Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:12](O)[CH3:13]>>[NH2:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCO
Reactant: NC1(C(=O)O)CCCCC1
Agent: Cl
Product: CCOC(=O)C1(N)CCCCC1
Reaction time: 72 h

Procedure:
Ethanol (4 l) was saturated at 0°-5° C. over 4 hours with hydrogen chloride. 1-Aminocyclohexanecarboxylic acid (600 g) was added in one portion and the mixture was stirred and heated under reflux for 8 hours, then allowed to stand at ambient temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in ice-water (1 l) and basified to pH 8-9 at 0°-5° C. by the addition of 2M aqueous sodium hydroxide solution. The product was extracted into dichloromethane (4×300 ml) and the extracts were combined and dried over sodium sulphate. The aqueous residues were basified to pH 10 by the addition of more 2M aqueous sodium hydroxide solution and further product was extracted into dichloromethane (4×200 ml). The extracts were combined and dried over sodium sulphate. The dried dichloromethane extracts were combined and the solvent was removed in vacuo to leave ethyl 1-aminocyclohexanecarboxylate as a pale yellow oil. Yield 669 g.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH3:16])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:17]>>[BrH:17].[CH2:15]([NH:14][CH:12]([CH3:13])[CH2:11][C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)[CH3:16]
Reactant: CCNC(C)Cc1ccc(OC)c(OC)c1
Agent: Br
Product: CCNC(C)Cc1ccc(O)c(O)c1

Procedure:
A solution of 1.1 g (4.92 mmol) of 2A in 10 mL of 48% HBr was heated to reflux under argon atmosphere for 3.5 hours and then concentrated to dryness under reduced pressure. To this was added 50 mL of dichloromethane and concentrated to dryness under reduced pressure to give crude 2B as a dark brown powder (M+Na, 318).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2SC=CN=2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:37]1[C:38]2[CH:39]=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=[CH:42][C:43]=2C(C)(C)C[CH:46]=1)(=O)=O>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:9][C:10]=2[C:5]([C:25]2[CH:42]=[CH:43][C:38]([CH3:39])=[CH:37][CH:46]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 200.0 mg (0.42 mmol) of ethyl 4-[(5-triflouromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 113.8 mg (0.835 mmol) of zinc chloride and 4-methylphenyllithium (prepared by adding 40.4 mg (0.42 ml, 0.63 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 108.0 mg (0.63 mmol) of 4-bromotoluene in 1.0 ml of THF).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28](OB(O)O)=[CH:27][C:26]=1[CH3:36])[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][C:26]=1[CH3:36])[CH3:20]
Reactant: CCOCCOc1c(C)cc(OB(O)O)cc1C
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCOc1c(C)cc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(2-ethoxyethoxy)-3,5-dimethylphenylboric acid (0.71 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.39 g) as a light yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[CH3:20][O:21][CH2:22]Br>C1COCC1>[CH3:20][O:21][CH2:22][CH:15]1[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]1
Reactant: O=C1CCOCC1
Reactant: COCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCC1COCCC1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
To a solution of diisopropylamine (6.1 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1.6 M solution of n-butyllithium in hexanes (37 mL, 60 mmol). The resulting solution was cooled to −78° C. To it was added tetrahydro-4H-pyran-4-one (5 g, 50 mmol) followed by phosphorous hexamethyltriamide (10 mL, 55 mmol). After 10 min, a solution of bromomethyl methyl ether (25 g, 200 mmol) in THF (50 mL) was added. Stirring was continued at 0° C. for 1 h and at room temperature overnight. The reaction was quenched by addition of a saturated solution of ammonium chloride in water. The resulting solution was extracted with ether three times. The combined extracts were dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 20% ether/petroleum ether afforded the desired product (0.9 g oil). 1H NMR (CDCl3) δ 4.2 (2H, m), 4.1 (3H, s), 3.6-3.4 (4H, m), 2.4-2.3 (3H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH:5]([CH3:7])[CH3:6].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:6][CH:5]([C:4]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][CH:3]=1)[CH3:7]
Reactant: CC(C)C(=O)CN
Reactant: CCOC(=O)C(=N)SC
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)c1ncc(C(C)C)[nH]1
Yield: 57 %

Procedure:
The same operation as in Example (lb) was performed using 1-amino-3-methylbutan-2-one hydrochloride obtained in Example (35c) (about 17.6 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 22 mmol), to obtain 1.83 g of the title compound as a yellow solid (57%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].[CH2:7]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][C:15](=[O:18])[CH2:16][NH:17][C:1](=[O:5])[C:2]([CH3:4])=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Product: CC(=O)C(=O)NCC(=O)OCc1ccccc1

Procedure:
More preferably the thionyl chloride or oxalyl chloride is added to a mechanically stirred suspension of sodium pyruvate in dichloromethane whereby a gas is evolved and pyruvyl chloride is yielded. The pyruvyl chloride is cooled during the dropwise addition of glycine benzyl ester solution to yield pyruvyl-glycine benzyl ester following the warming to room temperature, the addition of water, separation, washing with diluted hydrochloric acid and brine, drying with magnesium sulfate, evaporation of the dichloromethane, precipitation, filtering and drying again. The pyruvyl-glycine benzyl ester is then charged in a hydrogen pressure vessel with ethyl acetate and 4% to 20% palladium on carbon, with the hydrogen pressure being approximately 40-150 psi, such that hydrogen is digested whereby following warming, filtering, concentration, precipitation, filtering and drying there is yielded pyruvyl-glycine.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1.[OH:24]O>C(O)(=O)C>[O:24]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[CH:10]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: OO
Reactant: Clc1ccc2cc(N3CCNCC3)nc(N3CCSCC3)c2c1
Solvent: CC(=O)O
Product: O=S1CCN(c2nc(N3CCNCC3)cc3ccc(Cl)cc23)CC1
Yield: 13 %

Procedure:
1-(1-Oxido-thiomorpholino)-3-piperazino-7-chloro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-7-chloro-isoquinoline by oxidation with hydrogen peroxide in glacial acetic acid. M.p. 209°-211°C; yield: 13% of theory.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.Cl>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[CH3:27])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 56.8 %

Procedure:
To a solution of the compound (641 mg, 1.70 mmol) obtained in Example 178b in tetrahydrofuran (10 mL) was slowly added dropwise a solution (1.85 mL, 2.041 mmol) of 1.1M lithium hexamethyldisilazide in tetrahydrofuran under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min, iodomethane (0.16 mL, 2.55 mmol) was added dropwise at the same temperature, and the mixture was further stirred for 5 min. The reaction mixture was acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (378 mg, 57%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:35]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:35])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-Hydroxy-3′-tert-butyl-5′-bromomethylphenyl)-5-chlorobenzotriazole was prepared from the bromination of 2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 7.042 g (0.0223 mole) 2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mole) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-Hydroxy-3′-tert-butyl-5′-bromomethylphenyl)-5-chlorobenzotriazole was 7.2 g (81%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[OH:45][CH2:44][CH2:46][NH:47][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([NH:26][CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[N:30]([O:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCO
Product: CC1(C)CC(Nc2nc(NCCO)nc(NC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,5-triazine with ethanolamine according to the procedure of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=[CH:16][C:15](=[N+](C)C)[CH:14]=[CH:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O1CCN(C2C3N(C=C(/C=C/C4C=CC5C(=CC=CC=5)N=4)N=3)C(C3C=CC(N4CCC(C(O)=O)CC4)=CC=3)=CN=2)CC1.FC(F)(F)C(O)=O.N1CCC([C:83]2[N:88]3[CH:89]=[C:90]([CH2:92][O:93][C:94]4[CH:103]=[CH:102][C:101]5[C:96](=[CH:97][CH:98]=[CH:99][CH:100]=5)[N:95]=4)[N:91]=[C:87]3[C:86]([N:104]3[CH2:109][CH2:108][O:107][CH2:106][CH2:105]3)=[N:85][CH:84]=2)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:107]1[CH2:108][CH2:109][N:104]([C:86]2[C:87]3[N:88]([CH:89]=[C:90]([CH2:92][O:93][C:94]4[CH:103]=[CH:102][C:101]5[C:96](=[CH:97][CH:98]=[CH:99][CH:100]=5)[N:95]=4)[N:91]=3)[C:83]([CH:15]3[CH2:14][CH2:13][N:12]([S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:10])=[O:11])[CH2:17][CH2:16]3)=[CH:84][N:85]=2)[CH2:105][CH2:106]1
Reactant: c1ccc2nc(OCc3cn4c(C5CCNCC5)cnc(N5CCOCC5)c4n3)ccc2c1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Agent: O=C(O)C1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCC(c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(tert-Butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (38 mg, 0.12 mmol, prepared according to the Org. Lett., 2001, 3 (14), pp 2241-2243) was added to a solution of compound 111 (100 mg, 0.12 mmol, Example 26) and DIEA (54 μL, 0.38 mmol) in DCM (1 mL). The resulting mixture was stirred at rt for 3 h and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtAOc/hexane) to obtain compound 28a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C30H37N7O6S: 624.2 (M+H). Found 624.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:6]=1.NNC(N)=S.ClC1C=CC=CC=1C(Cl)=O.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O>CN(C)C=O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]2=[N:1][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][N:6]2[N:5]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nnc(-c2ccccc2Cl)s1
Agent: NNC(N)=S
Agent: O=C(Cl)c1ccccc1Cl
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nn2cc(-c3ccccc3)nc2s1

Procedure:
10.5 g (0.05 mol) of 2-amino-5-(2-chlorophenyl)-1,3,4-thiadiazole, melting point 189,5° C. (prepared by reacting thiosemicarbazide with 2-chlorobenzoyl chloride) together with 10 g (0.05 mol) of bromoacetophenone are warmed to 120° C. in 100 ml of dimethylformamide for 3 hours and the mixture is then cooled and concentrated in a rotary evaporator. After digesting the residue with water, the digestion mixture is filtered and the residue is recrystallised from alcohol. A second fraction is obtained by concentrating the alcoholic mother liquor. A total yield of 12.5 g, corresponding to 80% of theory, of colourless crystals of melting point 126° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]#[CH:11].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1/[CH:10]=[CH:11]\[CH:17]([S:18][CH:12](/[CH:11]=[CH:10]\[C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[F:9])[C:13]1[CH:20]=[CH:19][C:16]([CH3:17])=[CH:15][CH:14]=1)[C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: C#Cc1c(F)cc(F)cc1F
Reactant: Cc1ccc(CS)cc1
Agent: [Na]
Product: Cc1ccc(C(/C=C\c2c(F)cc(F)cc2F)SC(/C=C\c2c(F)cc(F)cc2F)c2ccc(C)cc2)cc1

Procedure:
A solution of 2,4,6-trifluorophenylacetylene (0.02 mol), 4-methylbenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to General Procedure 2 to form (Z)-2,4,6-trifluorostyryl-4-methylbenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to General Procedure 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15]C(=O)OC(C)(C)C)[CH:5]=[C:6]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:7]=1.[OH-].[Na+]>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[N:11][CH:10]=2)[CH:7]=1)[NH2:15]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Oc2cncnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cc(Oc2cncnc2)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Compound 8 (48 mg, 0.15 mmol, 1.0 eq) was dissolved in 4N HCl in dioxane (0.75 mL) and stirred at room temperature until determination of completion by TLC. The reaction was neutralized with 1N NaOH and extracted with EtOAc (3×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give 29 mg (88%) of an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.67 (s, 2H), 6.55 (s, 1H), 6.42 (s, 1H), 6.30 (s, 1H); ES-MS [M+1]+: 222.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(Cl)cc1Cl)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]([OH:38])[CH:8]=1.[N:39]1[C:46]([Cl:47])=[N:45][C:43](Cl)=[N:42][C:40]=1[Cl:41]>C1COCC1>[CH2:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:43]2[N:45]=[C:46]([Cl:47])[N:39]=[C:40]([Cl:41])[N:42]=2)=[CH:8][C:9]=1[OH:38])=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc(NC(=O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(O)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
NaHCO3 (300 mg, 3.58 mmol) was added to a solution of compound 40 (263.8 mg, 598 μmol) in THF (5 mL). Cyanuric chloride (110 mg, 598 μmol) in THF (3 mL) was added to the reaction mixture in an ice water bath. The reaction mixture was stirred from 0° C. to room temperature for 30 minutes. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was directly used in the next step. LC-MS (ESI): m/e=588.2 [M+H]+
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH:5]([CH:8]([CH:36]([CH3:38])[CH3:37])[CH:9]1[O:35][CH:10]1[C:11]1[N:15]=[CH:14][N:13]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1)([CH3:7])[CH3:6].[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+]>CO.O>[PH:1](=[O:2])([OH:4])[OH:3].[CH:5]([CH:8]([CH:36]([CH3:38])[CH3:37])[CH:9]([OH:35])[CH:10]([N:39]=[N+:40]=[N-:41])[C:11]1[N:15]=[CH:14][N:13]([C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:12]=1)([CH3:7])[CH3:6]
Reactant: CC(C)C(C(C)C)C1OC1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=[PH](O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)C(C(C)C)C(O)C(N=[N+]=[N-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 70.7 %

Procedure:
A mixture of diisopropyl (2RS,3SR)-2,3-epoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (6.83 g prepared as described in Example 51), sodium azide (4.18 g), ammonium chloride (1.51 g) and methanol-water (8:1, 125 ml) was heated under reflux for six hours, then concentrated under reduced pressure. The residue was filtered through silica in chloroform, then chromatographed on silica, using ethyl acetate-ethanol (20:1) as eluant, to give diisopropyl (2RS,3RS)-3-azido-2-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (5.22 g, m.p. 137°-139° C., after trituration with ether). IR (nujol): 3304, 2104 cm-1. NMR (CDCl3 : δ1.3(12H,m), 1.9-2.25(2H,m), 4.17(1H,d), 4.45(1H,m), 4.68(2H,m), 4.78(1H,d), 7.1-7.4(15H,m), 7.98(1H,s). 13C NMR confirmed the regiochemistry.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH2:25]O)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:27])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[NH:42]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]1>ClCCl.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH2:25][N:42]5[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:27])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)c1cnc2ccc(Br)cn12
Reactant: N#CC1CNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(CN3CC(C#N)C3)n2)cc1NC(=O)c1cnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142) (200 mg, 0.47 mmol) and DIEA (0.25 mL, 1.41 mmol) in dichloromethane (5 mL) was added MsCl (108.1 mg, 0.94 mmol). The mixture was stirred at room temperature for 10 minutes and then diluted with dichloromethane (10 mL) and washed with water. The organic layers were dried over Na2SO4, filtered and concentrated to give a residue which was dissolved in DMF (2 mL). Then azetidine-3-carbonitrile (116 mg, 1.41 mmol) was added and the reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated to give the crude product which was purified by silica chromatography to yield 6-bromo-N-(5-(5-((3-cyanoazetidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (143). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.62 (dd, J=0.8, 2.0 Hz, 1H), 8.60 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.68 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.06 (s, 2H), 3.67 (m, 2H), 3.51-3.60 (m, 3H), 2.37 (s, 3H). MS m/z 492.0, 494.0 (M+1)+.