Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 10)), sodium hydride and methanesulfonyl chloride, to give the desired product as a light yellow oil (53%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].[CH2:31](O)[CH2:32][OH:33].O.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([O:27][CH2:31][CH2:32][OH:33])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: OCCO
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)OCCO)c[nH]3)c2)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (70 mg, 0.17 mmol), ethylene glycol (1 ml), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl, 40 mg, 0.21 mmol) and 4-dimethylaminopyridine (DMAP, 10 mg, 0.08 mmol) in anhydrous DMF (10 ml) was stirred at 70° C. for 3 hours then room temperature for 16 hours. The mixture was poured into 100 ml of water. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜4% MeOH/CHCl3 to give 2-hydroxyethyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid. Yield: 40 mg, 51%.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6].C(Cl)(=O)C([Cl:28])=O>C1COCC1.CN(C=O)C>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([Cl:28])=[O:24])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)Cl)c1
Reaction time: 0.75 h

Procedure:
The carboxylic acid from the previous stage (0.33 g) stirred in dry THF (10 ml) was treated with oxalyl chloride (0.11 ml) and one drop of dry DMF. The reaction mixture was stirred for 45 minutes, stood overnight and then evaporated to give crude (E)-methyl 3-methoxy-2-(2-[3-chlorocarbonylphenoxy]phenyl)propenoate as an orange-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH2:28])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[C:31]1([C:34](Cl)=[O:35])[CH2:33][CH:32]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F
Reactant: O=C(Cl)C1=CC1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To the THF solution of 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.8 g, 7 mmol) was added cyclopropenyl carbonyl chloride (0.72 ml, 8 mmol) dropwise. The reaction mixture was then heated to reflux for 1 hour. The solvent was removed under vacuo. The mixture was dissolved in EtOAc (50 ml) and washed with water (50 ml×2). The organic layer was dried over Na2SO4 and concentrated under vacuo. The resulted solid was stirred with ether (20 ml) for 1 hour and filtered to give a total of 2.5 g (77% yield) white solid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:27](COCC[Si](C)(C)C)[CH:28]=[CH:29][N:30]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1-c1ncc[nH]1
Reaction time: 16 h
Yield: 55.9 %

Procedure:
A solution of 2-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (Step 2, 110 mg) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL) and the solution stirred for 16 h, then concentrated in vacuo and partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The phases were separated and the organic phase dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant 75% EtOAc/isohexane) to afford a colourless oil, which solidified on treatment with Et2O. The solid was washed with 50% EtOAc/isohexane and dried, to afford the title compound as a white solid (47 mg). δH (500 MHz, d6 DMSO): 12.11 (1H, s), 8.25 (1H, t, J 4.6), 7.85 (1H, q, J 8.1), 7.77–7.71 (2H, m), 7.69 (2H, d, J 8.4), 7.58 (2H, d, J 8.4), 7.51 (1H, t, J 4.4), 7.39–7.29 (3H, m), 7.23 (1H, s), 7.15 (1H, td, J 2.5, 8.5), 6.94 (1H, s); m/z (ES+) 422 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[C:46]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:45](=[O:52])[NH:44][CH2:43]2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]4([N:42]([C:39]5[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=5)[CH2:43][NH:44][C:45]4=[O:52])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH2:41]=O.[BH4-].[Na+].CO>C1COCC1>[CH3:39][N:9]1[CH:10]=[C:11]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:37])[F:38])[CH:21]=3)[O:18][CH:19]=2)=[O:14])[C:7]([N:5]2[CH2:6][C@@H:2]([NH:1][CH3:41])[CH2:3][C:4]2=[O:40])=[N:8]1
Reactant: C=O
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (83 mg) in THF (0.73 mL) was added 37% formalin (32 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled, sodium borohydride (28 mg) and methanol (0.73 mL) were added thereto, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (19 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:30][CH2:29][CH2:27][OH:28])[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: NCCO
Product: Cc1sc2cc(OCCCCNCCO)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and ethanolamine were converted to yield 2-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butylamino}-ethanol as colorless amorphous solid, MS: 424 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2ccnn2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C(#Cc1cnc2ccnn2c1)c1ccccc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (27 mg, 0.04 mmol) was dissolved in 1 ml of THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg, 0.76 mmol) and phenylacetylene (130 μl, 1.21 mmol) were added at room temperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg, 0.023 mmol) and copper(I) iodide (4 mg, 0.023 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with heptane:ethyl acetate 100:0→50:50. The desired compound was obtained as a yellow solid (150 mg, 90% yield), MS: m/e=220.3 (M+H+).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([CH3:20])=[N:17][NH:18][CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:16]([CH3:20])=[N:17][N:18]([C:24]4[N:23]=[C:22]([NH2:21])[C:27]([CH3:28])=[CH:26][N:25]=4)[CH:19]=3)=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Cc1cnc(Cl)nc1N
Reactant: Cc1n[nH]cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(-n2cc(C(=O)NCC34CC5CC(CC(C5)C3)C4)c(C)n2)nc1N
Temperature: 165 °C

Procedure:
A mixture of 3-methyl-1H-pyrazole-4-carboxylic acid (adamantan-1-ylmethyl)-amide (1.6 g, 5.85 mmol), 4-amino-2-chloro-5-methylpyrimidine (924 mg, 6.4 mmol) and potassium carbonate (1.6 g, 11.7 mmol) in DMSO (10 mL) is heated at 165° C. for 14 h. The mixture is cooled to RT and partitioned between EtOAc and water and separate the layers. The aqueous layer is extracted twice with further EtOAc. The extracts are combined, dried and evaporated. Purification by flash chromatography eluting with a mixture of 7% MeOH and 1% TEA in DCM affords the title compound.
Reaction SMILES: C(NCCO)C1C=CC=CC=1.C([C@H]1OC1)Cl.[OH-].[Na+].[OH:19][CH2:20][CH:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1.O1CCCNCC1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>CO.O.CC(O)C>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[OH:19][CH2:20][C@@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: OCC1CNCCO1
Agent: C1CNCCOC1
Agent: ClC[C@@H]1CO1
Agent: OCCNCc1ccccc1
Solvent: CC(C)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-benzylethanolamine (40.9 g, 0.270 mol), 2-propanol (25 ml) and water (25 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (25.0 g, 0.270 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 14.05 g, 0.351 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (75 ml) and, after partitioning, the organic layer was concentrated under reduced pressure. To the obtained residue (53.9 g) were added methanol (161.8 ml) and palladium carbon (18.9 g when dry), and the mixture was reacted under a hydrogen stream at 40° C. for 30 hr. Palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure and the residue was distilled (0.5 mmHg, 115 to 135° C.) to give a mixture of 2-hydroxymethylmorpholine and 1,4-oxazepane compound (21.6 g, 2-hydroxymethylmorpholine: 1,4-oxazepane compound=79.0:21.0). To this mixture was added methanol (22 ml), and trifluoroacetic acid (22.1 g, 0.194 mol) was added dropwise at 0 to 25° C. After stirring at 25° C. for 1 hr, the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate (108 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (22 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (26.49 g) (yield from (S)-epichlorohydrin 42.4%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][OH:18])[CH:9]=[C:8]2[C:19]1[N:27](S(C2C=CC(C)=CC=2)(=O)=O)[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][OH:18])[CH:9]=[C:8]2[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCO)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCO)c2cc1OC
Yield: 36.4 %

Procedure:
1.65 ml of a 5N aqueous potassium hydroxide solution are added to a solution of 0.18 g of 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}ethanol in 10 ml of methanol, at a temperature in the region of 20° C. The reaction medium is refluxed for 4 hours. After cooling, the solid formed is filtered off through sintered glass, and washed twice with 3 ml of methanol and then five times with 5 ml of water. The solid is purified by flash-pack chromatography (silica, 95/05 by volume dichloromethane/methanol as eluents). 0.045 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]ethanol is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2])(=[O:11])[CH3:10]
Reactant: Oc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1cc(O)ccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of hydroquinone in 500 ml of acetic acid, 102 g(1 mol) of acetic anhydride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of toluene was added to the reaction mixture and the unreacted excess hydroquinone was filtered and collected (recovered amount: 110 g, recycled without any purification process). A desired monoacetyl hydroquinone was obtained by evaporating the residue under vacuum. (Yield: 149.1 g(98%). mp: 60-62° C., 1H-NMR(200 MHz, CDCl3, ppm) 2.25(s, 3H), 5.78 (br, 1H), 6.70 (d,2H), 6.88 (d, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35](C)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.1 %

Procedure:
Indole-2-carboxylic acid (5.2 g) in THF (200 mL) was treated with carbonyldiimidazole (4.8 g) and stirred at ambient temperature for 10 min whereupon 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g) was added. The mixture was stirred at ambient temperature for 72 h and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was separated, dried over sodium sulfate and filtered, and solvent was evaporated to afford a solid. Recrystallization from hot ethanol afforded 4-(1H-Indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([OH:52])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:59][O:60][C@@H:61]1[C@@H:65]([O:66][N+:67]([O-:69])=[O:68])[CH2:64][C@H:63]([C:70]([O:72][CH:73](Cl)[CH3:74])=[O:71])[CH2:62]1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26]([C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:73]([O:72][C:70]([C@H:63]3[CH2:64][C@H:65]([O:66][N+:67]([O-:69])=[O:68])[C@@H:61]([O:60][CH3:59])[CH2:62]3)=[O:71])[CH3:74])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CO[C@H]1C[C@@H](C(=O)OC(C)Cl)C[C@@H]1O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)[C@@H]3C[C@H](OC)[C@@H](O[N+](=O)[O-])C3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C

Procedure:
A mixture of 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (2180 mg, 3.19 mmol), cesium carbonate (2150 mg, 6.60 mmol), and tetrabutylammonium hydrogen sulfate (538 mg, 1.59 mmol) was charged with a N,N-dimethylformamide (10 mL) solution of 1-chloroethyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (intermediate 2, 834 mg, 3.11 mmol). The reaction mixture was heated at 40° C. for 16 hours, and the reaction mixture was purified by column chromatography, eluting with 10/90→70/30 ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 1.36 (d, J=5.5 Hz, 3H, D1), 1.36 (d, J=5.5 Hz, 3H, D2), 1.41 (t, J=7.1 Hz, 3H), 1.94-2.05 (m, 2H), 2.19-2.27 (m, 1H), 2.46-2.54 (m, 1H), 2.76-2.87 (m, 1H), 3.30 (s, 3H, D1), 3.30 (s, 3H, D2), 3.76 (q, J=4.1 Hz, 1H), 4.61 (q, J=7.1 Hz, 2H, D1), 4.61 (q, J=7.1 Hz, 2H, D2), 5.23 (t, J=6.0 Hz, 1H), 5.53 (d, J=16.0 Hz, 1H), 5.58 (d, J=16.0 Hz, 1H), 6.75 (d, J=6.9 Hz, 2H), 6.88-6.95 (m, 7H), 6.98 (d, J=8.0 Hz, 2H), 7.17 (dt, J=2.0, 7.8 Hz, 1H), 7.23 (t, J=7.7 Hz, 6H), 7.26-7.34 (m, 4H), 7.40-7.48 (m, 2H), 7.54 (dd, J=1.1, 8.0 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H); LC-MS: m/z 913.6 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: BrCC1CCCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 61.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and bromomethyl cyclohexane (122 mg, 0.690 mmol) gave 2-[5-(4-cyclohexylmethyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (75 mg, 63%). MS(ESI) m/z 531.4 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1C2C=CC(O[CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:34]4([C:38]5[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=5)[CH2:37][CH2:36][CH2:35]4)=[O:33])[CH2:27]3)=CC=2OC1>>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:34]2([C:32]([N:28]3[CH2:29][CH2:30][CH2:31][CH:26]([CH2:25][O:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:27]3)=[O:33])[CH2:37][CH2:36][CH2:35]2)=[CH:39][CH:40]=1
Reactant: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2ccc(F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1

Procedure:
Compound 84 was synthesized from 4-fluorophenol (0.29 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.60 g of the desired product 84. C23H25ClFNO2, LRMS (m/z)=402 (MH+).