Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1>O>[ClH:1].[CH:39]1([CH2:42][N:19]2[CH2:18][CH2:17][C@:15]34[C:16]5[C:3]6[O:2][C@H:14]3[C:13](=[O:20])[CH2:12][CH2:11][C@@:10]4([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:31][CH3:32])[CH2:41][CH2:40]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (1.5 g, 3.57 mmol), potassium carbonate (3.00 g, 21.7 mmol) and cyclopropylmethylbromide (1.0 ml, 6.62 mmol) in water-free N,N-dimethylformamide (10 ml) was stirred for 4 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 10 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 50 ml dichloromethane, washed with water (3×50 ml) and saturated sodium chloride solution (4×50 ml), dried over sodium sulphate and evaporated down. The evaporation residue (1.42 g of yellow oil) was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 50 ml ether and precipitated by the addition of etherial HCl up to the acidic reaction. Yield: 0.60 g (53%) of the compound 3.HCl as colourless crystals. Fp. 130-133° C.; MS (EI): 473 (M+); IR (KBr): 1725 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.30 (s, wide, HN+), 7.31-7.18 (m, 5 arom. H), 6.88 (d, 1 arom. H, J=8.4 Hz), 6.78 (d, 1 arom. H, J=8.4 Hz), 4.96 (s, CH-5), 3.81 (s, CH3O), 0.80-0.40 (m, 5 cyclopropyl H).
Reaction SMILES: O=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]2)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:20][NH2:21]>CN(C)C=O>[O:6]=[C:5]1[CH2:4][CH2:3][C:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)=[N:21][NH:20]1
Reactant: CN1C(=O)Cc2cc(C(=O)CCC(=O)O)ccc21
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)Cc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
A solution of 7 g of 4-oxo-4-(1-methyl-2-oxoindolin-5-yl)butanoic acid and 3 ml of hydrazine hydrate in 70 ml of dimethylformamide was heated on a water bath for 4 hours. The precipitated crystals were filtered off and recrystallized from dimethylformamide to give 4.0 g of 5-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methylindolin-2-one as pale yellow prisms, melting at 261°-264° C.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[I:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH:22]=[C:23]([C:29]([O:31]CC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1>CC(CCC)C>[I:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]2=[O:31]
Reactant: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Solvent: CCCC(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O

Procedure:
Diphenyl ether (175 ml) was heated to reflux temperature, and Intermediate 10 was gradually added down an air condenser. Once all the reagent had been added the mixture was heated under reflux for a further 30 min. The mixture was then cooled and 2-methylpentane (200 ml) was added. The solid formed was collected by filtration to give the title compound (24.6 g).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
A mixture of benzyl N-Boc-5-aminovalerate (4 g) thus obtained in TFA (50 ml) was stirred at room temperature for 20 minutes. After the TFA was removed in vacuo, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The separated ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 2.7 g of benzyl 5-aminovalerate.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)Cl
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)C(CSC(C)=O)CC(C)C

Procedure:
2-Acetylthiomethyl-4-methylpentanoyl chloride and (L)-leucine, ethyl ester are reacted in methylene chloride in the presence of diisopropylethylamine at a temperature below 0° according to the procedure of Example 26 to yield (±)-N-[2-(acetylthiomethyl)-4-methyl-1-oxopentyl]-L-leucine, ethyl ester.
Reaction SMILES: [CH3:1][Mg]Cl.[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH2:13]1.Cl>O1CCCC1>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:1])([OH:18])[CH2:13]1
Reactant: O=C1CCCC(c2ccc(O)cc2O)C1
Reactant: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC1(O)CCCC(c2ccc(O)cc2O)C1
Reaction time: 16 h
Yield: 28 %

Procedure:
Methyl magnesium chloride (0.132 ml of a 22% w/w solution in tetrahydrofuran) was added to a solution of (±)-3-(2,4-dihydroxyphenyl)cyclohexanone (20 mg) in tetrahydrofuran (3 ml) at 0° C. under argon. After 16 hr, dilute hydrochloric acid (1 ml) was added dropwise and the reaction mixture was partitioned between ethyl acetate (50 ml) and brine (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by preparative HPLC to furnish the title compound as a white solid (6 mg, 28%). δH (d4-MeOH) 1.20 (3H, s), 1.22-1.39 (2H, overlapping m), 1.46 (1H, t), 1.54-1.87 (5H, overlapping m), 3.22 (1H, m), 6.19-6.25 (2H, overlapping m), 6.86 91H, d); m/z (ES−) 281 (M+60−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CC(C)(C)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (160 mg, 0.34 mmol) (as prepared in Example 1), 2,2-dimethyl-propionamide (100 mg, 1 mmol), xantphos (40 mg, 0.068 mmol), and cesium carbonate (222 mg, 0.68 mmol) were dissolved in dry dioxane (2 mL) and argon was bubbled through the mixture for 10 minutes. Pd(OAc)2 (8 mg, 0.034 mmol) was then added, and the solution was degassed for an additional 10 minutes. The mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to RT and diluted with EtOAc (20 mL) and water (15 mL). The organic layer was separated and washed with brine. The aqueous layer was extracted with EtOAc and the extracts were washed with brine. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-TLC to give N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (72 mg, 40% yield). 1H-NMR (400 MHz, DMSO-d6): δ 8.19-8.17 (m, 2H), 7.69 (s, 1H), 7.53-7.51 (m, 2H), 7.24 (br t, J=7.2 Hz, 1H), 7.10-7.05 (m, 2H), 6.73 (brs, 1H), 1.73-1.69 (m, 4H), 1.27 (s, 9H); MS (ESI); m/z 527.3 [M+H]+.
Reaction SMILES: C(OC(=O)C(N)(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=1)C)C.C(O)(C(F)(F)F)=O.C([O:39][C:40](=O)[C:41]([NH2:68])([C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([O:57][C@H:58]3[CH2:63][CH2:62][C@H:61]([C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:60][CH2:59]3)[C:49]=2[C:53]([F:56])([F:55])[F:54])[N:44]=1)[CH3:42])C>>[NH2:68][C:41]([C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([O:57][C@H:58]3[CH2:59][CH2:60][C@H:61]([C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:62][CH2:63]3)[C:49]=2[C:53]([F:54])([F:55])[F:56])[N:44]=1)([CH3:42])[CH2:40][OH:39]
Reactant: CCOC(=O)C(C)(N)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: CCOC(=O)C(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propan-1-ol Enantiomer 2 was synthesized as per 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propan-1-ol (Example 17) in 55% yield as bis-TFA salt using 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propionic acid ethyl ester Enantiomer 2 as starting material. MS: m/z=425.30 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.68 (d, J=8.5 Hz, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.56 (d, J=9.8 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 4.30-4.44 (m, 1H), 4.06-4.24 (m, 2H), 2.12-2.26 (m, 2H), 1.85-1.95 (m, 2H), 1.80 (s, 3H), 1.48-1.62 (m, 2H), 1.03-1.22 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O.O.N>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: Clc1ccnc2cccnc12

Procedure:
To 700 mg of 4-hydroxy-1,5-naphthyridine (CAS No. 5423-54-1, purchased from Specs), phosphorous oxychloride (15 ml) was added and heated to reflux for an hour. The reaction was put back to room temperature. The mixture was poured to ice, made alkaline with ammonia water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with magnesium sulfate, filtrated through NH silica gel, and the filtrate was concentrated under reduced pressure to obtain 456 mg of 4-chloro-1,5-naphthyridine (CAS No. 7689-63-6). To the obtained 4-chloro-1,5-naphthyridine (456 mg), pyridine (19 ml) and n-propylamine hydrochloride (1.32 g) were added and heated to reflux for 3.5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was partitioned between diethyl ether and 2N aqueous sodium hydroxide. The ether layer was separated and dried with magnesium sulfate. Solvent was distilled away and the residue was purified with NH silica gel (ethyl acetate/heptane system) to obtain 345 mg of the title compound (CAS No. 7689-63-6). The same operation was repeated to synthesize for another 952 mg. The structure of the obtained title compound and results from NMR measurement were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([O:35][CH3:36])[CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]([O:35][CH3:36])[CH2:33][CH3:34])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(CC)OC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CCC(CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC

Procedure:
631 mg (1.14 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoate (mixture of racemic diastereomers) in 22.5 ml of methanol/water (4/1) were reacted with 745 mg (2.29 mmol) of caesium carbonate according to General Method 4. Yield: 580 mg (purity 87%, 84% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:15]([O:17][CH3:18])=[O:16])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[O:22][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([O:17][CH3:18])=[O:16])([CH3:8])[CH3:10]
Reactant: COC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COCCOCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C(=O)OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
2-Methoxyethoxymethyl chloride (24.0 g, 192.7 mmol) is added dropwise to a 0° C. mixture of 25.0 g (94.6 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, methyl ester and 27.5 g (212.4 mmol) of diisopropylethylamine in 50 ml of CH2Cl2 under a nitrogen atmosphere. The reaction is stirred at 25° C. for 24 hours and then poured onto saturated aqueous NH4Cl and the layers are separated. The aqueous layer is extracted with t-butylmethylether (2×150 ml). The combined organic extracts are washed with saturated aqueous NH4Cl, water and brine (2×), dried over Na2SO4, and concentrated in vacuo to give 33.2 g of the desired product as an orange oil. The product is pure enough to use in subsequent reactions. A sample can be purified by chromatography (flash, SiO2, 230-400 mesh, 29×6.5 cm, 15% t-butylmethylether-hexane) followed by Kugelrohr distillation.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:17])[CH:10]=[C:11]([CH2:13][N:14]=[N+]=[N-])[N:12]=2)=[CH:4][CH:3]=1>CO.[Ni]>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:17])[CH:10]=[C:11]([CH2:13][NH2:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(CN=[N+]=[N-])nc1-c1ccc(I)cc1
Agent: [Ni]
Solvent: CO
Product: Cn1cc(CN)nc1-c1ccc(I)cc1
Reaction time: 1 h

Procedure:
A mixture of (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azide prepared above (46 mg, 0.14 mmol) and Ra—Ni (50% slurry in H2O, 100 mg) in MeOH (5 mL) was hydrogenated under balloon H2 for 1 h. It was filtered. The filtrate was concentrated in vacuo to give (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl amine (42 mg). MS 314.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=1[NH2:32]>>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:31]=[C:27]3[CH2:28][CH2:29][CH2:30][NH:25][C:26]3=[N:32][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccnc1N
Reactant: O=C(C(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2nc3c(nc2-c2ccc(C(F)(F)F)cc2)NCCC3)cc1

Procedure:
The title compound was prepared from 1,2-bis(4-(trifluoromethyl)phenyl)ethane-1,2-dione (this may be prepared according to the procedure of Bioorganic & Medicinal Chemistry Letters (2007), 17(21), 5825-5830) and pyridine-2,3-diamine analogously to Intermediate E;
Reaction SMILES: [CH2:1](/[C:3](=[CH:16]\[CH3:17])/[CH:4]=[CH:5]/[C:6]([O:8]N1C(=O)CCC1=O)=O)[CH3:2].[NH2:18][C@H:19]([C:23]([OH:25])=[O:24])[C@@H:20]([CH3:22])[OH:21].C(N(CC)CC)C.Cl>O1CCCC1.CN(C)C=O.O>[CH2:1](/[C:3](=[CH:16]\[CH3:17])/[CH:4]=[CH:5]/[C:6]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[C@@H:20]([CH3:22])[OH:21])=[O:8])[CH3:2]
Reactant: C/C=C(/C=C/C(=O)ON1C(=O)CCC1=O)CC
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C/C=C(/C=C/C(=O)N[C@H](C(=O)O)[C@@H](C)O)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.9 %

Procedure:
To a solution of N-[(E,E)-4-ethyl-2,4-hexadienoyloxy]succinimide (1.19 g) in a mixture of tetrahydrofuran (50 ml) and dimethylformamide (30 ml) was added a solution of L-threonine (2.38 g) and triethylamine (2.78 ml) in water (50 ml). The mixture was stirred at ambient temperature for 6 hours and then acidified with 1N hydrochloric acid. The resulting mixture was extracted with ethyl acetate, washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give N-[(E,E)-4-ethyl-2,4-hexadienoyl]-L-threonine (640 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:28]Cl)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:28][S:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
A solution of tert-butyl[(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-chloropropan-2-yl]carbamate (58, 390 mg, 0.87 mmol) in dry DMF (2.5 ml) was treated with neat 2-aminobenzenethiol (351 mg, 2.8 mmol) followed by cesium carbonate (560 mg, 1.72 mmol). The mixture was stirred at room temperature for 3 h, diluted with DCM and washed with 1M NaOH followed by saturated NaHCO3, dried over MgSO4, filtered and concentrated to afford the title compound (482 mg) as an oil, which was submitted without further purification to the next synthetic step. MS: m/z=537.2 (MH+).
Reaction SMILES: [NH:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH2:3][C:4]#[N:5].N[NH:11][C:12]([NH2:14])=[S:13].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:11][C:12]1[S:13][C:4]([CH2:3][CH2:2][NH:1][CH2:6][CH2:7][C:8]2[S:13][C:12]([NH2:14])=[N:11][N:9]=2)=[N:5][N:14]=1
Reactant: NNC(N)=S
Reactant: N#CCCNCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(CCNCCc2nnc(N)s2)s1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A mixture of 3,3′-iminodipropionitrile (1.50 g, 12.18 mmol) and thiosemicarbazide (2.22 g, 24.36 mmol) in TFA (10 mL) was heated at 85 for 4.5 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5-(2-((2-(5-amino-1,3,4-thiadiazol-2-yl)ethyl)amino)ethyl)-1,3,4-thiadiazol-2-amine (1005, 1.47 g). 1H NMR (300 MHz, DMSO-d6) δ 6.95 (s, 4H), 2.90 (d, J=6.0 Hz, 4H), 2.83 (d, J=6.3 Hz, 4H).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]2[C:18]([CH:19]=[N:20][C:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[N:22]2)=[CH:17][CH:16]=1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:37][N:34]1[CH2:35][CH2:36][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[O:8][CH2:7][C:6]([OH:38])=[O:5])[N:23]4[N:22]=3)=[CH:30][CH:29]=2)[CH2:32][CH2:33]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5OCC(=O)OC(C)(C)C)n4n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5OCC(=O)O)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
Into an 8-dram vial, (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenoxy)-acetic acid tert-butyl ester (0.180 g, 0.350 mmol), Methylene chloride (5.0 mL, 78 mmol), and Trifluoroacetic Acid (1.00 mL, 13.0 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenoxy)-acetic acid as a yellow solid (32 mg, 20%). LCMS (E/I+) 459.14 (M+H). NMR 1H (DMSO-d6)-13.28 (bs, 1H), 9.58 9 bs, 1H), 9.24 (s, 1H), 8.92 (s, 1H), 8.07 (d, 1H, J=7.44 Hz), 7.65 (d, 2H, J=8.12 Hz), 7.40 (t, 1H, J=8.12 Hz), 7.17-7.20 (m , 2H), 7.10 9 d, 1H, J=8.79 Hz), 6.85-6.93 (m, 3H), 4.75 (s, 2H), 3.74 (d, 2H, J=12.85 Hz), 3.53 (d, 2H, J=11.50 Hz), 3.18 (q, 2H, J=10.15 Hz), 2.80-2.93 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:14])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:5]1[CH2:4][CH2:3][CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CCCO)nc2cccnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(CCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 750 mg of 2-(3-hydroxy-propyl) -3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 34), 1.83 g of 5-(4-hydroxy-benzyl) -3-triphenylmethylthiazolidine-2,4-dione, 0.98 ml of tributylphosphine, 990 mg of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume as the eluent, to give 550 mg of the title compound, melting at 76-81° C.