Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1C(=O)N(O)C(=O)C1S([O-])(=O)=O.[Na+].C(Cl)CCl.Cl.[OH:21][CH:22]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1N>O>[O:21]=[CH:22][CH2:23][C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C1CC(S(=O)(=O)[O-])C(=O)N1O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydroxide (1N, 1 ml) was added to a stirred solution of EC (110 mg, 0.41 mmol) in water (5 ml). To this colorless solution, sulfo-NHS (241.6 mg, 1.12 mmol) and EDC (218.8 mg, 1.15 mmol) were added. D-Glucosamine hydrochloride salt (356.8 mg, 1.65 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hours using Spectra/POR molecular porous membrane with cut-off at 500 (Spectrum Medical Industries Inc., Houston, Tex,). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, Mo.). The product in the salt form weighed 568.8 mg. The synthetic scheme is shown in FIG. 59. The structure was confirmed by mass spectrometry (FIG. 60) and proton NMR (FIGS. 61 and 62). Radiochemical purity of 99mTc-EC-DG was 100% as determined by radio-TLC (FIG. 63) and HPLC (FIGS. 64 and 65) analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[N:6][CH:7]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=3[CH3:17])=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1)#[N:19]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cn2)s1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(NS(=O)(=O)c3ccc(C#N)cc3)cn2)s1

Procedure:
Using an analogous procedure to that described in Example 83, N-[5-(5-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide was reacted with 4-cyanophenylsulfonyl chloride to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.48 (s, 3H), 7.57 (m, 2H), 7.94 (d, 2H), 8.07 (d, 2H), 8.26 (m, 1H), 10.86 (br s, 1H), 12.06 (s, 1H); Mass Spectrum: M+H+ 414.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a stirred mixture of N-acetyl-4-hydroxypiperidine (7.1 g, 0.050 mol), 4-nitrophenol (7.1 g, 0.050 mmol, (PPh3 (16.3 g, 0.062 mol), and THF (50 mL) was added a solution of diethyl azodicarboxylate (10.8 g, 0.062 mol) in THF (16 mL). The mixture was stirred at room temperature for 48 hours, and then concentrated. The crude mixture was purified by flash chromatography (1% MeOH/EtOAc) to give 4.5 g (30%) of N-acetyl-4-(4-nitrophenoxy)piperidine as a yellow oil: 1H NMR (DMSO-d6): δ8.10 (d, 2H) 7.05 (d, 2H), 4.80 (m, 1H) 3.80 (m, 1H), 3.65 (m, 1H), 3.15 (m, 1H), 3.00 (m, 1H), 2.00 (s, 3H), 1.90 (m, 2H), 1.65 (m, 1H), 1.50 (m, 1H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:17][CH2:18]Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH:11]1([CH2:17][CH2:18][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[NH2:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccc(NN)cc1
Reactant: BrCCC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(N(N)CCC2CCCCC2)cc1
Temperature: 60 °C

Procedure:
The title compound was prepared by General Method 2. p-tolylhydrazine hydrochloride (0.96 g, 6.0 mmol) was added to a vigorously stirred mixture of tetra-n-butylammonium chloride (84 mg, 0.3 mmol) in 50% aqueous sodium hydroxide (6 mL) followed by 2-cyclohexylethyl bromide (1.26 g, 6.6 mmol). The mixture was heated at 60° C. (oil bath temp.) for 6 h. After cooling to room temperature, water (20-30 mL) was added and the mixture extracted with chloroform (3×10 mL). The total extract was dried (sodium sulfate), evaporated in vacuo to give a dark oil (1.49 g) which was chromatographed (45 g of silica gel, eluted with dichloromethane) to give the product as a yellow-orange oil (0.68 g, 2.93 mmol, 48.8%).
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[Br:9][C:10]1[C:11]([C:22](=[S:24])[NH2:23])=[CH:12][C:13]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[N:14][CH:15]=1>C(#N)C>[Br:9][C:10]1[C:11]([C:22]2[S:24][CH2:2][C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[N:23]=2)=[CH:12][C:13]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[N:14][CH:15]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CC#N
Product: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
3-Bromo-1,1,1-trifluoropropan-2-one (2.260 mL, 21.77 mmol) was added to a mixture of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 42, 1.1 g, 3.63 mmol) in acetonitrile (25 mL), and the reaction mixture was heated at 80° C. for 4 h. After a clear solution resulted within an hour, and the solution was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, then concentrated under reduced pressure to give light yellow solid, which was purified by normal phase column chromatography (silica, 2% MeOH in dichloromethane to 5% MeOH in dichloromethane) to give the title compound as a white solid (470 mg). MS (ESP): 414 (M+1) for C12H12BrF3N4O2S; NMR: 1.06 (t, 3H); 3.12-3.18 (m, 2H); 3.60 (dd, 1H); 3.90 (dd, 1H); 7.13 (brs, 1H); 7.98 (s, 1H); 8.47 (s, 1H); 9.41 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(Cl)nc(Nc2ccc(O)cc2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (9.00 g, 50.0 mmol) in 100 mL of acetone was cooled to 0° C. and, under stirring, solid 4-amino phenol (5.46 g, 50.0 mmol) was added in small portion, over ca 2 min. The white suspension was then let to warm to room temperature and stirred for further 1 h, while being neutralized with a 2 M aqueous solution of Na2CO3 during the reaction. The mixture was then poured into 500 mL of ice/water and the resulting white precipitate was filtered and dried, to give 9.6 g (38.0 mmol, yield 76%) of 4-[(4-chloro-6-methoxy-1,3,5-triazin-2-yl)amino]phenol that can be used without further purifications. An analytical sample can be obtained by flash chromatography (CC, SiO2, petroleum ether/Et2O 1:1, Rf=: 0.14). The NMR analysis (DMSO d6) reveals the presence, in solution, of 2 rotational isomers (molar ratio 7:3). M.p was 172° C. IR ν(NH) 3476 cm−1. ν(OH) 3269 cm−1. Major isomer: 1H NMR (DMSO d6) δ=3.94 (s, 3H, OCH3); 6.79 (d, J=8.8 Hz, 2H, CH Ar), 7.48 (d, J=8.8 Hz, 2H, CH Ar), 9.40 (s, 1H, OH), 10.46 (s, 1H, NH). 13C NMR (DMSO d6) δ 55.52 (1C, OCH3); 115.46 (2C, CH Ar), 123.91 (2C, CH Ar), 129.49 (1C, C Ar), 154.44 (1C, C Ar), 164.81 (1C, C Ar), 169.57 (1C, C Ar), 171.23 (1C, C Ar). Minor isomer: 1H NMR (DMSO d6) δ 3.96 (s, 3H, OCH3); 6.79 (d, J=8.9 Hz, 2H, CH Ar), 7.39 (d, J=8.9 Hz, 2H, CH Ar), 9.42 (bs, 1H, OH), 10.10.32 (s, 1H, NH). 13C NMR (DMSO d6) δ=55.10 (1C, OCH3); 115.46 (2C, CH Ar), 123.03 (2C, CH Ar), 129.26 (1C, C Ar), 154.76 (1C, C Ar), 165.20 (1C, C Ar), 170.48 (1C, C Ar), 170.64 (1C, C Ar).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:17])[N:9]=[CH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.O.[OH-].[Na+]>C(OCC)C>[CH3:7][N:8]([CH3:17])[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)N=Cc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)NCc1cccnc1
Temperature: 5 °C
Yield: 20.6 %

Procedure:
In 100 ml of dry ethyl ether was suspended 4.6 g of lithium aluminum hydride and with stirring in a nitrogen gas stream, a solution of 12.0 g of 1,1-dimethyl-2-(3-pyridylmethylidene)hydrazine in 50 ml is of dry ethyl ether was added dropwise. The mixture was refluxed for 5 hours and, then, cooled (5° C.) and with stirring, 5 ml of water, 5 ml of 20% aqueous sodium hydroxide and 15 ml of water were added dropwise in succession. The insoluble matter was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroformethanol=10:1). The resulting oil was distilled under reduced pressure to give 2.5 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[CH2:39][C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[C:39](=[CH:20][C:3]4[NH:4][C:5]5[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]6[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]6)[C:7](=[O:19])[C:6]=5[C:2]=4[CH3:1])[C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 46.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (44 mg, 46.8%) as an orange solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CSC.[F:10][C:11]([F:35])([F:34])[C:12]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:13]=1[CH2:14][N:15]1[CH2:22][CH:21]2[CH2:23][CH:17]([CH2:18][CH:19]([CH2:24][OH:25])[CH2:20]2)[CH2:16]1.[OH-].[Na+]>C1COCC1.C(N(CC)CC)C>[F:35][C:11]([F:10])([F:34])[C:12]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:13]=1[CH2:14][N:15]1[CH2:16][CH:17]2[CH2:23][CH:21]([CH2:20][CH:19]([CH:24]=[O:25])[CH2:18]2)[CH2:22]1
Reactant: OCC1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CSC
Solvent: C1CCOC1
Product: O=CC1CC2CC(C1)CN(Cc1ccc(C(F)(F)F)cc1C(F)(F)F)C2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 5.1 %

Procedure:
A solution of oxalyl chloride (1.19 mL) in THF (34.7 mL) was cooled to −78° C., and dimethyl sulfide (1.48 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 20 min, and a solution of {3-[2,4-bis(trifluoromethyl)benzyl]-3-azabicyclo[3.3.1]non-7-yl}methanol (2.65 g) in THF (20 mL) was added dropwise. The mixture was warmed to 0° C., stirred for 30 min, cooled again to −78° C., and triethylamine (4.84 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, poured into 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.135 g).
Reaction SMILES: O=[C:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C(O)C>[O:10]=[C:8]1[NH:20][C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:19]=[C:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1ccccc1N
Solvent: CCO
Product: CCOC(=O)c1nc2ccccc2[nH]c1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.8 %

Procedure:
Diethyl ketomalonate (8 g) was added to an ethanol (100 ml) solution of 1,2-phenylenediamine (5 g). The reaction mixture was stirred at 50° C. for 14 hours. The precipitated crystals were filtrated, which was washed with IPE to obtain the entitled compound (8.2 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:18](=[O:20])[CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1(C)[CH2:16][CH2:15]1)=[N:5]2.BrC1C(F)=CC=C2C=1N=C(NC(C)C)C(C)=N2>>[F:1][C:2]1[C:3]([C:18](=[O:20])[CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:5]2
Reactant: CC(=O)c1c(F)ccc2nc(C)c(NC3(C)CC3)nc12
Agent: Cc1nc2ccc(F)c(Br)c2nc1NC(C)C
Product: CC(=O)c1c(F)ccc2nc(C)c(NC(C)C)nc12
Yield: 90 %

Procedure:
1-(6-Fluoro-3-(isopropylamino)-2-methylquinoxalin-5-yl)ethanone (619b) (3.58 g, 90% yield) as an orange solid was prepared according to the procedures described for Intermediate 610b, using 8-bromo-7-fluoro-N-isopropyl-3-methylquinoxalin-2-amine (373a) (2.00 g, 6.70 mmol) as the starting material. 19F NMR (377 MHz, DMSO-d6) δ ppm −116.42. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (1H, dd, J=9.0, 6.1 Hz), 7.20 (1H, t, J=9.2 Hz), 7.01 (1H, d, J=7.4 Hz), 4.23 (1H, m), 2.66 (3H, s), 2.52 (3H, s), 1.26 (6H, d, J=6.7 Hz). m/z (ESI, +ve) 262.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(#N)C>[N:29]1([CH2:28][CH2:27][NH:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCCN1CCCCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.775 mmol) in acetonitrile (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and 1-(2-aminoethyl)piperidine (119 mg, 0.93 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (266 mg, 94% yield) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:29][CH2:30][S:31]([CH2:34][CH2:35]Br)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:35][CH2:34][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: O=S(=O)(CCBr)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CS(=O)(=O)CCN1CCC(N2N=C(c3ccc(OC)c(OC)c3)[C@H]3CC=CC[C@H]3C2=O)CC1
Reaction time: 18 h

Procedure:
A solution of 10 mmol of compound 5c, 10 mmol of 1-bromo-2-(2-bromo-ethanesulfonyl)-ethane and 30 mmol of potassium carbonate in 30 ml of dimethylformamide is stirred at RT. After 18 h, the mixture is poured into water (150 ml) and subsequently extracted with ethyl acetate. Crystallisation from diethyl ether. M. p. 165-166° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[N:15]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: CC(C)COC(=O)Cl
Reactant: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Solvent: ClCCl
Product: CC(C)COC(=O)n1c(CN2CCN(c3ccccn3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a stirred solution of Example 1A (0.77 g, 2.6 mmol) in dichloromethane (7 mL) was added isobutyl chloroformate (0.375 mL, 2.9 mmol). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and the residue was purified by flash column on SiO2 eluting with 1.3% methanol/dichloromethane to give 0.5 g (49%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz) δ 1.10 (d, J=6 Hz, 6H), 2.22 (m, 1H), 2.86 (bm, 4H), 3.67 (bm, 4H), 4.18 (bs, 2H), 4.33 (d, J=7 Hz, 2H), 6.66 (m, 2H), 7.35 (m, 2H), 7.53 (m, 1H), 7.76 (m, 1H), 7.93 (m, 1H), 8.19 (m, 1H). MS (DCI/NH3) m/z 394 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[CH2:25][CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:27][CH2:26][CH2:25][C:16]2[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=2[F:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4 ml of 4-tert-butylbenzaldehyde (24 mmol), 3.9 g of 2-(2-fluoro-5-trifluoromethyl -phenyl)-ethylamine hydrochloride (16 mmol) and 2.2 g of potassium carbonate (18.1 mmol) were suspended in 55 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 0.91 (24 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 5 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:4) to give 6.28 g light yellow oil (100%). MS (ISP) 354.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([NH:16][C:17](=[O:27])[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([Si](C)(C)C)#[CH:30].CC(OC)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCN(CC)CC.C1COCC1.[Cu]I.O>[C:1]([O:5][C:6](=[O:28])[CH:7]([NH:16][C:17](=[O:27])[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:29]#[CH:30])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(C)c(C(=O)NC(Cc2ccc(I)cc2)C(=O)OC(C)(C)C)c(C)c1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(CC(NC(=O)c2c(C)cc(C)cc2C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
500 mg (1.01 mmol) of (2), 38 mg (0.203 mmol) of CuI and 71 mg (0.1 eq.) of PdCl2(PPh)3 were dissolved in 10 ml of Et3N. to The solution was flushed with Argon and 1.68 ml (1.216 mmol) of ethynyl-trimethyl silane were added and stirred for 2 h at room temperature. The reaction mixture was poured into MTBE, washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The crude product was dissolved in 20 ml of THF and cooled to −78° C. 2 ml (2 mmol) of 1 M TBAF solution in THF were added and the reaction mixture was stirred for 45 min at −78° C. 10 ml of water were added and the product was extracted with diethyl ether. The organic layer was extracted with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 195 mg of (3).
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CO>[CH2:23]([O:22][C:20]([NH:1][C:2]([CH3:11])([CH2:6][C:7]([F:8])([F:9])[F:10])[C:3]([OH:5])=[O:4])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(N)(CC(F)(F)F)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(CC(F)(F)F)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-amino-4,4,4-trifluoro-2-methylbutanoic acid (255 mg, 1.4 mmol) and triethylamine (800 ul, 4.2 mmol) in MeOH (3 ml) was cooled to 0° C. and benzyl chloroformate (509 mg, 2.98 mmol) was added dropwise. The solution was warmed to RT overnight and concentrated in vacuo. The residue was suspended in EtOAc and extracted with sat. NaHCO3, the aqueous layers acidified with conc. HCl, and the resulting milkly suspension extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound. LRMS (ESI/APCI, negative): 304 [M−H+].
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[C:33]=1[CH2:34]Br.Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[C:32]([F:31])=[CH:39][C:38]([F:40])=[CH:37][C:36]=3[F:41])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1cc(F)c(CBr)c(F)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2c(F)cc(F)cc2F)c1=O
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4,6-trifluorobenzyl bromide (337 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (240 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s, 1 H), 10.08 (br. s, 1 H), 7.11-7.19 (m, 2 H), 5.06 (s, 2 H), 4.61 (t, J=12.00 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.19-2.30 (m, J=12.25, 12.25, 12.13, 2.53 Hz, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.59 (t, J=13.01 Hz, 3 H), 1.28 (q, J=12.88 Hz, 2 H), 1.06-1.17 (m, 1 H).