Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B.CO>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: B
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc(CO)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-nitrobenzoic acid (3.2 g, 13.0 mmol) was suspended in tetrahydrofuran (25 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 26 mL, 26 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 3.0 g (99%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 8.24 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 4.78 (s, 2H). Mass spec.: 233.88 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[CH2:5][CH2:6][S:7]([CH3:10])(=[O:9])=[O:8].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:10][S:7]([CH2:6][CH2:5][C@H:4]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[CH2:3][O:2][CH3:1])(=[O:8])=[O:9]
Reactant: COC[C@H](CCS(C)(=O)=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COC[C@H](CCS(C)(=O)=O)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.6 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methanesulfonyl-propyl)-amide (35 mg, 0.058 mmol) and TFA (0.5 ml, 6.5 mmol) were combined with dichloromethane (1.5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.19 ml, 2.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 12 mg (44%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-3-methanesulfonyl-1-methoxymethyl-propyl)-amide as a light yellow solid. MS: [M+Na]+=497; 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (br. s., 1H), 9.12 (s, 1H), 8.54 (dd, J=8.7, 5.3 Hz, 1H), 8.47 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.19 (td, J=9.1, 2.3 Hz, 1H), 4.35-4.55 (m, 1H), 4.15 (s, 3H), 3.60 (dd, J=9.8, 4.2 Hz, 1H), 3.51 (dd, J=9.4, 4.2 Hz, 1H), 3.26 (s, 3H), 3.20-3.28 (m, 2H), 2.97 (s, 3H), 2.02-2.23 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH2:10][CH2:9][CH2:8][N:7]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[O:24][C:23]([CH3:25])=[N:22][CH:21]=5)=[C:16]([O:26][CH3:27])[CH:15]=4)=[N:12][N:13]=[C:6]23)[CH2:3][CH2:2]1.[OH2:36].[OH2:37].O.O.O.O.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][C:5]2([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH3:35])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[CH2:10][CH2:9][CH2:8][N:7]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[O:24][C:23]([CH3:25])=[N:22][CH:21]=5)=[C:16]([O:26][CH3:27])[CH:15]=4)=[N:12][N:13]=[C:6]23)[CH2:3][CH2:2]1
Reactant: O
Reactant: COc1cc(-c2nnc3n2CCCC3(CC2CC2)c2ccc(SC)cc2)ccc1-c1cnc(C)o1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc3n2CCCC3(CC2CC2)c2ccc(S(C)(=O)=O)cc2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a mixture of 8-(cyclopropylmethyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-[4-(methylsulfanyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (86.0 mg) in DMF (1 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (87.4 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. Monoperoxyphthalic acid magnesium salt hexahydrate (87.4 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with aqueous sodium thiosulfate solution (1M) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (27.8 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:22]([OH:29])([CH2:27][CH3:28])[C:23](OC)=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(OCC)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:22]([OH:29])([CH2:27][CH3:28])[CH2:23][OH:24])[CH:18]=[C:19]([F:21])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCC(O)(C(=O)OC)c1cc(F)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)(CO)c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (0.345 g) was added to a solution of the ester so obtained in diethyl ether (70 ml) and the mixture was stirred at ambient temperature for 1 hour. Water (10 ml) was added dropwise and the mixture was filtered. The organic layer was dried (MgSO4) and evaporated to give (-)-2-(3-benzyloxy-5-fluorophenyl)butane-1,2-diol (2.2 g), as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=O)[CH:10](C([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl[C:32](=[CH2:37])[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClC(Cl)C.C(OCC)(=O)C>[CH2:9]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12][N:11]2[CH:14]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:10]12
Reactant: CC(C)(C)OC(=O)N1CCN(C=O)C(C(=O)[O-])C1
Reactant: C=C(Cl)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccn2c1CN(C(=O)OC(C)(C)C)CC2

Procedure:
To a suspension of 29 g of the compound obtained in Step B (103 mmoles) in 800 mL of dichloroethane there are added in succession 24 g of tosyl chloride (124 mmol), 12.6 mL of methyl 2-chloroacrylate (124 mmol) and then 35 mL of triethylamine (247 mmoles). The whole is stirred at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate, and the organic phase is washed with a saturated NaCl solution until neutral. After drying over MgSO4, filtration and concentration to dryness, the title product is isolated by chromatography over silica gel (petroleum ether/AcOEt gradient: 0-20%) in the form of a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To 22.7 g of 4-(3-fluoro-5-nitrophenoxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6), 250 mL of anhydrous DMF, and 36.3 g of MeI at 0° C. was added 3.9 g of 60% NaH, in several portions. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated to remove excess MeI then diluted with H2O. The mixture was diluted with 500 mL of saturated NH4Cl and extracted 3 times with 500 mL of EtOAc. The combined organic layers were dried and concentrated to yield 23 g of 4-(3-fluoro-5-nitro-phenoxy)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7).
Reaction SMILES: Cl.[C:2](=[NH:10])([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:9][C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:10]1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1cccnc1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Yield: 50 %

Procedure:
Nicotinimidamide hydrochloride (4.97 g, 31.5 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (5.89 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccsc1C
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)sc1C
Yield: 77.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using 2,3-dimethylthiophene (5.00 g, 44.6 mmol), 2.5M BuLi/hexanes (17.9 mL, 44.6 mmol) and benzyl bromide (5.30 mL, 44.6 mmol) in THF (44.6 mL). Purification on Biotage KP-Sil eluting with 1% EtOAc/pet ether gave 6.96 g (77%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 2.01 (s, 3 H), 2.21 (s, 3 H), 3.98 (s, 2 H), 6.58 (s, 1 H), 7.18-7.37 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH3:11])[C:4]=1[CH3:12].ClC1C=C(C=CC=1)C(OO)=[O:18].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-:18])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: COc1cnc(C)c(C)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c[n+]([O-])c(C)c(C)c1OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
6.3 g of 4,5-dimethoxy-2,3-dimethylpyridine are dissolved in 120 ml of methylene chloride, 20 g of m-chloroperoxybenzoic acid are added successively and the mixture is stirred first at 20° C. for 2 hours and then at 40° C. for 4 hours. After addition of 20 ml of 5N sodium hydroxide solution, the mixture is washed three times with a mixture of 5% strength sodium thiosulfate solution and 5% strength sodium carbonate solution, the aqueous phase is back-extracted twice with methylene chloride and the combined organic phases are dried over magnesium sulfate and concentrated. 4.6 g (66% of theory) of 4,5-dimethoxy-2,3-dimethylpyridine 1-oxide are obtained. The Rf value in methylene chloride/methanol 19:1 is 0.25.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: O[C@@H](CCCl)c1ccccc1
Reaction time: 7 h

Procedure:
A solution of 3-chloropropiophenone (8.93 50 mmol in 25 ml THF) was added to (-) diisopinocampheylchloroborane (Ipc2BCl, 18.0 g, 56 mmole, in 25 ml THF at -24° C.). The reaction was complete within 7 hours after which all volatiles were removed under reduced pressure. The residue was dissolved in ether, and diethanolamine (2 equivalents) was added. The resulting suspension was stirred for two hours and filtered. The solid residue was washed with ether and the combined washings and filtrate were concentrated. Distillation furnished [S]-(-)-1-chloro-3-phenyl-3-propanol. Yield: 6.1 g, 72%; mp 56°-57° C.; [α]D23 -25.25, c=7.05, CHCl3 ; 97% ee.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=O.[CH3:13][N:14]1C2C(=CC=CC=2)C(C)=C1C=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:14][CH3:13]
Reactant: O=Cc1c[nH]c2c(F)cccc12
Reactant: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2c(F)cccc12
Yield: 90 %

Procedure:
According to the procedure of Preparation 13 (c),except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.5 g, 90%) was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([CH3:30])[CH2:7][C:6]=2[CH:27]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccn4)CC3)n1-2
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the compound from example 1 (100 mg, 0.26 mmol) in dichloromethane (3 mL) was added formaldehyde (37% aqueous solution, 142 μL, 1.75 mmol) followed by sodium triacetoxyborohydride (55 mg, 0.26 mmol). The solution was stirred for 5 hours at room temperature, then sodium triacetoxyborohydride (20 mg, 0.09 mmol) was added. After 10 minutes, saturated sodium hydrogen carbonate solution was added and the mixture was stirred vigorously for 5 minutes. The phases were separated and the organic phase evaporated in vacuo to give the crude residue which was azeotroped twice with ethyl acetate and then diethyl ether to furnish the desired product, 63 mg (61%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[NH3:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Reactant: N
Solvent: CCO
Product: NC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1

Procedure:
0.8 g (2.5 mmole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 50 ml of aqueous ammonia and 10 ml of absolute ethanol was stirred at room temperature for 24 hours. The white precipitate obtained was collected by filtration. Recrystallization from isopropyl alcohol gave 0.45 g (56%), m.p. 213°-214° C. The formula C14H13BrN2O2 was verified through elemental analysis, C calculated 52.4, found 51.9. ##STR29##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.I[CH2:26][CH:27]([CH3:29])[CH3:28].[C:30]([C:32]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:36]2[N:46]=[C:47]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:48]=[C:35]2[N:34]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=2)[C:33]=1[CH3:70])#[N:31].C(O)(=O)C>CN(C=O)C>[C:30]([C:32]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:36]2[N:46]=[C:47]([N:49]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:50](=[O:59])[O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:48]=[C:35]2[N:34]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([C:66]([F:69])([F:68])[F:67])[CH:61]=2)[C:33]=1[CH3:70])#[N:31]
Reactant: CC(C)CI
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15.7 mg, 113 μmol, 2.1 eq.), 18-crown-6 (30 mg, 113 μmol, 2.1 eq.) and 1-iodo-2-methylpropane (21 mg, 113 μmol, 2.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol) in DMF (2 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure. The residue was acidified with acetic acid (3 eq.) and then purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 76% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:29])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[C:8]2[NH:7][C:6]=1[CH3:30])=[O:4].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:29])[N:20]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[C:8]2[N:7]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:6]=1[CH3:30])=[O:4]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)C1=C(C)Nc2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
Intermediate 6 (100 mg, 0.24 mmol), 3-trifluoromethylphenylboronic acid (95 mg, 0.5 mmol), Et3N (250 μl, 1.8 mmol), and copper (II) acetate (50 mg, 0.4 mmol) were dissolved in DCM (10 mL), and stirring at RT was continued for 48 hours. The reaction mixture was filtered to remove the solid and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-15% MeOH in DCM. Appropriate fractions were combined and concentrated in vacuo and the resulting residue further purified using preparative HPLC system 2 to yield the title compound as a white solid (20 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccncc2)nc2c1c(C)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)C)c2nc(-c3ccncc3)cc(C(=O)O)c12

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (36 mg, 0.111 mmol), Ethanol (2 ml) and sodium hydroxide (0.185 mL, 0.555 mmol). The final product was collected as 26 mg 79%). LCMS E-S (M+H)=297.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.4 Hz, 6 H), 2.65 (s, 3 H), 5.35 (m, 1 H), 8.17 (s, 1 H) 8.24 (m, 2 H), 8.78 (m, 2 H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12](Cl)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1Cl)[CH:2]([CH3:4])[CH3:3].[CH2:17]([OH:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(N([CH2:41][CH3:42])CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12]([O:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:11][CH2:10]2)[CH2:8][O:7][P:6]1[O:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:41][CH3:42])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CCN(CC)CC
Reactant: CC(C)CN1P(Cl)OCC12COP(Cl)OC2
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOP1OCC2(CO1)COP(OCCCCCCCCCCCCCCCCCC)N2CC(C)C
Yield: 94.5 %

Procedure:
The procedure of Example 10 is repeated using 10.89 g (36 mmol) of 1-isobutyl-2,8-dichloro-3,7,9-trioxa-1-aza-2,8-diphosphaspiro[4.5]decane (compound of Example 8) in 200 mL of toluene and 19.25 g (77 mmol) of n-octadecanol and 7.92 g (10.9 mL, 78 mmol) of triethylamine in 100 mL of toluene to give 26.34 g of white solid. The residue is purified by flash chromatography (basic alumina, 3% ethyl acetate/97% hexane) to give 9.23 g (34% yield) of a white solid melting at 33°-39° C. The product is identified by mass spectroscopy: m/z=773.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:26]CCCCC.[C:32]([C:34]1[CH:35]=[C:36](/[CH:40]=[CH:41]\[C:42]([O:44]CC)=O)[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:44])/[CH:41]=[C:40](\[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)/[CH3:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reactant: CCCCCC
Reactant: CCOC(=O)/C=C\c1cccc(C#N)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: C/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (198 mg, 0.65 mmol) in 5 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.98 ml, 1.95 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (Z) 3-(3-cyanophenyl)-2-propenoate (140 mg, 0.65 mmol) in 1 ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5 ml 1N HCl after which an additional 20 ml dichloromethane was added. Organic was washed with 2×25 ml water, dried over magnesium sulfate and concentrated to give (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (200 mg, 65%) as a light brown residue which was sufficiently pure to be used without further purification.