Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][C:23](=O)[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC1(F)CC[NH:30][CH2:29]1>O1CCCC1.CO.CC(N(C)C)=O>[CH3:29][NH:30][C@@H:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)[CH2:22]1
Reactant: O=C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Reactant: FC1(F)CCNC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
A suspension of 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-one (50 mg, 0.15 mmol) and 3,3-difluoropyrrolidine (42 mg, 0.29 mmol) in tetrahydrofuran/methanol/dimethylacetamide (1.0 mL each) was heated to 80° C. for 2 hours then NaBCNH3 (18 mg, 0.29 mmol) was added. After 2 hours the solution was cooled to room temperature and concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluting with chloroform/acetone (5-50%) followed by a second column on a 12M cartridge eluting with chloroform/ethyl acetate (25-100%) to afford the title compound (25 mg, 40%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:21](=[O:22])[N:20]([C:23]3[CH:36]=[CH:35][C:26]([O:27][C:28]([CH3:34])([CH3:33])[C:29](OC)=[O:30])=[CH:25][CH:24]=3)[C:19]([CH3:37])=[N:18][C:17]=2[CH2:38][CH2:39][CH3:40])=[C:11]([F:41])[CH:10]=1)#[N:2].[BH4-].[Li+].C(OCC)(=O)C.O>O1CCCC1>[F:41][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:21](=[O:22])[N:20]([C:23]2[CH:36]=[CH:35][C:26]([O:27][C:28]([CH3:33])([CH3:34])[CH2:29][OH:30])=[CH:25][CH:24]=2)[C:19]([CH3:37])=[N:18][C:17]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 24 h
Yield: 43.2 %

Procedure:
To a solution of methyl 2-{4-[5-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate (1.00 g) in tetrahydrofuran (11 mL) was added lithium tetrahydroborate (0.056 g), and the mixture was stirred for 24 hr. Ethyl acetate and water were added, to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.41 g, 73%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[Br:13][C:14]1[CH:21]=[CH:20]C(CO)=[CH:16][CH:15]=1.N1CC=CC1>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:2]([CH2:1][N:3]2[CH2:6][CH:7]=[CH:5][CH2:4]2)=[CH:16][CH:15]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: C1=CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1ccc(CN2CC=CC2)cc1
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
Triethylamine (0.135 ml, 0.958 mmol) and 60 μl (0.760 mmol) of methanesulphonyl chloride were added to a solution of 70.5 mg (0.377 mmol) of 4-bromobenzylalcohol in dichloromethane (2 ml) under ice cooling, and the mixture was stirred for 1.5 hr. The reaction solution was diluted with 10 ml of ethyl acetate, and the diluted solution was washed with an 8% aqueous sodium hydrogencarbonate solution. The aqueous layer was extracted twice with 3 ml of ethyl acetate. The organic layers were combined, were washed with 25% brine, and were dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under the reduced pressure. The residue was dissolved in 1.8 ml of N,N-dimethylformamide, 87 μl of 2,5-dihydro-1H-pyrrole (70% purity, 0.793 mmol) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was diluted with 10 ml of ethyl acetate, and the diluted solution was washed thrice with 5 ml of water. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined, were washed with 25% brine, and were dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform:methanol=18:1) to give 63.8 mg (yield 71%) of the title compound.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>C(Cl)Cl.CN(C=O)C>[OH:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: OCCNCCO
Reactant: C#CCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCCC(=O)N(CCO)CCO
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A mixture of 4-pentynoic acid (2.00 g; 20.4 mmol) and 4-methylmorpholine (2.24 ml; 20.4 mmol) in DCM (20 ml) is cooled to −5° C. Isobutyl chloroformate (2.68 ml; 20.4 mmol) is added, followed by DMF (10 ml). The resulting mixture is added in portions to a solution of diethanolamine (2.25 g; 21.4 mmol) in DCM (10 ml). The resulting mixture is stirred overnight and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM/methanol 100:0→82:18 to yield N,N-bis(2-hydroxyethyl)pent-4-ynamide.
Reaction SMILES: CC1SC(C2C=C(C)C=CC=2)=C(C(N2C(CN[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[O:26][C:25]([I:27])=[CH:24][C:23]=34)=[O:17])CSC2)=O)N=1.FC(F)(S(F)(=O)=O)C(OC)=[O:38].CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.CCCCCCC>CN(C=O)C.[Cu]I>[I:27][C:25]1[O:26][C:22]2[C:23](=[C:18]([C:16]([OH:17])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH:24]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2CSCC2CNC(=O)c2cccc3oc(I)cc23)c1
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: O=C(O)c1cccc2oc(I)cc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
A mixture of 2-iodo-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide (57 mg), copper (I) iodide (91 mg, 5 eq), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.08 mL, 6.5 eq), HMPA (0.17 mL, 10 eq) in dry DMF (2.5 mL) was stirred at 80° C. for 16 hours under nitrogen. After cooling to rt, the reaction mixture was partitioned between water and EtOAc, the organic phase was washed again with water, dried (MgSO4), filtered and concentrated in vacuo to yield a crude yellow-orange oil. FC (AlO3, EtOAc/n-heptane: 7/3) gave the title compound (4.2 mg, 8%) as a white solid. LC-MS: tR=1.08 min; [m+H]+=546.22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cn1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole following a procedure analogous to that described in Example 28. LC (method 7): tR=1.11 min; Mass spectrum (ESI+): m/z=385 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.O[C:16]1[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.ClC1C=C(O)C=NC=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][O:1][C:16]2[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CCOC(=O)c1ncccc1O
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OCC1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate and ethyl 3-hydroxypicolinate instead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(O)(=O)C.[Fe]>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:11]2[CH2:12][CH2:13][CH2:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[N:10]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCCC(c3ccc(Cl)c(Cl)c3)=N2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)N2CCCC(c3ccc(Cl)c(Cl)c3)=N2)cc1

Procedure:
(3,4-Dichlorophenyl)-1-(4-nitrobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine (4.7 g, 11.3 mmol) was suspended in acetic acid at 80° C. Iron filings (3.17 g) were added to this suspension and the resulting reaction mixture was heated at 60°-80° C. until the TLC did not show any starting nitro compound. The mixture was filtered concentrated and purified by column chromatography and recrystallization to give the title compound as a solid: mp 232°-234° C.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:17]=[N:16][S:15][N:14]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:17]=[N:16][S:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cnsn1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1cnsn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
4M Hydrogen chloride in dioxane (10 ml) was added to a solution of 3-[2-(t-butoxycarbonylamino)ethoxy]-1,2,5-thiadiazole (Method 76; 1.17 g, 4.74 mmol) in dioxane (20 ml) and the mixture was stirred at ambient temperature for 2 days. The resulting solid was collected by filtration, washed with ether and dried to give the title compound (803 mg, 93%) as a white solid NMR 3.20 (m, 2H), 4.58 (t, 2H), 8.36 (m, 4H); m/z 146.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[C@@H:10]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N#N>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:16]=[CH:17][C:12]([CH2:11][C@H:10]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:9]([O:8][CH3:7])=[O:34])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
Potassium carbonate (50 mg, 0.4 mmol) in water (0.2 mL) was added to a solution of (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid methyl ester (50 mg, 0.1 mmol), and phenylboronic acid (Aldrich, Cat P20009) (21 mg, 0.18 mmol) in 1,4-dioxane (3.0 mL). The reaction was degassed by N2 for 5 min Tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) was added, and the reaction was degassed for another 5 min The reaction vial was sealed and stirred for 5 h. at 80° C. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash chromatography on a silica gel column (EtOAC:Hexanes, 1:3 to 1:1) to give the (S)-methyl 3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoate (30 mg, 70%). Analytical LCMS (M+H-Boc)+: m/z=256.1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6](OCC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][CH2:6][OH:7]
Reactant: CCOC(=O)C=Cc1ccccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC=Cc1ccccc1Br
Temperature: 25 °C
Yield: 61 %

Procedure:
Ethyl o-bromocinnamate (66.3 g; 260 mM) was dissolved in 750 ml of anhydrous toluene under nitrogen in a three-neck round bottom flask equipped with addition funnel and condensor. A toluene solution of diisobutylaluminum hydride (520 mM; 1.53M) was transferred via canula to the addition funnel and then added dropwise to the reaction mixture, which had been chilled to -78°. After the addition was completed the reaction was warmed to ambient temperature over a 1.5 hour period and quenched by the dropwise addition of 50 ml of water. Some cooling was required. The resulting emulsion was added to 640 ml of 2N aqueous hydrochloric acid. After partitioning the slightly acidic (pH 5) aqueous layer was extracted twice with ether. The combined organic fractions were dried (MgSO4), filtered (fritted funnel), and evaporated to afford an oil. The oil was chromatographed in two portions on the Waters Prep 500 equipped with two cartridges eluting with a total of two gallons of 35% ethyl acetate in hexane. This produced 33.8 g (61% yield) of o-bromocinnamylalcohol.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[S:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl>C(O)C>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[S:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1sc2ccncc2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCO
Product: O=C(NOCCO)c1sc2ccncc2c1Nc1ccc(I)cc1F
Reaction time: 2 h
Yield: 39.9 %

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (91 mg, 0.18 mmol) was dissolved in ethanol (2 ml) and 1M hydrochloric acid (0.5 ml) added. The mixture was allowed to stir for 2 hours then evaporated to dryness to give a residue. The resultant residue was partitioned between aqueous saturated NaHCO3 solution (3 ml), water (20 ml) and DCM (20 ml). The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The resultant yellow solid was purified by flash chromatography (Si-SPE, DCM:MeOH, gradient 100:0 to 98:2) followed by reversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl, 0.1% TFA in water on a gradient of methanol 95:5 to 40:60) to afford the title compound as a yellow solid (34 mg, 40%). LCMS (method A): RT=6.00 min, M+H+=474. 1H NMR (d4-MeOH, 400 MHz) 8.68 (s, 1H), 8.44 (d, J=5.7 Hz, 1H), 7.98 (dd, J=5.7 Hz, 0.8 Hz, 1H), 7.55 (dd, J=10.5 Hz, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 6.7 (dd, J=8.5 Hz, 8.5 Hz, 1H), 3.98 (t, J=Hz, 2H), 3.74 (t, J=Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15]C=O)[CH:8]=[CH:7][CH:6]=1)[CH3:3].[OH-].[K+]>CO.C(OCC)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(OCCCNC=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CN(C)Cc1cccc(OCCCN)n1
Yield: 77.2 %

Procedure:
N-[3-(6-dimethylaminomethyl-2-pyridyloxy) propyl]formamide (2.7 g, 0.013 mol) is added to a solution of 85% potassium hydroxide pellets (3.0 g) dissolved in methanol (30 ml) and heated at gentle reflux for 21 hours. The reaction is cooled, diluted with diethyl ether (30 ml), the precipitated salts filtered, and the solvent removed under vacuum. The residue is dissolved in water and the product exhaustively extracted into ethanol/chloroform, dried and evaporated to give 2.1 g of pure product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:30])[NH:15][CH:16]1[CH2:20][C:19](=[O:21])[O:18][CH:17]1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])(C)(C)C.CCN(C(C)C)C(C)C.[C:40]([NH:47][C@H:48](C(O)=O)[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(OCC)C>[C:43]([O:42][C:40](=[O:41])[NH:47][CH:48]([CH3:49])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:30])[NH:15][CH:16]1[CH2:20][C:19](=[O:21])[O:18][CH:17]1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:46])([CH3:45])[CH3:44]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
2-(2-Benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (100) was dissolved in 20% TFA in CH2Cl2 (25 mL) and stirred at room temperature for 50 min. The solvent was evaporated and the residual acid azeotroped with CH2Cl (4×). The resulting oil was dissolved in CH2Cl2 (20 mL) and DMF (5 mL), cooled to 0° C. and treated with DIEA (4.7 mL, 27.0 mmol), Boc-alanine (970 mg, 5.1 mmol), HOBT (924 mg, 6.8 mmol) and EDC (1.31 g, 6.8 mmol) and the solution stirred under N2 for 18 hours. The solvent was concentrated in vacuo then dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to give an orange solid that was dissolved in CH2Cl2 and added dropwise to diethyl ether to afford a white precipitate. The title compound as a white solid (1.21 g, 73% yield). 1H-NMR (500 MHz, CDCl3) δ 1.10-1.79 (m, 18H), 1.98-2.19 (m, 0.5H), 2.28-2.88 (m, 3H), 2.89-3.13 (m, 0.5H), 3.78-3.95 (m, 0.5H), 4.21-5.16 (m, 5.5H), 5.38-5.59 (m, 0.3H), 5.66 (d, 0.4H), 5.80 (d, 0.3H), 7.24-7.40 (m, 5H). LC-MS (ES+) m/e=490.3 (MH+).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([CH:20]([C@H:34]1[CH2:39][CH2:38][C@H:37]([O:40][CH3:41])[CH2:36][CH2:35]1)[CH2:21][CH2:22][C:23]1(OCC[O:30]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])#[N:19]>C(O)C.C(=O)(O)[O-].[Na+]>[C:18]([CH:20]([C@H:34]1[CH2:39][CH2:38][C@H:37]([O:40][CH3:41])[CH2:36][CH2:35]1)[CH2:21][CH2:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])#[N:19]
Reactant: CCCCCCC1(CCC(C#N)[C@H]2CC[C@H](OC)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(=O)CCC(C#N)[C@H]1CC[C@H](OC)CC1
Temperature: 25 °C

Procedure:
Pyridinium p-toluenesulfonate (0.9 g, 3.6 mmol) was added to a solution of 1-cyano-1-(trans-4-methoxycyclohexyl)-4,4-(ethylenedioxy)decane (47) (6.2 g, 18.3 mmol) obtained in the first step dissolved in 120 mL of ethanol, and refluxed under heating for 10 hours. The reaction mixture was cooled to room temperature and then put in 100 mL of a saturated sodium bicarbonate aqueous solution, and then extracted with 100 mL of ethyl acetate. The resulting organic layer was washed with water (100 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=9/1, column packing: silica gel) to obtain 1-cyano-1-(trans-4-methoxy cyclo hexyl)-4-decanone (48) (5.1 g, 17.4 mmol). The resulting compound was in the form of a colorless liquid, and the yield based on the compound (47) was 95%.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: F[n+]1ccccc1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(-c2ccccn2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 4-nitro-1H-imidazole (0.5 g, 4.4 mmol) in DMF (15 ml) was cooled to 0° C. and treated with sodium hydride (0.23 g, 5.3 mmol). Stirring was continued at 0° C. for 1 h and subsequently cooled to −30° C. A solution of N-fluoropyridinium triflate (0.55 g, 2.2 mmol) in DMF (10 ml) was added within 5 min. After warming-up to ambient temperature, the reaction mixture was stirred at that temperature overnight. The crude product was obtained after extraction with ethyl acetate (2×100 ml), washing of the combined organic phases with 10% aqueous potassium bisulphate solution, water and brine and finally drying and solvent evaporation. This off-white solid material (0.33 g, 39%) was used without any further purification for the next step. MS: M=191.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3OC=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.C1(C(Cl)=O)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([CH:21]3[CH2:25][CH2:24]3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: O=C(Cl)C1CC1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)C3CC3)nn2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and cyclopropanecarbonyl chloride (0.043 mL, 0.45 mmol), except the reaction was stirred for 1 h at −78° C., to afford N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclopropanecarboxamide (110 mg) as a yellow solid. 1H NMR (DMSO): δ9.87 (s, 1H), 8.64 (d, J=8.0 HZ, 1H), 8.35 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 5.05 (m, 1H), 3.74 (s, 3H), 1.63 (m, 1H), 1.47 (d, J=7.0 Hz, 3H), 0.65 (m, 4H).