Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: OCc1cc(Br)cc2ccoc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cc(Br)cc2ccoc12
Yield: 95.3 %

Procedure:
A solution of (5-bromo-benzofuran-7-yl)-methanol (327 mg) in 1,4-dioxan (20 ml ) was treated with manganese dioxide (371 mg) and heated at reflux for 2 h. The reaction mixture was filtered, the cake was washed with chloroform (30 ml) and the combined filtrates were evaporated in vacuo to give the title compound as an orange solid (309 mg).
Reaction SMILES: [CH3:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH2:3][C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C([Li])CCC.[Cl-].[CH3:26][C:27]([NH:30][SiH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C1COCC1>[CH3:13][C:2]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:1])[CH2:3][C:4]1[CH:12]([Si:31]([CH3:33])([CH3:32])[NH:30][C:27]([CH3:29])([CH3:28])[CH3:26])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: C[SiH](C)NC(C)(C)C
Reactant: CC(C)(CC1=Cc2ccccc2C1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C(CC(C)(C)c2ccccc2)=Cc2ccccc21
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a mixture of 2-(2-methyl-2-phenyl propan-1-yl)indene (1.55 g, 6.2 mmol) in 50 mL of hexanes were added 4.0 mL of butyl lithium (1.6 M hexane; 1.02 equiv.). The mixture was stirred overnight, filtered, the solid was washed with hexanes and dried, recovering 1.05g (66 percent of indenyl lithium salt) of very pale yellowish solid. The solid was dissolved in THF and a solution of N-(1,1-dimethylethyl)dimethylsilanamine chloride (0.7 g, 1.03 equiv.; 4.2 mmol) in 20 mL of THF was added and the solution was stirred overnight. The volatiles were pumped off, the residue extracted with hexane, filtered and the filtrate was then dried in vacuo to give 1.5 g (96 percent) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][C@H:26]([N:29]=[N+:30]=[N-:31])[C@H:25]([OH:32])[CH2:24]1)(=O)=O.FC1C(F)=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[N:29]([C@H:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:24][C@H:25]1[OH:32])=[N+:30]=[N-:31]
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Reactant: CS(=O)(=O)OCCN1CC[C@H](N=[N+]=[N-])[C@H](O)C1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: O=C([O-])[O-]
Agent: [H-]
Product: [N-]=[N+]=N[C@H]1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)C[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (389 mg, 2.15 mmol) was deprotonated with sodium hydride (95 mg, 60% in oil, 2.36 mmol) and alkylated with cis(±) 2-(4-azido-3-hydroxypiperidin-1-yl)ethyl methanesulfonate (Intermediate 44) (2.15 mmol) as described for Intermediate 20, except after 24 hours, potassium carbonate (100 mg, 0.72 mmol) was added and the resulting mixture was stirred for another 24 hours at room temperature to give the product as a colorless hard foam, 195 mg (26%).
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3](=[CH2:5])[CH3:4].[C:7]([CH:10]1[C:15]([CH3:17])([CH3:16])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)(=[O:9])[CH3:8].[Cl-].[NH4+]>C(OCC)C>[CH2:2]([C:7]([CH3:8])([CH:10]1[C:15]([CH3:16])([CH3:17])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)[OH:9])[C:3](=[CH2:5])[CH3:4]
Reactant: C=C(C)CCl
Reactant: CC(=O)C1C2C=CC(C2)C1(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)CC(C)(O)C1C2C=CC(C2)C1(C)C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Into a 1 liter reaction flask equipped with a reflux condenser, thermometer, stirrer, dropping funnel and nitrogen inlet tube are placed 12 g (0.5 moles) of magnesium turnings and 250 cc anhydrous diethyl ether. Over a 2 hour period, 45.3 g (0.5 moles) of methallyl chloride is added. The Girgnard solution is stirred for 1/2 hour and 28 g of 2-acetyl-3,3-dimethyl-5-norbornene is added over a 20 minute period. The mixture is stirred at reflux for one-half hour and then is hydrolyzed by the addition of saturated ammonium chloride solution. The organic layer is washed with water and dried over magnesium sulfate. The mixture is then filtered and the solvent evaporated to yield 40 g of an oil, which is then fractionated on a micro Vigreux column after adding thereto 5 g Primol® and a trace quantity of Ionox®.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20](O)=[O:21])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=[CH:26]1)=O.CN(C)C=O.CNC>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:20](=[O:21])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A suspension of 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole) and 1,1'-carbonyldiimidazole (1.6 g, 0.0101 mole) and dry dimethylformamide (10 ml) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (26.4 ml of a 2.29 M solution, 0.0606 mole) was added. The resulting solution was heated at 45° C. overnight under nitrogen. The solvents were evaporated under reduced pressure. The residue was triturated in water (300 ml), and the resulting solid was collected by filtration, rinsed with water, 5% potassium 5% potassium hydroxide solution and again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and allowed to cool to room temperature. A solid precipitated which was collected by filtration and dried under high vacuum to give 1.26 g (38%) of title compound, mp 204°-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:28])[N:14]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[C:19](=[O:27])[C:15]3=[N:16]2)=[CH:11][CH:10]=1)=O)(C)([CH3:3])[CH3:2].C(OC[C@@H]1OC1)(=[O:33])CCC.[H-].[Li+]>CN(C=O)C.C(Cl)(Cl)Cl>[OH:33][CH2:2][CH:1]1[O:5][CH2:6][N:8]([C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:28])[N:14]4[C:25]5[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=5)[C:19](=[O:27])[C:15]4=[N:16]3)=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=O)c1cc(F)ccc1-3
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(F)ccc2-n2c1nc1cc(N3COC(CO)C3)ccc1c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(N-t-butyloxycarbonylamino)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione (0.5 mmol), (R)-glycidyl butyrate (0.55 mmol) and lithium hydride (0.60 mmol) in DMF is allowed to stir at room temperature overnight. The reaction mixture is diluted with CHCl3, washed with 0.1N HCl, sodium bicarbonate solution, dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (1% MeOH/CHCl3) gives 3-(5-hydroxymethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([CH:54]=O)[CH2:50][CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CS(C)=O.O1CCCC1>[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51](/[CH:54]=[CH:16]/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:50][CH2:49]1)=[O:47])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc([P+](Cc2ccccc2OCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 70 °C
Yield: 39.5 %

Procedure:
1.75 g of [[2-(cyclohexylmethyloxy)phenyl]methyl]triphenylphosphonium chloride was dissolved in 10 ml of dimethyl sulfoxide, 144 mg of 60% sodium hydride was added thereto, and the mixture was stirred at 70° C. After leaving to cool to room temperature, a solution of 800 mg of 1-(benzyloxycarbonyl)-4-piperidinecarboxaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise thereinto and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, an aqueous saturated sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 554 mg of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.[BH4-].[Na+]>C(O)(=O)C.CO>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: c1ccc2c(c1)NCCCN2
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1cncc(CN2CCCNc3ccccc32)c1
Temperature: 25 °C

Procedure:
To solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 15A (0.50 g, 3.38 mmol) in 1% acetic acid/methanol (25 ml), at room temperature, was added pyridine-3-carboxaldehyde (0.35 ml, 03.72 mmol). The mixture was stirred at reflux for 18 h and then allowed to cool to room temperature. Sodium borohydride (0.050 g, 0.80 mmol) was added. The mixture was stirred for 2 h and then evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacua. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 0.386 g (40%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:21]=2)[CH2:16][CH2:15]1>C(Cl)Cl.CN(C=O)C>[C:40]([N:37]1[CH2:38][CH2:39][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:22]3[N:21]=[C:20]([N:17]4[CH2:16][CH2:15][CH:14]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:19][CH2:18]4)[C:25]([F:26])=[CH:24][N:23]=3)=[CH:29][CH:30]=2)[CH2:35][CH2:36]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 30 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(4-(4-aminopiperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (70 mg, 0.17 mmol) and TEA (0.478 mL, 3.43 mmol) in DMF (2 mL) was added drop wise. The mixture was then stirred at room temperature for 3 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 481.5 (M+H); UV 204.7, 266.3 nm
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.[CH2:17]([SH:19])[CH3:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:17]([S:19][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:18]
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Reactant: CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCSc1ccc(N)nc1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
In a 100 mL round-bottomed flask, 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (519 mg, 1.65 mmol), ethanethiol (102 mg, 122 μl, 1.65 mmol), xantphos (47.6 mg, 82.3 μmol) and Hunig's base (425 mg, 575 μl, 3.29 mmol) were combined with dioxane (10.0 ml) to give a light yellow solution. Pd2(dba)3 (37.7 mg, 41.1 μmol) was added and the mixture was evacuated and filled with Argon. The reaction mixture was heated to 110° C. and stirred for 17 h under argon. The mixture was cooled to 25° C. and conc. in vacuo. The residue was partitioned between 1M HCl and ether. Separated and basified aqueous phase with 3M NaOH. The aqueous layer was extracted with EtOAc (2×125 mL). The organic layers were combined, washed with H2O (1×50 mL), sat NaCl (1×25 mL), dried over Na2SO4 and concentrated in vacuo to an orange oil. The oil was dried overnight at 25° C. under vacuum to give an orange gum that was used crude in the subsequent oxidation. (M+H)+=155 m/e.
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[CH3:25])[C:9]2=[N:8][C:7]=1[CH3:26])(OCC)=[O:2].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:23][C:22]1[CH:21]=[C:20]([F:24])[CH:19]=[C:18]([CH3:25])[C:17]=1[CH2:16][NH:15][C:14]1[C:9]2[N:10]([C:6]([CH2:1][OH:2])=[C:7]([CH3:26])[N:8]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cccn12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(F)cc(C)c1CNc1cccn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 0.6 g (1.7 mmol) of 3-carboethoxy-8-(2,6-dimethyl-4-fluorobenzylamino)-2-methylimidazo[1,2-a]pyridine in 30 ml toluene was cold with ice-water. Red-l 65% 2.1 g (6.6 mmol) in toluene was added during 30 min. The solution was stirred 1 h at rt. 25 ml of Rochelle-salt solution, (35 g sodium potassium tartrate tetrahydrate/250 ml water) was added dropwise and the organic layer was separated. The water layer was washed with methylene chloride which was separated. The combined organic solvents were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluent dichloromethane:methanol 95:5, to give 0.42 g, (79%) of the title compound.
Reaction SMILES: [CH2:1](N(CC)CC)C.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[C:23]([N:30]1[CH2:37][C@@H:36]([N:38]=[N+:39]=[N-:40])[CH2:35][C@H:31]1[C:32]([OH:34])=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClC(Cl)C.CSC>[CH3:1][O:33][C:32](=[O:34])[C@@H:31]1[CH2:35][C@H:36]([N:38]=[N+:39]=[N-:40])[CH2:37][N:30]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CSC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
1-(2-(S)-4-(S)-(Azido)-N-pyrrolidin-2-yl-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide. To 2b (R9′=H) (200 mg, 0.788 mmol) in DMF (5 mL) at 0° C., triethylamine (0.164 mL, 1.18 mmol) and bis-(trimethylsilyl)trifluoroacetamide (0.93 mL, 3.94 mmol) were added and then left stirring at room temperature overnight. After which, N-Boc-(2S,4S)-4-azidoproline (300 mg, 1.18 mmol) and HATU (444 mg, 1.18 mmol) was added at 0° C. and then left stirring for four hours. At the end, DMF was removed and the residue was taken in ethyl acetate (100 mL) and washed with citric acid (10%, 30 mL), saturated sodium bicarbonate (30 mL) and brine (30 mL). After drying the organic portion with sodium sulfate, the solvent was removed to obtain the crude product which was taken as such for the next deprotection step. To the crude product in dichloroethane 30% trifluoroacetic acid (10 mL) and dimethylsulfide (0.5 mL) was added and the reaction mixture was stirred for an hour. The solvent was removed and the crude product obtained was chromatographed on silica gel column using 20% methanol in DCM to obtain the title compound as a white solid (278 mg, 90%): TLC: Rf=0.38 (40% methanol in DCM); 1H NMR (300 MHz, CD3OD) δ 4.24 (d, J=5.4, 1), 4.16 (s, 1), 4.03–4.13 (m, 3), 3.95 (d, J=3.6, 1), 3.80 (dd, J=4.5, 9.9, 1), 3.51–3.56 (dd, J=3.3, 10.2, 1), 3.13–3.22 (m, 1), 2.95–3.00 (m, 1), 2.35–2.45 (m, 1), 2.08 (s, 3), 1.93–2.04 (m, 1), 1.29 (t, J=7.2, 1), 0.97 (m, 3); MS (ESPOS): 392 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 2 h

Procedure:
2.7 ml of 15N sodium hydroxide solution are added to 8.3 g (21.4 mmol) of methyl 4-[2-benzenesulphonamido-indan-5-yl]-4-oxobutyrate in 20 ml of ethanol and the mixture is boiled for 2 hours. The mixture is evaporated in vacuo, the residue is taken up in water, and the reaction product is precipitated with hydrochloric acid. It is crystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11]([O-])(O)=[O:12].[Na+]>CO>[CH3:11][O:12][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: O=C(Cl)c1ccnc(Cl)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccnc(Cl)n1
Yield: 100 %

Procedure:
A solution of 0.5 g (2.82 mmol) of 2-chloropyrimidine-4-carboxylic acid chloride in 10 ml of methanol was stirred for 45 minutes at room temperature. Then the reaction solution was poured on 80 ml of saturated NaHCO3 solution and extracted three times with 50 ml of ethyl acetate each. The combined organic phase was washed with 60 ml of saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation on a rotary evaporator. After drying on a high vacuum, 0.50 g of product was obtained as white solid, corresponding to a yield of 100 percent relative to the 2-chloropyrimidine-4-caboxylic acid chloride used. The melting point of the product was 93.6° to 96.6° C. Other data for the product was:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C@@:19]([OH:27])([C:21]4[N:25]=[C:24]([CH3:26])[O:23][N:22]=4)[CH3:20])[CH:15]=3)[C:10]([C:28](O)=[O:29])=[N:9]2)[C:5]([Cl:31])=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH:57]1[CH2:60][CH:59]([OH:61])[CH2:58]1.C(N(CC)CC)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C@@:19]([OH:27])([C:21]4[N:25]=[C:24]([CH3:26])[O:23][N:22]=4)[CH3:20])[CH:15]=3)[C:10]([C:28]([N:57]3[CH2:60][CH:59]([OH:61])[CH2:58]3)=[O:29])=[N:9]2)[C:5]([Cl:31])=[CH:4][N:3]=1
Reactant: OC1CNC1
Reactant: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(=O)O)nn(-c4nc(N)ncc4Cl)c3c2)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(=O)N4CC(O)C4)nn(-c4nc(N)ncc4Cl)c3c2)no1
Reaction time: 5 h

Procedure:
To a solution of 1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylic acid (100 mg at 65% purity, 0.14 mmol) in DMF (3 mL) was introduced O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (105 mg, 0.28 mmol), azetidin-3-ol hydrochloride (30 mg, 0.28 mmol) and triethylamine (0.06 mL, 0.42 mmol). After 5 hr at RT, the reaction mixture was retreated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (105 mg, 0.28 mmol), azetidin-3-ol hydrochloride (30 mg, 0.28 mmol) and triethylamine (0.06 mL, 0.42 mmol). The reaction was given a further 1 hr at RT, then diluted with water (2 ml) and extracted with EtOAc (2×5 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (DCM containing a 2-12% gradient of methanol) furnished a solid which was suspended in acetonitrile (2 mL). Filtration furnished the title compound as a colorless solid: 1H NMR (500 MHz, DMSO-d6) delta 1.86 (3H, s), 2.62 (3H, s), 3.85 (1H, dd, J=10.9, 4.1 Hz), 4.19-4.45 (2H, m), 4.45-4.67 (1H, m), 4.71-4.97 (1H, m), 5.80 (1H, s), 6.76 (1H, s), 7.26-7.58 (3H, m), 8.02-8.35 (2H, m), 8.54 (1H, s); LC-MS: m/z=+495.05/497.10 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24].C(N(CC)C(C)C)(C)C.O>C1COCC1>[CH3:21][O:20][C:3]1[C:4]([CH:14]([OH:19])[C:15]([F:18])([F:16])[F:17])=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[NH:1][C:23](=[O:24])[O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28]
Reactant: COc1c(N)cc(N2CCOCC2)cc1C(O)C(F)(F)F
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(N2CCOCC2)cc1C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a solution of 1-(3-amino-2-methoxy-5-morpholinophenyl)-2,2,2-trifluoroethanol (2.35 g, 7.67 mmol) in THF (20.4 mL), 2,2,2-trichloroethyl chloroformate (1.14 mL, 8.28 mmol), N,N-diisopropylethylamine (4.02 mL, 23.0 mmol) was added, and the mixture was stirred at 0° C. for 15 minutes. Water was added to the reaction solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20-60/40) to obtain 3.45 g (93% yield) of the captioned compound.