Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].C(N(CC)CC)C>C(#N)C>[CH3:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:22]=[C:23]([NH2:25])[S:24][C:3]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(=O)C(Br)c2ccncc2)cc1
Reactant: NC(N)=S
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Yield: 70 %

Procedure:
To a solution of 2-bromo-1-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 12 mmol) and thiourea (0.95 g, 13 mmol) in acetonitrile (60 mL) was added dropwise triethylamine (1.8 ml, 13 mmol) and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The precipitated solid was collected by filtration. The obtained crude crystal was recrystallized from ethanol to give the title compound (2.6 g, 8.4 mmol, yield 69%).
Reaction SMILES: [NH2:1][C:2]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:26]>CN(C)C=O>[NH2:1][C:2]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[C:3]([C:4]#[N:5])[C:6](=[S:26])[NH2:7]
Reactant: CCN(CC)C(N)=C(C#N)C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)C(N)=C(C#N)C(N)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 72.6 g of 3-amino-2-cyano-3-(diethylamino)propenenitrile, 44.7 g of triethylamine, 200 ml of pyridine, and 50 ml of dimethylformamide was saturated at 60° with hydrogen sulfide. The temperature was increased to 75° while hydrogen sulfide was passed through the solution. After heating at 75° for 2 hours, thin-layer chromatographic analysis indicated the reaction was incomplete. After about 60 hours at room temperature the mixture was heated at 75° for an additional 4 hours. The mixture was allowed to cool to ambient temperature, then was poured into 1750 ml of ice-water mixture. The cold slurry was stirred for 1 hour and the solid was isolated by filtration. The solid was washed with ice-water and recrystallized from 250 ml of ethanol to give 56 g of 3-amino-2-cyano-3-(diethylamino)propenethioamide, m.p. 151°-152°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [K].[CH3:2][C:3]([OH:6])([CH3:5])[CH3:4].[I:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:18]CC(=O)C[CH2:14]2)[CH:12]=1.[Cl-].C[S+](C)(C)=O.CCOC(C)=O>CS(C)=O>[I:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:5][C:3]3([O:6][CH2:4]3)[CH2:2][CH2:14]2)[CH:12]=1
Reactant: CC(C)(C)O
Reactant: O=C1CCC(n2cc(I)cn2)CC1
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Ic1cnn(C2CCC3(CC2)CO3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methyl-propan-2-ol potassium (466 mg; 4.15 mmol; 1.2 eq.) was added in one portion to a solution of 4-(4-Iodo-pyrazol-1-yl)-cyclohexanone (1.02 g; 3.50 mmol; 1.0 eq.) and trimethylsulfoxonium chloride (531 mg; 4.13 mmol; 1.2 eq.) in DMSO (50 mL). The reaction mixture was stirred at RT for 16 h. It was then poured into EtOAc. Organic phase was separated and washed with brine (three times), dried over magnesium sulfate, filtered and concentrated to give the title compound a white solid (813 mg, 76%). 1H NMR (300 MHz, DMSO) δ 8.01 (d, J=0.5 Hz, 1H), 7.52 (d, J=0.5 Hz, 1H), 4.41-4.26 (m, 1H), 2.66 (s, 2H), 2.13-1.85 (m, 6H), 1.34-1.21 (m, 2H). MS (ESI+): 305.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[Cl:20])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.2 %

Procedure:
A stirred solution of 38.0 grams (0.136 mole) of diethyl (4-chlorophenyl)hydroxymethylphosphonate in 250 ml of methylene chloride was cooled to 0° C., and a solution of 18.8 grams (0.158 mole) of thionyl chloride in 12 ml of methylene chloride was added via syringe. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 60 hours. After this time the reaction mixture was washed with two portions of aqueous 1N hydrochloric acid. The organic layer was filtered through silica gel. The silica gel was eluted with 1:1-hexane/ethyl acetate. The combined filtrates were concentrated under reduced pressure, yielding 40.5 grams of diethyl (4-chlorophenyl)chloromethylphosphonate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 1 h

Procedure:
To a suspension of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16 mmol) in EtOAc (100 mL) and MeOH (100 mL) was added 10% Pd/C (400 mg) and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1 h, the catalyst was filtered off and the filtrate was concentrated to yield the title compound as a pale brown solid. MS: m/z=218 (M+1).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[C:7](SC1C=CC=CC=1)=[CH:8][C:9](=[O:54])[N:10]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2C2N=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=[CH:20][CH:19]=1)[CH3:4].[CH3:62][OH:63]>>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:54])[N:10]2[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29]([C:62]([OH:63])=[O:1])=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)[CH3:4]
Reactant: CO
Reactant: CCc1cc2c(c(Sc3ccccc3)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reactant: [OH-]
Agent: [Na+]
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(-c3ccccc3C(=O)O)cc2)c(CC)n1
Temperature: 25 °C

Procedure:
2M Sodium hydroxide solution (3 ml) was added to a solution of methyl 4'-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]biphenyl-2-carboxylate (A) (300 mg) in methanol (5 ml) and the mixture was heated at reflux for 2 hours. The mixture was cooled to ambient temperature and volatile material was removed by evaporation. The residue was dissolved in water and the solution adjusted to pH 5 with acetic acid. The precipitated solid was collected by filtration to give 4'-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]biphenyl-2-carboxylic acid (100 mg) as a solid; m.p. 238°-240° C.; NMR (d6 -DMSO): 1.18(t, 3H), 1.26(t, 3H), 2.72(q, 2H), 3.60(q, 2H), 5.2(s, 2H), 6.70(d, 1H), 7.15(s, 1H), 7.23-7.71(m, 5H), 8.21(d, 1H), 12.65(broad s, 1H); mass spectrum (+ve FAB, methanol/NBA): 435 (M+Na)+, 413(M+H)+ ; microanalysis, found: C, 74.1; H, 5.6; N, 6.5%; C26H26N2O3.0.5.H2O requires; C, 74.0; H, 5.9; N, 6.6%.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[K+].CN(C)C=O.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1>CCO>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
In 20 ml of EtOH, 9.4 g (6.4×10-2 mole) of phthalimide and 4.2 g of KOH were stirred for 30 minutes, followed by addition of 100 ml of DMF (dimethylformamide) and 5.2 g (2.5×10-2 mole) of 6-chloro-3-pyridylmethyl chloride. The mixture was stirred at 60° C. for 1 hour. The EtOH and DMF were distilled off under reduced pressure and the residue was chromatographed on a silica gel column and eluted with CH2Cl2. The above procedure gave 6.7 g of the title compound as colorless needles.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15](=[O:22])[N:16]([O:18][CH2:19][CH:20]=[CH2:21])[CH3:17])[CH:7]=1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl.N>C(OCC)(=O)C>[CH2:1]([O:4][C:5](=[O:23])[C:6]1[CH:7]=[C:8]([C:15](=[O:22])[N:16]([O:18][CH2:19][CH:20]=[CH2:21])[CH3:17])[CH:9]=[C:10]([NH2:12])[CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)N(C)OCC=C)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)c1cc(N)cc(C(=O)N(C)OCC=C)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of (8(b)) (0.523 g), tin(II) chloride dihydrate (1.84 g) and ethyl acetate (50 ml) was heated under reflux for 6 hours. The mixture was allowed to cool to ambient temperature and ammonia solution (sp. g. 0.880) was added dropwise until the solution reached pH 8. The white precipitate which had formed was filtered off. washed with ethyl acetate (2×50 ml) and the combined washings and filtrate evaporated to dryness to give the desired starting material (8(c)) as a yellow oil (0.472 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([OH:27])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CCC(C)(C)c1ccc(Cl)c(OC)c1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)CC(C)(C)c1ccc(Cl)c(OC)c1
Temperature: -70 °C
Yield: 84.1 %

Procedure:
24.1 g (84.63 mmol) of ethyl-4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate is dissolved in 296 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within 1¾ hours, 236.9 ml of a 0;5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture then is stirred for 75 more minutes at −70° C. 30.9 g (118.48 mmol) of Davis reagent, dissolved in 296 ml of tetrahydrofuran, is now added in drops within 60 minutes. After two hours of stirring at −70° C., 152 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed, and it is vigorously stirred for 30 minutes. After extraction with diethyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 21.4 g (84.2%) of the desired compound is isolated (easily contaminated).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=[O:6].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.O>CC(C)=O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([NH2:21])=[S:23]
Reactant: COc1ccc(C(N)=O)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(N)=O)cc1NC(N)=S
Temperature: 25 °C

Procedure:
To a solution of 3-amino-4-methoxybenzamide (2.49 g, 15.0 mmol, Alfa) in acetone (30 mL) at reflux was added benzoyl isothiocyanate (2.22 mL, 16.5 mmol) and the mixture was stirred at reflux for 30 min, then was poured into water. The precipitate was collected by vacuum filtration and was treated with 10% aq. NaOH (15 mL). The mixture was heated to reflux for 40 min, cooled to room temperature, and poured into a mixture of ice and 6 N aq. HCl. The mixture was basified to pH 10 with conc. aq. NH4OH and the resulting white solid precipitate was collected by vacuum filtration, affording the crude title compound, which was used without further purification.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19]N.S(=O)(=O)(O)O>C(O)C>[NH2:5][C:4]1[N:19]([C:9]2[C:10]([Cl:18])=[CH:11][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]=2[Cl:7])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: C/C(N)=C/C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminocrotononitrile (5.0 g) was added to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (15.0 g) in ethanol (100 ml), then the resulting solution treated with concentrated sulphuric acid (1.0 ml) to produce a white solid precipitate. The mixture was heated under reflux for 6 hours, allowed to cool and stirred for a further 18 hours at room temperature; this cycle was repeated, then more concentrated sulphuric acid (4 ml) added. The reaction mixture was heated at 60° C. for 8 hours, allowed to cool, stirred at room temperature for 18 hours and evaporated under reduced pressure. The resulting orange oil was partitioned between dichloromethane (100 ml) and water (100 ml), then the organic phase dried, allowed to stand at room temperature for 18 hours and filtered to remove some white solid material. The filtrate was evaporated under reduced pressure to give an orange oil which was triturated with hot hexane. On cooling, the hexane solution deposited a yellow oil which slowly crystallised to furnish the title compound as a white solid, m.p. 80-830C. Found: C, 42.73; H, 2.62; N, 13.58. C11H8Cl2F3N3 requires C, 42.61; H, 2.60; N, 13.55%. δ(CDCl3): 2.25 (s,3H), 3.48 (br.s,2H), 5.52 (s,1H), 7.70 (s,2H). MS (thermospray): M/Z [M]310.0; C11H8Cl2F3N3 requires 310.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].Cl[C:13]1[C:18]([C:19](OCC)=[O:20])=[CH:17][N:16]=[C:15]([S:24][CH3:25])[N:14]=1.C(N(CC)CC)C>C(#N)C>[CH3:25][S:24][C:15]1[N:16]=[C:17]2[N:6]=[C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][C:19](=[O:20])[C:18]2=[CH:13][N:14]=1
Reactant: COc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 18 h

Procedure:
2-Methoxybenzamidine (from sodium, 0.15 g, in ethanol, 20 ml, and 2-methoxybenzamidine methanesulphonate, 1.70 g) was dissolved in acetonitrile (20 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) suspension of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (2.33 g) in acetonitrile (20 ml). Triethylamine (0.66 g) was added and the reaction mixture was stirred at 2° C. for one hour and at ambient temperature for 18 hours. Acetonitrile was removed under reduced pressure and water (25 ml) was added. The mixture was cooled and a white solid was collected, washed with water and recrystallised from ethanol to yield the title compound, 0.46 g, m.p. 229°-231° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([OH:20])[C:10]([C:21]([OH:23])=[O:22])=[N:9]1.C(N(CC)C(C)C)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:20][C:11]1[C:10]([C:21]([OH:23])=[O:22])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:35])[CH3:34]
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid I-6c (572.0 g, 1.64 mol) was combined with 8 liters of methylene chloride to give an off-white suspension. N,N-Diisopropylethylamine (427.9 g, 3.29 mol) was added over 15 minutes while keeping the temperature between 20–25° C. A clear yellow solution resulted. Acetic anhydride (334.5 g, 3.24 mol) was added over 5 minutes keeping the temperature between 20–25° C. The reaction was stirred at room temperature for 16 hours. The crude reaction solution was washed twice with 4 liters portions of 0.5 M citric acid and once with 4 liters of brine. The crude solution was concentrated in vacuo to a total volume of 1 liter. This milky suspension was then added to 4 liters of hexanes causing the desired product to precipitate instantly. The solids were granulated for 30 minutes and then collected by filtration. The filtercake was rinsed with 3 liters of hexanes and then air-dried for 16 hours. The isolated product was then further dried at 60° C. and 8 mm for 2 hours. 4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (601.6 g, 94%) was isolated as a powdery, off-white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][N:41]3[CH2:40][CH2:39][N:38]([C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[F:27])[CH2:43][CH2:42]3)[C:16]=2[N:15]=1
Reactant: O=C(Cc1ccc(F)cc1F)N1CCNCC1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(C(=O)Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, (2,4-difluorophenyl)piperazin-1-yl-ethanone hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 1-(4-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)-2-(2,4-difluorophenyl)ethanone: LC/MS (M+1=507.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.45 (m, 4H), 2.72 (t, 2H, J=6.4 Hz), 3.43 (m, 2H), 3.48 (m, 2H), 3.69 (s, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=32 Hz), 6.71 (m, 1H), 7.01 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.17 (m, 3H), 7.28 (m, 1H), 7.49 (br s, 2H, NH2), 7.91 (s, 1H). Anal. calculated for (C25H24F2N8O2+⅓H2O): C, 58.59; H, 4.85; F, 7.41; N, 21.86; 0, 7.28. Found C, 58.73; H, 5.06; N, 21.22.
Reaction SMILES: [P:1]([O-:47])([O-:46])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[O:34][CH3:35])=[CH:7][C:6]1=[O:37])=[O:2]>CC#N.O.CC(O)=O>[P:1]([OH:46])([OH:47])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:24])([F:25])[C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[O:34][CH3:35])=[CH:7][C:6]1=[O:37])=[O:2]
Reactant: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c(=O)c1
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 43.9 %

Procedure:
A solution of ditert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (21) (35 mg, 0.05039 mmol) in CH3CN (700.0 μL), water (700.0 μL) and AcOH (700.0 μL) was refluxed for 1 hour then evaporated to dryness. The material was then co-evaporated with CH3CN (3×), triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (2) (13 mg, 0.02210 mmol, 43.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.9, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.91-6.84 (m, 1H), 6.77 (s, 1H), 6.47 (dd, J=7.6, 2.2 Hz, 1H), 5.54 (d, J=9.7 Hz, 2H), 3.74 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −1.93 (t, J=9.7 Hz, 1H) ppm.
Reaction SMILES: [CH:1]1([CH:5]([OH:17])[C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.O.[OH-].[Li+]>CO>[CH:1]1([CH:5]([OH:17])[C:6]2[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
To a flask containing ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (530 mg, 2.26 mmol) was added tetrahydrofuran (5.60 mL), water (5.60 mL), and methanol (5.60 mL). Lithium hydroxide monohydrate (475 mg, 11.3 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 490 mg of crude material. Purification by silica gel flash chromatography (0-20% ethyl acetate in heptane) afforded 4-(cyclobutyl(hydroxy)methyl)benzoic acid (360 mg, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.2 Hz, 2H), 7.43 (dd, J=8.0, 1.0 Hz, 2H), 4.67 (d, J=7.6 Hz, 1H), 2.62 (d, J=8.0 Hz, 1H), 2.09-1.98 (m, 2H), 1.91-1.80 (m, 4H). MS (M−1): 205.2.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30]>>[CH3:24][NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:30]
Reactant: CNC(=O)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CNC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N-methylsuccinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-(methylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=427; RT=1.06 min; UPLC Method I