-benzyloxy-2-hydroxymethyl-pyran-4-one (30.0 g, 0.129 mol) in dichloromethane (500 mL) were added, successively, triethylamine (21.0 mL, 0.151 mol) and a solution of methanesulfonyl chloride (8.3 mL, 0.129 mol) in 10 mL of dichlroromethane. The progress of the reaction was monitored by TLC (CH2Cl2/MeOH, 10/1, v/v), and by HPLC Method 1 as described above. An additional methanesulfonyl chloride (0.5 mL, 7.70 mmol) and triethylamine (2.0 mL, 14.2 mmol) were added to the solution after 50 min. Again, an additional methanesulfonyl chloride (1.0 mL, 15.4 mmol) and triethylamine (2 mL, 14.2 mmol) were added an hour later. The reaction was quenched with 150 mL of brine. The organic phase was separated and collected, dried over sodium sulfate and concentrated in vacuo to give an oil. The oil was diluted with 200 mL of hexanes and a precipitate was formed. The solid was collected by suction filtration, and dried in a vacuum oven to give methanesulfonic acid 5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl ester (39 g, 85% yield). HPLC purity (peak area percent) is 82.1% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 8.32 (m, 1H), 7.43-7.37 (m, 5H), 6.62 (m, 1H), 5.18 (m, 2H2OCH2), 4.98 (m, 2H, OCH2), 3.36 (m, 3H, SCH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:15]1.[H-].[Na+].CI>ClCCl>[C:1]([O:5][C:6](=[O:13])[N:7]([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCNC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Product: C#CCCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 500 mL round bottom flask was charged with pent-4-ynyl-carbamic acid tert-butyl ester (5.0 g, 27.3 mmol) and tetrahydrofuran (138 mL) and the resulting mixture cooled with an ice/water bath. Sodium hydride (830 mg, 32.9 mmol) was added in 3 portions and the resulting mixture stirred at room temperature for 20 minutes. Methyl iodide (8.6 mL, 138.1 mmol) was slowly added and the resulting mixture stirred for 72 h. The resulting mixture was diluted with dichlormethane (350 mL), washed with 1N HCl (100 mL), 1N, NaOH (100 mL), and water (100 mL). The organic layer was washed with MgSO4, filtered, then concentrated in vacuo to yield methyl-pent-4-ynyl-carbamic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ 3.31 (t, J=7.0 Hz, 2H), 2.86 (s, 3H), 2.17-2.24 (m, 2H), 1.96 (s, 1H), 1.72-1.79 (m, 2H), and 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[C:22]([F:25])([F:24])[F:23])[C:9]2[C:4](=[C:5]([O:26][CH3:27])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1>CN(C)C=O>[ClH:1].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[C:22]([F:23])([F:24])[F:25])[C:9]3[C:4](=[C:5]([O:26][CH3:27])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:31]([CH3:36])[CH:30]=1
Reactant: COc1cccc2c(N3CCc4ccccc4C3C(F)(F)F)nc(Cl)nc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3C(F)(F)F)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 53 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.9 g of the compound (4.82 mM) prepared in Example 8 and 15 ml of dimethyl-formamide, 0.82 ml of 4-fluoro-2-methyl aniline(10.1 mM) was added, 1.32 g of the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]2[C:6](=[O:32])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:35][N:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]1.FC(F)(F)C(O)=O.C(Cl)[Cl:57]>>[ClH:57].[ClH:57].[OH:1][C:2]1[CH:34]=[CH:33][C:5]2[C:6](=[O:32])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(C(F)(F)F)cc4)c4ccccc24)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1/C(=C/c2cn(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of tert-butyl (Z)-4-([6-hydroxy-3-oxo-2-({1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indol-3-yl]methylene)-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0500 g, 0.0731 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (4 mL) was added with a 5% solution of hydrogen chloride in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain the objective (Z)-6-hydroxy-7-(piperazin-1-ylmethyl)-2-({1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indol-3-yl}methylene)benzofuran-3(2H)-one dihydrochloride (0.0311 g, 64%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]2[O:13][C:12]([CH3:15])(O)[CH2:11][CH2:10][C:9]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2].[ClH:20]>CCOCC>[C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]2[O:13][C:12]([Cl:20])([CH3:15])[CH2:11][CH2:10][C:9]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reactant: Cl
Solvent: CCOCC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(Cl)O2
Yield: 40.2 %

Procedure:
A mixture of 10 g (37.9 mmol) of rac-3,4-dihydro-6-acetyloxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol and 10 g of 4A molecular sieves in 200 mL of anhydrous ether was stirred with ice-bath cooling while HCl gas was bubbled in for 30 min. The mixture was filtered and the filtrate concentrated in vacuo. The residue was taken up in 600 mL of hexane and anhydrous CaCl2 was added. The mixture was stirred for 1 hr then filtered and the filtrate was concentrate in vacuo giving 4.3 g (40.2% yield) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol acetate as a colorless solid, mp 102°-106° C., which was unstable to column or thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:22])C(=O)C1.O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cn2ccnc(Cl)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc2c(Cl)nccn2c1Br
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (9.9 g, 46.8 mmol) in acetonitrile (600 mL) was added NBS (8.9 g, 50.1 mmol), and benzoyl peroxide (90 mg, 0.37 mmol). The mixture was then heated to reflux for 1 h, cooled to r.t., and water (1800 mL) was added. The resulting solids were filtered, washed with water, and air dried to give the title compound (11 g). LRMS (ESI) calc (M+H)+=289.9/291.9. found 290.0/292.0
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2C(O)=O)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:34]([C:36]([O:40]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:66]([O:70][C:71]([N:73]1[CH2:78][CH2:77][CH2:76][CH:75](N)[CH2:74]1)=[O:72])([CH3:69])([CH3:68])[CH3:67]>CN(C=O)C>[C:66]([O:70][C:71]([N:73]1[CH2:74][CH2:75][CH:76]([NH:34][C:36](=[O:40])[C:26]2[CH:25]=[CH:24][C:23]([C:21]3[N:22]=[C:18]([NH:17][C:16]([CH:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[O:32])[S:19][CH:20]=3)=[CH:28][CH:27]=2)[CH2:77][CH2:78]1)=[O:72])([CH3:67])([CH3:68])[CH3:69]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=C(O)c1ccccc1-c1csc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3csc(NC(=O)C4CCCN4C(=O)OCc4ccccc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
125 mg (0.28 mmol) of 2-[4-(2-carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (IS2277-52) was dissolved in 4 mL of DMF. To this solution was added HATU (160.9 mg, 0.42 mmol) and DIEA (0.05 mL, 0.36 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 56.1 mg (0.28 mmol) of 3-amino-piperidine-1-carboxylic acid tert-butyl ester. Reaction mixture was stirred overnight at room temperature, and then purified using reverse phase HPLC. MS: 634.2 (M+H+); H1 NMR (meOH-d4): δ(ppm) 8.02 (m, 2H), 7.89 (m, 2H), 7.58 (m, 1H), 7.39 (m, 3H), 7.19 (m, 1H), 7.07 (m, 2H), 5.03 (m, 2H), 45.2 (m, 1H), 4.11 (m, 3H), 3.61 (m, 4H), 3.19 (m, 1H), 2.97 (m, 2H), 2.41 (m, 1H), 2.28 (m, 1H), 2.01 (m, 4H), 1.48 (s, 9H).