Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:27])[CH3:26])[CH2:20]1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:19]([OH:23])[CH2:20][C@@H:21]([CH:25]([CH3:27])[CH3:26])[C:22]([NH:2][CH3:1])=[O:24])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h
Yield: 91 %

Procedure:
Gaseous methylamine was introduced into a solution of 1.33 g (3.76 mmole) of (3S, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-isopropyldihydrofuran-2(3H)-one (prepared as described in Preparation 1) in 10 ml of methanol to ensure saturation, whilst ice-cooling. The reaction vessel was then stoppered tightly and allowed to stand overnight. At the end of this time, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from hexane to afford 1.32 g (yield 91%) of the title compound as white crystals, melting at 154°-157° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[Cl:18])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>C(O)C>[Cl:2][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH2:1])[C:8]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[Cl:18]
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Reactant: N
Solvent: CCO
Product: COc1ccc(Cl)c(Oc2c(N)ncnc2Cl)c1
Temperature: -78 °C
Reaction time: 50 h

Procedure:
About 500 ml of NH3 were conducted at -78° C. into a solution of 9.9 g of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine from Example 1e) in 400 ml of ethanol. Thereafter, the reaction mixture was stirred at -78° C. for 15 hours and at room temperature for 50 hours and finally evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was worked-up. 8.53 g of 6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylamine were thus obtained as yellow crystals. MS: 285 (M).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH2:26])=O)[CH2:19]1.O>C1COCC1>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH2:26])[CH2:19]1
Reactant: NC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 66 °C

Procedure:
To a suspension of LiAlH4 (0.62 g, 16.30 mmol) in dry THF (15 ml) was added 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid amide (0.45 g, 01.63 mmol) in dry THF (5 ml). The reaction mixture was heated under microwaves at 66° C. for 1 h. Water was slowly added and the mixture extracted with EtOAc (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the desired product, which was purified by column chromatography (DCM/MeOH, 98:2).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: COCCCN
Agent: Cl
Product: COCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 20.1 mg (0.23 mmol) of 3-methoxypropylamine are reacted together by general method E. 29.2 mg (49.8% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14](#[N:17])[CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:14](=[NH:17])[CH2:15][CH3:16])[CH2:9][CH2:10]1
Reactant: CCC#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (5.34 g), propionitrile (4.7 g) and anhydrous aluminium chloride (12 g) was heated at 160°-170° C. for six hours to yield N-(2-morpholinophenyl)propionamidine (m.p. 114° C.) which was recrystallised from hexane.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1Cl
Product: Nc1ccc(-c2ccccc2Cl)cc1
Yield: 49.7 %

Procedure:
The title compound (176 mg) was prepared from 4-bromoaniline (300 mg, 1.74 mmol) and 2-chlorophenylboronic acid (354 mg, 2.26 mmol) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.NN.Cl>CCO>[NH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=1
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1Br
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CN)cc1Br
Yield: 75.8 %

Procedure:
To a suspension of 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (8.0 g, 23.5 mmol) in EtOH (150 mL) was added hydrazine hydrate (85%, 2.76 g). The mixture was refluxed for 3 h. At room temperature 2 N HCl (60 mL) was added (pH=3), and the mixture was filtered and rinsed with water (50 mL×4). The filtrate was concentrated to about 150 mL and filtered again. After addition of NaHCO3 to pH=9, the filtrate was extracted with CH2Cl2 (100 mL×3). The combined extract was washed with brine, dried over anhydrous sodium sulfate. After removing the solvent, 1N HCl in MeOH (50 mL) was added and the solvent was concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O yielded 4.3 g of the product, 4-(aminomethyl)-2-bromobenzonitrile (yield: 75.8%). 1H NMR (400 MHz, D2O): δ 4.21 (S, 2 H), 7.43 (dd, J=8.0 Hz, J=1.2 Hz, 1 H), 7.71 (d, J=8.0 Hz, 2 H); 13C NMR (100 MHz, D2O): δ 42.3, 115.5, 118.0, 125.6, 128.4, 133.4, 135.5, 139.9; HPLC: retention time: 4.709 min; purity: 99.7%.
Reaction SMILES: [N:1]#[C:2]Br.[CH:4]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]>C(OCC)C>[CH:4]([C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:2]#[N:1])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: N#CBr
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCOCC
Product: CC(C)c1ccc(NC#N)cc1
Yield: 83.2 %

Procedure:
A solution of cyanogen bromide (1.59 g, 15 mmol) in diethylether (20) was added dropwise to a solution of 4-isopropylaniline (3.24 g) in diethylether (50 mL) at 4° C. with stirring. After the addition, the reaction mixture was kept stirring at room temperature for 18 h. Then a solution with white precipitates formed and the precipitates were removed by filtration. The etherate solution was washed with aqueous HCl (1N, 30 mL, two times) as well as brine, dried over MgSO4, filtered, concentrated, and dried under vacuum to yield 4-isopropylphenyl cyanamide (2.0 g, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:26])[CH2:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:26])[CH2:15][S:16]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:17])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CS(=O)(=O)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CS(=O)(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylmethanesulfonyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]([CH3:22])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][N:15]=[CH:16][CH:17]=2)[N:12]2[N:19]=[N:20][N:21]=[C:11]2[CH:10]=1>C(O)(=O)C>[CH3:5][CH:6]([CH3:22])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][N:15]=[CH:16][CH:17]=2)[N:12]2[N:19]=[N:20][N:21]=[C:11]2[C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)CNc1cc2nnnn2c2cnccc12
Solvent: CC(=O)O
Product: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2cnccc12

Procedure:
Nitric acid (2 equivalents of 16M) was added to a solution of N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine (2.0 g, 8.26 mmol) in acetic acid. The reaction mixture was heated on a steam bath for about an hour then concentrated under vacuum. The residue was poured into ice water and the resulting mixture was neutralized with sodium bicarbonate. The resulting precipitate was extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, and dried over magnesium sulfate. Thin layer chromatography indicated a mixture so the material was filtered through a layer of silica gel eluting with 5% ethyl acetate in dichloromethane. The reaction was rerun on 4 g of starting material but using only one equivalent of nitric acid. The resulting material was also a mixture. The material from both reactions was combined then purified by flash chromatography eluting with mixtures of hexanes/ethyl acetate. The fractions containing the slower moving material were combined to provide about 0.3 g of N5-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine as a yellow solid, m.p. 173-174° C. Analysis: Calculated for C12H13N7O2: %C, 50.17; %H, 4.56; %N, 34.13. Found: %C, 49.85; %H, 4.53; %N, 34.26.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[S:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.CCOCC>[OH:17][CH2:16][CH2:15][S:14][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCCSCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(OCCSCCO)cc1
Temperature: 22 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
A solution of methyl 3-[4-hydroxyphenyl)propionate (30.0 g, 0.166 mol), 2,2′-thiodiethanol (61.0 g, 0.50 mol) and triphenylphosphine (48.0 g, 0.183 mol) in dry benzene (450 ml) was treated at 22° C. with diethyl azodicarboxylate (33.2 g, 0.19 mol) added dropwise over 10 min and the resulting mixutre was stirred at 22° C. for 5 h. The reaction mixture was then diluted with ether (300 ml) washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate 85:15) to give 37.64 g (79%) of the starting material as a white solid: mp 47-48° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]=[CH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH3:4].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[C:19]([C:7](=[CH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:6]([O:5][CH2:3][CH3:4])=[O:18])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)C=CNc1ccccc1OC
Reactant: CC(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C(C)C
Temperature: 25 °C
Yield: 77.6 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether and suspended in dry tetrahydrofuran (50 ml) under nitrogen at -10° C. Ethyl3-(2-methoxyphenylamino)acrylate (22.4 g. 0.1 mol) in dry tetrahydrofuran (70 ml) was added dropwise to the suspension keeping the temperature to below 0° C. Cooling was removed and the mixture was stirred at ambient temperature until a deep orange colour was obtained. The mixture was recooled to -20° C. and treated dropwise with a solution of isobutyryl chloride (11.0 ml, 0.11 mol) in dry tetrahydrofuran (30 ml). The cooling bath was again removed, and the mixture stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with dilute hydrochloric acid and brine, dried, filtered and evaporated. The crude product was chromatographed (silica gel, petroleum ether/dichloromethane) to afford ethyl 2-isobutyryl-3-(2-methoxyphenylamino)acrylate as an oil (22.6 g, 77.5%).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>CN(C)C=O>[CH:1]([S:4][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)S
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Sc1ncccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
181.2 g of isopropylmercaptan are added dropwise at a temperature of 0° to +2° C. in the course of 25 minutes to a suspension of 324 g of anhydrous potassium carbonate and 335.6 g of 2,3-difluoropyridine in 4500 ml of dimethylformamide. After the reaction mixture has been stirred for 18 hours at room temperature, it is poured into a mixture of 8000 ml of ice-water and 4000 ml of ethyl acetate. The organic phase is subsequently separated off and washed with ice-water and then with ethyl acetate. The combined organic phases are dried with sodium sulfate and subsequently concentrated. Purification by column chromatography over silica gel with ethyl acetate/n-hexane (1:9) gives 362.9 g of 2-isopropylthio-3-fluoropyridine in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si](C(C)(C)C)(C)C)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To an ice cold solution of [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester (1.15 g, 3.45 mmol) in THF (11.5 ml) was added a 1 M solution of tetrabutylammonium fluoride in THF (3.45 ml, 3.45 mmol) within 15 min. The reaction mixture was stirred for 1 h at ambient temperature, poured onto 1 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined organic layers were washed with brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 590 mg (2.7 mmol, 78%) of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH2:25][CH2:26][CH3:27])=[CH:23][CH:24]=1)#N>C(O)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[C:2]([NH:1][C:32]2[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[N:21][C:20]=3[N:28]=[CH:29][N:30]=2)[CH:7]=1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(O)c3)ncnc2n1
Temperature: 130 °C

Procedure:
3-(2-amino-4-methyl-phenylsulfanyl)-phenol (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature a solid in the acetic acid solvent appeared which was collected by filtration to provide the title compound as an acetic acid salt (78 mg, 68%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J=7.3 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.40 (s, 3H), 2.88 (t, J=7.6 Hz, 2H), 6.57 (m, 3H), 7.00 (t, J=7.7 Hz, 1H), 7.13 (m, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 8.50 (s, 1H), 8.70 (d, J=8.5 Hz, 1H); MS (ESI)+ m/z 403 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][S:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH2:20](N(CC)CC)[CH3:21].ICC>O>[C:1]([NH:4][C@@H:5]([CH2:9][S:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:20][CH3:21])=[O:7])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)NC(CSC(=O)c1ccc(C)cc1)C(=O)O
Solvent: O
Solvent: CCI
Product: CCOC(=O)[C@H](CSC(=O)c1ccc(C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 2-acetylamino-3-(4-methyl-benzoylsulfanyl)-propionic acid (1.1 g, 3.91 mmol) and triethylamine (0.68 mL, 4.89 mmol) N,N-dimethylformamide (5 mL) was added iodoethane (0.39 mL, 4.89 mmol) and the resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was added slowly to water (50 mL) with rapid stirring. After stirring for 2 hours, the resulting slurry was filtered and the solid was rinsed with water and dried under vacuum to give the product as a white solid (780 mg, 60%). 1H NMR (300 MHz, DMSO) δ=8.47 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.80-7.78 (m, 1H), 7.35 (d, J=7.6 Hz, 2H), 4.46 (dt, J=5.3, 8.1 Hz, 1H), 4.09 (q, J=6.8 Hz, 2H), 3.50 (dd, J=5.4, 13.6 Hz, 1H), 3.24 (dd, J=8.2, 13.8 Hz, 1H), 2.37 (s, 3H), 1.83 (s, 3H), 1.16 (t, J=7.0 Hz, 3H). MS (ESI) m/z 310 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)C.Br[CH2:15][CH2:16]Br>>[Br:12][C:8]1[N:7]=[C:6]([C:5]2([C:4]([OH:3])=[O:13])[CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1cccc(Br)n1
Product: O=C(O)C1(c2cccc(Br)n2)CC1
Yield: 57 %

Procedure:
The title compound was prepared from (6-bromo-pyridin-2-yl)-acetic acid ethyl ester and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4; under these conditions the ester group was hydrolyzed. Yield: 57% of theory; LC (method 3): tR=2.60 min; Mass spectrum (ESI+): m/z=242/244 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@H:3]([OH:6])[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1.ClCCl>[CH3:10][S:11]([O:5][CH2:4][C@@H:3]([OH:6])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)[C@H](O)CO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(C)(=O)=O)[C@H](O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
To a 0° C. solution of 25.3 g (189 mmol) of (2S)-3,3-dimethyl-1,2,4-butanetriol in 170 mL of pyridine was added dropwise 29.1 mL (378 mmol) of methanesulfonyl chloride. The reaction mixture was allowed to warm slowly to room temperature, and was stirred for 18 h. It was then diluted with dichloromethane. To the resulting solution was added 200 mL of 1 N hydrochloric acid, followed by enough concentrated hydrochloric acid to acidify the aqueous phase (pH=2). The mixture was extracted with dichloromethane, and the combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with acetone:dichloromethane (1:9) to afford 21.75 g (52%) of (2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butyl methanesulfonate. 1H-NMR (300 MHz, DMSO-d6): δ 5.48 (d, J=6 Hz, 1H), 4.30 (dd, J=3 Hz, J=10 Hz, 1H), 4.05–3.91 (m, 3H), 3.16 (d, J=4 Hz, 6H), 0.90 (d, J=13 Hz, 6H).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:40][C@H:41]([C:51]1[NH:52][C:53]([I:56])=[CH:54][N:55]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][CH3:50])=[O:48]>CN(C=O)C>[I:56][C:53]1[NH:52][C:51]([C@@H:41]([NH:40][C:6]([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[O:8])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][CH3:50])=[O:48])=[N:55][CH:54]=1
Reactant: CNC(=O)CCCCC[C@H](N)c1ncc(I)[nH]1
Reactant: O=C(O)c1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(I)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of thiazole-5-carboxylic acid (1.5 eq.) in DMF (1 M) was treated with EDC.HCl (1.5 eq.), HOBt (1.5 eq.) and DIPEA (1.5 eq.), Reaction mixture was stirred at room temperature for 10 min and then added to a solution of D7 in DMF (0.33 M). The reaction mixture was stirred at room temperature for 1 h and subsequently partitioned between DCM and sat. aq. NaHCO3. The organic phase was separated and the aqueous phase extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude that was purified by flash chromatography (Biotage; 25M; DCM/MeOH) to afford the title compound as a white powder. 1H-NMR (400 MHz, 300K, DMSO-d6) δ 12.25 (br s, 1H), 9.23 (s, 1H), 9.02 (d, 1H, J 8.0 Hz), 8.58 (s, 1H), 7.65 (br s, 1H), 7.23 (s, 1H), 5.05 (m, 1H), 2.55 (d, 3H, J 5.2 Hz), 2.02 (t, 2H, J 7.6 Hz), 1.97 (m, 1H), 1.82 (m, 1H), 1.47 (m, 2H), 1.25 (m, 4H); MS (ES+) C15H20IN5O2S: 462 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH:5]([OH:15])[C:6](=[N:13][OH:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([NH:23][C:24]([O:14][N:13]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([OH:15])[CH2:4][CH2:3][CH:2]([CH3:16])[CH3:1])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CCC(O)C(=NO)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)CCC(O)C(=NOC(=O)Nc1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
2.2 g (0.01 Mol) of 5-methyl-2-hydroxy-caprophenone-oxime are dissolved in 25 ml of toluene and may be slightly heated in this process. Then 1.2 g (0.01 Mol) of phenylisocyanate are added, with the mixture being swirled. The mixture is allowed to stay for one hour, before the solvent is evaporated under vacuum conditions causing crystallisation of residue. Colourless crystals, between 117° C. and 120° C. in flash point, are obtained by recrystallisation from ethanol or ethanol/water.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([I:17])[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(Oc2nn3ccnc3s2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2-(4-Fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazole (0.6 g, 2.55 mmol) was dissolved in N,N-dimethylformamide (10 mL) and N-iodosuccinimide (0.63 g, 2.81 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight in the absence of light. The yellow suspension was filtered and rinsed with diethylether (2×2 mL) to give 2-(4-fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole as a white solid (0.65 g, 71%). The filtrate was evaporated and the residue was triturated with diethylether (6 mL) and filtered. This solid was purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0:10 to 1:9) to give 2-(4-fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole as a white solid (0.15 g, 16% yield).