Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH2:8][Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=[O:13])C1>CO.O>[C:1]1([S:7]([CH2:8][Cl:9])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCSc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: O
Product: O=S(CCl)c1ccccc1
Yield: 41.8 %

Procedure:
Chloromethyl phenyl sulfide (3 g, 18.9 mmol) was dissolved in a mixture of methanol (15 mL) and water (3 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (4.04 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 solution (10%, 15 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layer was dried with anhydrous MgSO4 and concentrated. The crude product was purified by medium pressure chromatography (Ethyl Acetate/Hexane 2:8) to give 1.381 g (42%) of the desired product as a colourless liquid. 1H NMR (CDCl3, 400 MHz): δ 7.71-7.69 (2H, m), 7.57-7.56 (3H, m), 4.41 (2H, ABQ, J=10.8 Hz). 13C NMR (CDCl3, 100 MHz): δ 140.8, 132.1, 126.3, 124.8, 61.3. FT-IR (NaCl): 3058, 3004, 2935, 1472, 1444, 1384, 1218, 1085, 1052 cm−1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:17].[C:18](=[O:20])=[O:19].[Cl-].[Na+]>CN(C)C=O.O.CN(C)C=O.O>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[C:18]([O-:20])=[O:19])([CH3:14])([CH3:13])[CH3:12].[Na+:17]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)[O-])cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of dimethylformamide/water is distilled from a solution of 206 g (1 mol) of 2,6-di-tert.-butylphenol and 80 g of a 50% strength aqueous sodium hydroxide solution in 500 ml of dimethylformamide at boiling point 30°-50° C./approx. 20 mm Hg until the water content in the last sample of the distillate is approx. 1.5%. After releasing the vacuum with nitrogen, carbon dioxide gas is passed into the reaction solution, with vigorous stirring, in the course of which the temperature of the solution rises to approx 85° C. After 11/2 hours at this temperature, the reaction mixture is cooled to 60° C. and 450 ml of a 20% strength sodium chloride solution are added under carbon dioxide gas. The resulting clear reaction solution is thereafter cooled, whereupon crystallisation starts at room temperature and is completed by stirring for 0.5 hours at 0°-5° C. Filtration, successive washing with 200 ml of 20% strength sodium chloride solution and 200 ml of n-hexane and drying the crystals to constant weight in vacuo at 40° C. yields colourless sodium 3,5-di-tert.-butyl-4-hydroxy-benzoate, containing water of crystallisation; when this substance is dissolved in 500 ml of water and precipitated with concentrated hydrochloric acid, it yields 189 g (yield, 77% of theory) of 3,5-di-tert.-butyl-4-hydroxybenzoic acid of melting point 215° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.ClCCl>CN(C=O)C>[F:41][C:37]1[CH:36]=[C:35]([N:5]2[C:4](=[O:28])[CH2:3][C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]2=3)[CH:40]=[CH:39][CH:38]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccc(F)c3)c3ccccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To a stirring solution of 500 mg (1.3 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 5 mL DMF is added 248 mg (3.9 mmol, 3 equiv) of Cu powder, 255 mg (2.6 mmol, 2 equiv) of potassium acetate, and 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene. The reaction is heated to 100° C., and after 3 h an additional 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene and 248 mg (3.9 mmol, 3 equiv) of Cu powder were added. The reaction is heated at 100° C. for 20 h then is poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 2:1-1:1 hexanes:ethyl acetate) to afford 497 mg of 2-[5-(3-Fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ7.45-7.25 (m, 4H), 7.18-6.93 (m, 8H), 5.04 (m, 1H), 4.35 (d, 1H, J=16.3), 4.17 (d, 1H, J=16.1), 3.88 (s, 3H), 3.56 (dd, 2H, J=12.0, 29.8), 1.12 (d, 6H, J=6.8); low resolution MS (FAB)m/e 476 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]1.Cl[C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1>C1COCC1>[OH:7][C@H:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:3]1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: N[C@H]1CC[C@H](O)C1
Solvent: C1CCOC1
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
TEA (0.84 mL, 6.04 mmol) was added to a solution of trans-3-amino-cyclopentanol (1.83 g) in anhydrous THF (10 mL), under argon atmosphere. 4-Chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (1.13 g, 6.04 mmol) was then added in two portions and the resulting mixture was stirred, at RT, under argon atmosphere, for 2 h. The liquid layer was decanted and THF was added to the gummy residue. The extraction procedure was repeated and the combined extracts were evaporated under reduced pressure. The crude residue was absorbed onto silica gel and purified by flash chromatography (EtOAc/hexane) to give 1.0 g of trans-4-(3-hydroxy-cyclopentylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile.
Reaction SMILES: [CH3:1][Si:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[CH:9]=1.C1C(=O)N([Br:63])C(=O)C1>CC#N>[CH3:55][Si:2]([CH3:1])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1[Br:63]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Solvent: CC#N
Product: COCCOC(=O)C1(OCCOC)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (2.28 g, 2.87 mmol) in CH3CN (50 mL) was added NBS (511 mg, 2.87 mmol) and stirred at rt for 30 min. Both TLC and LCMS showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-30%, EtOAc/Hexanes, Rf=0.65 in 50% EtOAc) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a yellow oil (2.50 g). HPLC-MS TR=1.99 min (UV 254 nm, 3 min method); mass calculated for formula C40H61BrN6O7Si2 872.3, observed LCMS m/z 873.3 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:8][C@@H:7]([C:9]([N:11]([C:13]2[C:14]([Cl:24])=[N:15][N:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=2)[CH3:12])=[O:10])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:3][C@H:4]1[CH2:8][C@@H:7]([C:9]([N:11]([C:13]2[C:14]([Cl:24])=[N:15][N:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=2)[CH3:12])=[O:10])[CH:6]=[CH:5]1)(=[O:34])[CH3:33]
Reactant: CN(C(=O)[C@H]1C=C[C@@H](N)C1)c1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C=C[C@H](C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Reaction time: 24 h

Procedure:
To a suspension of (1R,4S)-4-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylcyclopent-2-enecarboxamide dihydrochloride (0.065 g, 0.17 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.084 g, 0.83 mmol) followed by acetyl chloride (1 M in CH2Cl2, 0.25 mL, 0.25 mmol). After stirring for 24 hours, the reaction product was purified by direct application to silica gel chromatography eluting with MeOH/CH2Cl2 to provide the title compound F86 as yellow foam (0.040 g, 67%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:22])=O)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:22])=[O:8]
Reactant: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 15b (0.14 g, 0.53 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 15c.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:4][CH:3]=1.[NH2:17][C:18](N)=[O:19].O>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:15][C:18](=[O:19])[N:17]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1nc(-c2ccc(F)cc2)c2ccccc2[nH]1

Procedure:
4'-Fluoro-2-aminobenzophenone (164.5 g, 1.20 mol) is heated with urea (72.09 g, 0.500 mol) at 195° C. (1 h) in NMP (500 mL). The solution is cooled and poured into water (2 L). The product is collected by filtration and dried. The product is purified by recrystallization.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([C:20]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To 250 ml of a suspension of 12.56 g of methyl 2-aminoacetate hydrochloride in dichloromethane, 20.24 g of triethylamine was added, and stirred for 30 minutes at room temperature. After ice-cooling, 20 ml of a solution of 14.66 g of 2-thenoyl chloride in dichloromethane was added dropwise slowly. The ice-bath was removed and the mixture was stirred for 14 hours at room temperature. The precipitated crystals were collected by filtration and washed with dichloromethane. The solvent was removed from the filtrate by distillation under reduced pressure. To the residue was added t-butyl methyl ether to precipitate. The both products were combined to provide 17.20 g of the objective compound as brownish crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([NH2:14])[N:13]=[C:9]3[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:25][N:26]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:27]>ClCCl>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([NH:14][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([CH2:28][N:26]([CH3:25])[CH3:27])=[CH:30][CH:31]=4)[N:13]=[C:9]3[CH:8]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1
Reactant: CN(C)Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)Cc1ccc(C(=O)Nc2nc3cc(C(F)(F)F)cc(NC4CC4)n3n2)cc1
Yield: 51.9 %

Procedure:
To a reaction vessel containing N5-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A18), 77 mg, 0.3 mmol, 1 eq.) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-dimethylaminomethyl-benzoyl chloride (118 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (65.1 mg, 52%). HPLC, Rt: 2.59 min (purity: 100%). LC/MS M+(ESI): 419.2, M−(ESI) 417.2.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](CO)[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.O1CCOC[CH2:34]1>CO>[NH2:22][C:18]1[CH:17]=[C:16]([C@H:15]([NH:14][C:9]2[C:8]3[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH3:34])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cc(CO)cc23)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [3-({[8-(aminocarbonyl)-6-(hydroxymethyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate (20 mg; 0.05 mmol; 1.00 eq.) in methanol (1 ml) was added 4.0M hydrogen chloride in dioxane (1 ml; 4.00 M; 4.00 mmol; 84.69 eq.). The reaction mixture was stirred at RT for 3 h. Concentrated to obtain title product. MS (M+1) 324.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:5][CH:4]=1.N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>C(O)(=O)C.O>[N:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:7][CH:8]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 20 ml of water and 11 ml of concentrated hydrochloric acid at <10° was added a solution of 14.17 g of 2-(4-aminophenyl)-3-methylbutanoic acid, benzyl ester in 50 ml of acetic acid. At 0° to 5° was added a solution of 3.62 g of sodium nitrite in 12.5 ml of water. The mixture was stirred at 0° to 5° for an additional 45 minutes, then poured into a stirred solution of 3.25 g of sodium azide in 12.5 ml of water in an ice-cooled beaker. Gas evolved immediately along with formation of orange oil. After 3-4 minutes, the mixture was diluted with water to 400 ml, then extracted with butyl chloride. The butyl chloride solution was washed with water (3 times) and saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to 13.5 g of oil, 2-(4-azidophenyl)-3-methylbutanoic acid, benzyl ester, which began to solidify. The infrared spectrum of the oil shows absorption peaks at 2130 cm-1 (azide) and 1740 cm-1 (ester carbonyl). Thin-layer chromatography on silica gel-coated plates in chloroform or butyl chloride showed only one spot.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N+:39]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)([O-:41])=[O:40]>CN(C=O)C>[C:33]([O:32][C:30]([NH:29][C@H:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:19][C@@:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:46][C:45]1[CH:48]=[CH:49][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@](Cc1ccc([N+](=O)[O-])cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (1 g, 1.970 mmol) was dissolved in DMF (20 ml) and sodium hydride (53 mg, 1.773 mmol) was added. After stirring for 60 min, a solution of 4-nitrobenzyl bromide (426 mg, 1.970 mmol) in 10 ml DMF was added and the mixture was stirred at 60° C. for 90 min. The mixture was then concentrated in vacuo, the residue was taken up in water (50 ml) and ethyl acetate (100 ml), and the organic phase was washed with brine (3×50 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed over silica gel (hexane, ethyl acetate) to yield 1.04 g (82%) of a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>C(#N)C.CCOCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1.[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CN(C)CCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Yield: 190.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.31 mmol), cesium carbonate (6.72 g, 20.61 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (2.227 g, 15.46 mmol) were suspended in acetonitrile (30 mL) and the mixture was heated at reflux for 5 h, then cooled to room temperature, diluted with Et2O and filtered. The filtrate was concentrated in vacuo to give N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine dimethyl{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}amine (2.61 g, 9.84 mmol, 95% yield) as an amber oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[NH:6]2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([F:14])([F:15])[F:16])[N:6]2[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])[O:21][N:20]=1
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1Cl
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: Cc1noc(C)c1-c1nc(Cn2c(C(F)(F)F)cc3c(Cl)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 5.93 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H); MS (ES) m/z 422 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH2:38][O:39][CH:40]([CH3:42])[CH3:41])[O:11][C:12]1[N:17]=[C:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=2[F:27])[N:15]=[C:14]([NH:28][S:29]([C:32]2[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=2)(=[O:31])=[O:30])[CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:27][C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:18][C:16]1[N:15]=[C:14]([NH:28][S:29]([C:32]2[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=2)(=[O:31])=[O:30])[CH:13]=[C:12]([O:11][C@H:10]([CH2:38][O:39][CH:40]([CH3:41])[CH3:42])[CH2:9][OH:8])[N:17]=1
Reactant: CC(C)OC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)OC[C@H](CO)Oc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 34 using N-{6-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(isopropoxymethyl)ethoxy]-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}-1-methyl-1H-imidazol-4-sulfonamide (the product from step (v) (90 mg) in THF (5 mL) and 1M solution of tetrabutylammoniumfluoride in THF (0.28 mL) to give the title compound as a white solid. Yield: 30 mg.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[C:14](=O)(OCC)[O:15]CC.Cl>C1(C)C=CC=CC=1>[OH:13][C:11]1[C:5]2[C:4](=[CH:9][C:8]([CH3:10])=[CH:7][CH:6]=2)[O:3][C:14](=[O:15])[CH:12]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(C)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(O)cc(=O)oc2c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a mechanically stirred suspension of sodium hydride (60% in oil, 30 g, 749 mmol) in toluene (400 mL), heated at 80° C., a solution of the commercially available 2′-hydroxy-4′-methylacetophenone (50 g, 0.333 mmol) in 150 mL of toluene was added dropwise over 1 h. After complete addition, the mixture was stirred 15 min and a solution of diethyl carbonate (81 mL, 666 mmol) in toluene (500 mL) was added dropwise over 1 h. The reaction mixture was then stirred overnight at reflux. After cooling, the reaction mixture was poured into 800 mL of 2N HCl. The precipitate formed was collected by filtration, co-evaporated twice with toluene and dried under high vacuum at 55° C. 1H NMR (400 MHz, acetone-d6): 11.1 (bs, 1H), 7.76 (d, 1H), 7.18 (d, 1H), 7.14 (s, 1H), 5.60 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][CH:22]([CH2:24][CH2:25][CH:26](Br)[CH3:27])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:26]([CH3:27])[CH2:25][CH2:24][CH:22]([Br:21])[CH3:23])[CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(Br)CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(Br)CCC(C)Oc1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(t-butyloxycarbonylamino)ethyl]-5-hydroxy-1H-indole (1.34 g, 4.86 mmol) in acetonitrile (50 mL) were added 2,5-dibromohexane (2.4 g, 9.72 mmol) and potassium carbonate (1.3 g, 9.72 mmol) and the resulting mixture was stirred at reflux for 60 hours. After cooling to room temperature, the solution was poured into ethyl acetate (40 mL), washed with water (40 mL), dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel using hexane/ethyl acetate (4:1, 2:1 and 1:1) provided the title compound as a syrup (0.65 g, 30%).