Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>ClCCl>[C:12]1([C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][S:21](=[O:6])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(C2(c3ccccc3)CCSCC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=S1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 20.3 g of 3-chloroperoxybenzoic acid (at 85%) in 300 cm3 of dichloromethane is added over 40 minutes to a solution, cooled to 0° C., of 25.4 g of 4,4-diphenyltetrahydrothiapyran in 130 cm3 of dichloromethane After stirring for 2 hours at 0° C., 250 cm3 of a 5% aqueous solution of potassium hydrogen carbonate are added to the mixture and it is then stirred for 15 minutes. The organic phase is again washed with 250 cm3 of a solution of potassium hydrogen carbonate and it is then dried over magnesium sulphate and concentrated to dryness (after verifying the absence of peroxides) under reduced pressure (2.7 kPa). 26.9 g of 4,4-diphenyltetrahydrothiapyran 1-oxide are obtained in the form of a white solid; melting point 122° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O)C.Cl>[Fe].O>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(I)cnc1N
Temperature: 100 °C
Yield: 59.8 %

Procedure:
5-Iodo-3-nitro-2-aminopyridine (2.0 g, 7.55 mmol), ethanol (7 mL), water (2 mL), and concentrated HCl (0.10 mL) were added to a 25 mL round bottom flask and allowed to stir. Iron (4.8 g, 85.9 mmol) was added in portions to the reaction followed by heating at 100° C. for 30 min. The iron was then removed and washed with ethanol over a flitted filter while the ethanol washings were concentrated under reduced pressure. The residue was purified by flash chromatography using 1:2 hexane:ethyl acetate as eluent to give 5-Iodo-2,3-diaminopyridine as a light brown solid (60%, 1.061 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[CH:13]=[N:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[Cl:16]N1C(=O)CCC1=O>ClCCl>[Cl:16][C:15]1[N:14]=[CH:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1cncc(-c2ccnc3cncn23)c1
Solvent: ClCCl
Product: Clc1ncn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mol of 4-(3-pyridyl)imidazo[1,5-a]pyrimidine (prepared as described in Example 24) and N-chlorosuccinimide (0.013 mol) in 50 ml. of dichloromethane can be refluxed on a steam bath for 3 hours. The reaction mixture can be poured into 100 ml. of ice cold 2.5 N sodium hydroxide solution, the organic layer separated, and dried over anhydrous sodium sulfate, and then passed through a short column of hydrous magnesium silicate. The effluent can be refluxed on a steam bath with the gradual addition of n-hexane until crystallization occurs. The mixture can be cooled and the desired product collected by filtration to produce 8-chloro-4-(3-pyridyl)imidazo[1,5-a]pyrimidine.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[C:35]([F:37])[CH:36]=1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([S@@:5]([NH:7][C@H:8]([C:33]1[CH:32]=[C:31]([F:30])[CH:36]=[C:35]([F:37])[CH:34]=1)[CH2:9][CH2:10][C@@:11]1([C:26]([O:28][CH3:29])=[O:27])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: COC(=O)[C@]1(CC/C=N/[S@@](=O)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC[C@H](N[S@@](=O)C(C)(C)C)c2cc(F)cc(F)c2)CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 1-benzyl 2-methyl (2R)-2-((3E)-3-{[(S)-tert-butylsulfinyl]imino}propyl)pyrrolidine-1,2-dicarboxylate from Step B (1.56 g, 3.70 mmol) in toluene (30 mL) at −78° C. was added 3,5-difluorophenylmagnesium bromide (14.8 mL of a 0.5 M solution in THF, 7.41 mmol) dropwise. The reaction mixture was stirred for 30 min at −78° C., 3.5 h at −10° C., and then at ambient temperature for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 0:100, to give the title compound. MS: m/z=537 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][NH:32][C:33]([NH2:35])=[S:34]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:31][NH:32][C:33](=[S:34])[NH2:35])=[O:14]
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: NC(=S)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reaction time: 8 h

Procedure:
To a solution of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (360 mg; 1.01 mmol) was added 1,1′-carbonylbis(1H-imidazole) (196 mg; 1.21 mmol). The mixture was stirred overnight. The dark yellow colored solution was treated with thiosemicarbazide (110 mg mg; 1.21 mmol). The reaction mixture was stirred at room temperature overnight. Water (10 mL) was added, and extracted with ethyl acetate. Concentrated and purified on Flashmaster to obtain 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine carbothioamide. (300 mg, 69%) MS m/z: 432 M+1
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][N:16](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].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:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:15]#[N:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 205 °C
Yield: 80 %

Procedure:
To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (2.13 g, 8.2 mmol) and Zn(CN)2 (770 mg, 6.56 mmol) in DMF (10 mL) was added Pd(PPh3)4 (474 mg, 0.41 mmol) under a nitrogen atmosphere. The mixture was heated in a sealed vessel at 205° C. for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc-Hexane) to give 2-tert-butyl-5-nitrobenzonitrile (1.33 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.3 Hz, 1H), 8.36 (dd, J=8.8, 2.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 1.60 (s, 9H); HPLC ret. time 3.42 min, 10-100% CH3CN, 5 min gradient.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)([F:12])[F:11])=[N:6][C:5]=1[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[H][H]>CO.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:11])[F:12])=[N:6][C:5]=1[CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCCc1nc(C(F)(F)Cl)ccc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COCCCc1nc(C(F)F)ccc1C(=O)OC
Yield: 113.4 %

Procedure:
A solution of 194 g of 6-(Chloro-difluoro-methyl)-2-(3-methoxy-propyl)-nicotinic acid methyl ester (prepared according to WO 04/078729) in methanol (ca. 2 liter) and triethylamine (100 ml) is hydrogenated at 1 Atm hydrogen pressure in the presence of 2 g of 5% palladium supported on carbon. After completion of the reduction the reaction mixture is filtered through hyflo, and the filtrate diluted with water and the water/methanol mixture then extracted with ethyl acetate. The combined ethyl acetate extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated in vacuo to give 194.2 g 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid methyl ester as a pale coloured oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28].C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: CCN(CC)CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(CCCNCCN(CC)CC)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (8.24 g, 21 mmol) was dissolved in N,N-diethylethylenediamine (15 ml, 100 mmol) under stirring at room temperature, and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with 100 ml of ethyl acetate and 100 ml of saturated brine, stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (100 ml×4), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain brown oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-[3-(2-diethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 h (8.2 g, yield 95%) as a colorless oil.
Reaction SMILES: BrC1C=C(C([N:16]2[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=O)OC=1C1C=CC=C(Cl)C=1.[Br:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1>>[Br:23][C:24]1[O:28][C:27]([C:29]([N:16]2[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=[O:31])=[CH:26][C:25]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(Br)o1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)o2)CCN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 22A. 48.0 mg (79% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[OH:15])=[N+:2]=[N-:3].BrC1CCN(C(OCC)=O)CC1O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[O:15][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: CCOC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Reactant: CCOC(=O)N1CCC(Br)C(O[Si](C)(C)C(C)(C)C)C1
Product: CCOC(=O)N1CCC(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)C1

Procedure:
The title compound was prepared in a manner analogous to (Intermediate 238) starting with ethyl 4-bromo-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1-carboxylate (Intermediate 241). MS (GC-EI)[(M-N2)+]: 300 for C14H28N4O3Si.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
A mixture of 5.04 g (40 mmol) 3-fluorobenzyl alcohol and 1.29 g (4 mmol) tris-(dioxa-3,6-heptyl)amine is treated with 2.47 g (44 mmol) of potassium hydroxide. The mixture is stirred at RT for 10 min, then 5.55 g (44 mmol) of 4-fluoro-nitrobenzene is slowly added through a dropping funnel. The mixture is kept for 45 min at 80° C., cooled to RT and diluted with about 75 ml water. Extraction with ethyl acetate and washing with 2M aqueous hydrochloric acid yields a yellowish organic phase, which is dried and evaporated. The residue is recrystallised from methanol to give 6.07 g (61%) of the title compound. Yellow crystals, mp=104–105° C.
Reaction SMILES: [C:1]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])[CH2:2]CC(OCC1C=CC=CC=1)=O.F[C:27](F)(F)[C:28]([O:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=[O:29]>C1COCC1.[Pd]>[C:1]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])[CH2:2][CH2:27][C:28]([O:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=[O:29]
Reactant: CC(C)(C)OC(=O)CCCOC(=O)CCC(=O)OCc1ccccc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCOC(=O)CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Compound 3 (2.0 g, 5.7 mmol) was hydrogenated for 20 h at 40 psi in THF (100 mL) in the presence of 0.2 g of 10% Pd/C. The catalyst was removed by filtration through Celite and filtrate concentrated. The acid was dissolved in 20 mL of anhydrous CH2Cl2. Diisopropylethylamine ((0.88 g, 6.8 mmol) was added followed by pentafluorophenyl trifluoroacetate (1.9 g, 6.8 mmol). After being kept at room temperature for 1 h solvent was evaporated and residue chromatographed on silica (ethyl acetate-hexane) to afford 2.2 g (91%) of 4 as viscous liquid. 1H NMR (DMSO-d6) δ 4.05 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.72 (t, J=6 Hz, 2H), 2.26 (t, J=7 Hz, 2H), 1.78 (q, 2H), 1.38 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of 168 mg (0.47 mmol) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and 157 mg (0.71 mmol) of 2-bromomethylnaphthalene in 2 ml of dimethylformamide was treated with 28 mg (0.7 mmol) of sodium hydride (60% dispersion in refined oil) and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:4 mixture of ethyl acetate and hexane as the eluent. There were obtained 173 mg (74% of theory) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow oil; MS: 439, 441 (M-C4H8)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][C:15]#[C:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.C[N:33](C=O)C.N>CCO>[F:31][C:2]([F:1])([F:30])[CH2:3][N:4]=[C:5]([NH2:33])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][C:15]#[C:16][CH2:17][NH2:18])[N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: CN(C)C=O
Agent: N
Solvent: CCO
Product: NCC#CCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobut-2-ynylthio)pyrimidine (0.37 g.), DMF (10 ml.), saturated ethanolic ammonia (1 ml.), EtOH (10 ml.) and yellow mercuric oxide (0.32 g.) was stirred at room temperature for 2 hours and then filtered and the filtrate evaporated to dryness. The residue was treated with EtOH (20 ml.) and 98% hydrazine hydrate (1 ml.) and the mixture heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N aqueous HCl and then filtered. The filtrate was basified with 10N aqueous NaOH and the mixture extracted four times with ether. The combined extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobut-2-ynylthio)pyrimidine (0.17 g.) characterised as the bis hydrogen maleate, m.p. 153°-155° (decomp.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1>CCO.C(Cl)(Cl)Cl.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C#N)c1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cccc(CCCN)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of trans-3-(3-Methoxyphenyl)-2-propenenitrile (27.6 g, 173 mmol) and PtO2 (2.76 g) in 200 mL of EtOH and 30 mL of CHCl3 was shaken in a Parr apparatus under an atmosphere of 50-60 psi H2 overnight at RT. The reaction mixture was filtered through Celite and concentrated in vacuo to provide a brown solid which was then partitioned between CH2Cl2 and 1N NaOH. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic layers were then dried over MgSO4, filtered and concentrated in vacuo to provide 24.2 g of the desired product as a yellow oil (85% yield). 1H NMR (CDCl3) δ 7.15-7.22 (m, 1H), 6.70-6.80 (m, 3H), 3.80 (s, 3H), 2.72 (t, J=6.0 Hz, 2H), 2.58-2.65 (m, 2H), 1.70-1.85 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:28]=[C:27]([CH:29]4[CH2:31][CH2:30]4)[N:26]([CH3:32])[C:25]=3[CH:33]=2)[C:17](=[O:34])[CH:16]=1.O>CC(N(C)C)=O>[CH:29]1([C:27]2[N:26]([CH3:32])[C:25]3[CH:33]=[C:21]([N:18]4[CH:19]=[CH:20][C:15]([O:9][CH2:8][C:5]5[S:6][CH:7]=[C:3]([C:2]([F:10])([F:1])[F:11])[CH:4]=5)=[CH:16][C:17]4=[O:34])[CH:22]=[CH:23][C:24]=3[N:28]=2)[CH2:30][CH2:31]1
Reactant: OCc1cc(C(F)(F)F)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)cc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of (4-(trifluoromethyl)thiophen-2-yl)methanol (50 mg) in DMA (2 ml) was added NaH (60% in oil, 18.3 mg) at room temperature, and the mixture was stirred for 30 min. 4-Bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (79 mg) was added to the mixture, and the mixture was heated at 120° C. for 30 min under microwave irradiation. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 solution and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/MeOH), followed by crystallized from hot EtOAc to give the title compound (15.3 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Vb, 60 mg, 0.139 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.092 mL, 0.835 mmol), 2-amino-N-methylacetamide-HCl (31.2 mg, 0.250 mmol), and HATU (95 mg, 0.250 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.0 min) to give single enantiomer 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (33 mg, 0.064 mmol, 46.4% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.23 (2 H, m), 7.66-7.79 (4 H, m), 7.52-7.66 (3 H, m), 5.20 (1 H, s), 3.88-4.00 (2 H, m), 3.78-3.88 (2 H, m), 2.75 (3 H, s); HPLC Peak RT=9.1 min (Analytical Method B).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[N:24]1([CH2:30][CH2:31][N:32]([CH2:44][CH2:45][CH3:46])[CH:33]2[CH2:42][C:41]3[CH:40]=[C:39]([OH:43])[CH:38]=[CH:37][C:36]=3[CH2:35][CH2:34]2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[OH:43][C:39]1[CH:40]=[C:41]2[C:36]([CH2:35][CH2:34][CH:33]([N:32]([CH2:44][CH2:45][CH3:46])[CH2:31][CH2:30][N:24]3[CH2:25][CH2:26][N:27]([CH2:3][C:4]4[CH:13]=[CH:12][C:11]([OH:14])=[C:10]5[C:5]=4[CH:6]=[CH:7][CH:8]=[N:9]5)[CH2:28][CH2:29]3)[CH2:42]2)=[CH:37][CH:38]=1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCN(CCN1CCN(Cc2ccc(O)c3ncccc23)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a mixture of 5-chloromethyl-8-quinolinol hydrochloride, 11 (0.20 g, 0.86 mmol) and diisopropylethylamine (0.3 mL, 1.73 mmol, 2.2 equiv) in 25 mL CHCl3 at 0° C. was added 9a (0.25 g, 0.78 mmol). The mixture was stirred for 24 h at room temperature. CHCl3 (100 mL) was added and the solution obtained was washed with 10% NaHCO3, brine, and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was made hydrochloride salt and crystallized from ethanol to yield 12a as yellow solid (0.28 g, 57.3%). 1H NMR of HCl salt (400 MHz, DMSO-d6) δ ppm 0.88-0.99 (m, 3H), 1.79-1.81 (bs, 4H), 2.298 (bs, 1H), 2.476-2.48 (m, 2H), 2.74 (s, 2H), 2.96-3.02 (t, 1H, J=12 Hz), 3.122 (bs, 3H), 3.34-3.65 (m, 12H), 6.51-6.56 (m, 2H), 6.86-6.88 (d, 1H, J=8 Hz), 7.50-7.52 (d, 1H, J=8 Hz), 7.997-8.008 (m, 2H); 9.06-9.07 (d, 1H, J=4 Hz); 9.49-9.51 (d, 1H, J=8 Hz). The hydrochloride salt mp 242-242° C. Analysis calculated for (C29H40.6N4O3.3, 4HCl) C, H, N.