Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:16]2[S:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[N:21]1([C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([C:8]3[C:16]4[S:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc2cccc(Br)c2s1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(-c3ccc(N4CCOCC4)cc3)c2s1
Temperature: 80 °C

Procedure:
3.42 ml of 2 M sodium carbonate solution and 83.5 mg (0.11 mmol) of PdCl2(dppf) are added to a solution of 619.1 mg (2.28 mmol) of methyl 7-bromo-1-benzothiophene-2-carboxylate (Example 6A) and 520 mg (2.51 mmol) of 4-(4-morpholinyl)phenylboronic acid in 10 ml DMF. The mixture is heated at 80° C. for 16 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC. The concentrated product is dried under high vacuum. 146.7 mg (16.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[O:20]=[C:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(CCCc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 14 h
Yield: 72 %

Procedure:
(Method J15A) A solution of 4-phenyl-butyric acid (1/95) (6.570 g, 40 mmol) and N-hydroxysuccinimide (4.830 g, 42 mmol) in acetonitrile (100 ml) was treated with N,N′-dicyclohexylcarbodiimide (8.650 g, 42 mmol) at 0° C. The resulting suspension was allowed to stand for 14 hours at 4° C., the precipitate was filtered off and washed with ethyl acetate (3×30 ml). The solvents were removed in vacuum and the residue was crystallized from isopropanol (50 ml) to give the activated ester 15/95 (7.520 g, 72%) as colorless crystals. 1H NMR (DMSO-d6, HMDSO) δ: 1.78-2.20 (2H, m); 2.53-3.00 (8H, m); 6.84-7.67 (5H, m); 10.80 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[S:28])=[C:14]([C:17]3[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[N:21]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[OH-].[Na+:33]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([O-:29])=[S:28])=[C:14]([C:17]3[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[N:21]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[Na+:33].[Na+:33].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([O-:29])=[S:28])=[C:14]([C:17]3[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[N:21]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(O)CCc1csc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4cccs4)[C@H]3SC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1csc(C2=C(C([O-])=S)N3C(=O)[C@@H](NC(=O)Cc4cccs4)[C@H]3SC2)n1

Procedure:
To a solution of 7β-[2-(2-thienyl)acetamido]-3-[4-(2-carboxyethyl)thiazol-2-yl]thio-3-cephem-4-carboxylic acid (100 mg) in water (50 ml) was added 0.1 mol/l-sodium hydroxide solution (3.9 ml). The solution was lyophilized to give disodium 7β-[2-(2-thienyl)acetamido]-3-[4-(2-carboxyethyl)thiazol-2-yl]thio-3-cephem-4-carboxylate (108.3 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cccc(C#N)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(CNC(=O)OC(C)(C)C)n1
Reaction time: 24 h

Procedure:
To a solution of 6-methyl-2-cyanopyridine (5 g) and BOC2O in EtOAc was added 10% Pd/C. The reaction mixture was stirred under a balloon of H2 for 24 h, and then filtered through diatomaceous earth and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a colorless oil. 1H NMR (d6-DMSO, 400 MHz) δ 7.6 (t, 1H), 7.4 (br s, NH), 7.2 (d, 1H), 7.1 (d, 1H), 4.2 (d, 2H), 2.4 (s, 3H), 1.4 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][NH2:19].C(N(CC)CC)C>C1COCC1.O>[Cl:9][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([NH:19][CH2:18][C:14]2[S:13][CH:17]=[CH:16][N:15]=2)[C:7]=1[F:8]
Reactant: CSc1nc(Cl)c(F)c(Cl)n1
Reactant: NCc1nccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(F)c(NCc2nccs2)n1
Reaction time: 96 h
Yield: 117 %

Procedure:
4,6-Dichloro-5-fluoro-2-(methylthio)pyrimidine (see Intermediate E) (0.422 g, 1.991 mmol), commercially available (1,3-thiazol-2-ylmethyl)amine hydrochloride (0.300 g, 1.992 mmol) and triethylamine (0.61 mL, 4.3765 mmol) were dissolved in THF (3 mL) and left to stir for 4 days. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated to produce 6-chloro-5-fluoro-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a yellow-orange solid (0.6773 g). LCMS: (M+H)+=291.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: C[C@H](N)c1ccc(Cl)cc1
Product: COc1cccc2c(N[C@@H](C)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 41. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and (S)-1-(4-chloro-phenyl)ethylamine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:25])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
1.28 g of 4-(quinolin-2-ylmethyloxy)benzoic acid, in 4.6 ml of oxalyl chloride and 3 drops of dimethylformamide are combined in 50 ml of methylene chloride. The mixture is refluxed for 30 minutes and then concentrated in vacuo to give 4-(quinolin-2-ylmethyloxy)benzoyl chloride
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([F:26])=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C(O)(=O)C>C(O)C>[NH2:17][C:10]1[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:7]([F:26])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(F)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(F)nc(-c2ccccc2)c(N)c1C(=O)OCC

Procedure:
In 5 ml of ethanol was dissolved 160 mg of 3,4-diethoxycarbonyl-2-fluoro-5-nitro-6-phenylpyridine, and 120 mg (5 eq.) of reduced iron was added to the solution, followed by addition of 0.5 ml (20 eq.) of acetic acid. After the mixture was refluxed for 30 minutes, the solvent was distilled off. The residue was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. After the precipitate was removed by filtration, the obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Then, the solvent was distilled off.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[CH:23][C:24]([C:32]#[C:33][Si](C)(C)C)=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:26]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:32]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:39])[F:38])=[CH:26][C:25]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29])#[CH:33]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(C(F)(F)F)cc1CC(=O)OC

Procedure:
TBAF (1.0 M in THF; 4.29 mL, 4.29 mmol) was added to a solution of methyl 2-(5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetate (A104) (0.900 g, 2.86 mmol) in THF (25 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 minutes before the addition of EtOAc (50 mL) and 10% aqueous NaHCO3 (50 mL). The layers were separated and the organic phase dried (MgSO4) then the solvent was evaporated under reduced pressure. The residue was adsorbed onto silica gel and purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A105 as a light brown coloured liquid (0.498 g, 72%); 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 3.89 (s, 2H), 3.71 (s, 3H), 3.40 (s, 1H). LCMS-A: rt 6.094 min; m/z 243.1 [M+H]+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:37])[C:26]([NH:28][N:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH3:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O.NN.O>[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:37])[C:26]([N:28]([CH3:1])[N:29]=[CH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH3:15]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: NN
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a 50 mL volume three-necked flask, 7.6 mg of hydrazine hydrate, 2.3 ml of toluene, 629 mg of potassium carbonate and 574 mg of dimethyl sulfate were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 5° C. and 1.6 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6) solved in 2.3 g of toluene was added thereto. The reaction mixture was stirred at 5° C. for 31.5 hours. 5 mL of water was added and the resultant was neutralized to pH 7 with 20 wt % of sulfuric acid. The organic layer was removed and the aqueous layer was extracted with toluene two times. The organic layers were combined and concentrated under reduced pressure to give 1.22 g of a mixture (22:1 (GC area %)) of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5) and methyl 2-(2,6-diethyl-4-methylphenyl)-2-oxo-N-(phenylmethylidene)ethanehydrazonate (x-1).
Reaction SMILES: N1([NH:7][C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])CCOCC1.N[C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH:50]=[C:49]([OH:52])[CH:48]=[CH:47]2>>[OH:52][C:49]1[CH:50]=[C:51]2[C:46]([CH:45]=[CH:44][CH:43]=[C:42]2[NH:7][C:8]([C:10]2[CH:40]=[CH:39][C:13]3[N:14]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)[C:15]([C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[C:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:21]=[N:20]5)=[N:16][C:12]=3[CH:11]=2)=[O:9])=[CH:47][CH:48]=1
Reactant: O=C(NN1CCOCC1)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: Nc1cccc2ccc(O)cc12
Product: O=C(Nc1cccc2ccc(O)cc12)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 20 %

Procedure:
The general procedure described for Compound 574 was used with 8-amino-naphthalen-2-ol (15.9 mg), producing 5 mg of the title compound (20% yield). MS: 590.25 (M+H+) HPLC Procedure A, retention time=15.31 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.Cl>[CH3:30][O:29][N:28]([CH3:27])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (15.8 g, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 g, 114 mmol), DIEA (41 mL, 228 mmol), and BOP (69 g, 156 mmol), were suspended in 80 mL DMF and stirred at room temperature over night. The reaction mixture was diluted with 1 (M) HCl (100 mL), extracted with EtOAc, and the organic portions were washed with 1 (M) aqueous HCl, NaHCO3 and brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide: MS m/z: (M+H) 458.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]1([CH2:30][C:31]([O:33][CH3:34])=[O:32])([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl[C:36]([O:38][CH3:39])=[O:37].Cl>O1CCCC1.O>[CH3:34][O:33][C:31]([CH2:30][C:19]1([CH:25]([C:36]([O:38][CH3:39])=[O:37])[C:26]([O:28][CH3:29])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:32]
Reactant: COC(=O)CC1(CC(=O)OC)CCCCC1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)CC1(C(C(=O)OC)C(=O)OC)CCCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (1.01 mL, 7.2 mmol) in tetrahydrofuran (8 mL) under cooling to −78° C. were added a solution of 1.5M n-butyl lithium/hexane solution (4.4 mL). After stirring the solution at −78° C. for 1 hour, a solution of dimethyl 1,1-cyclohexanediacetate (685 mg) in tetrahydrofuran (7 mL) was added thereto. The solution was stirred at −78° C. for 1 hour. Methyl chloroformate (0.93 mL) was then added to the solution, and it was stirred at −78° C. for 1 hour. Water and 3N hydrochloric acid were added to the solution, and it was extracted with ethyl acetate. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=85:15) to give the title compound (490 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[S:21])[C@H:12]([CH2:13]O)[C@@H:11]([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:9][O:10][C@H:11]([C:15]([F:16])([F:17])[F:18])[C@H:12]1[CH2:13][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:19]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
N-(((3 S,4R,5 S)-3-(2-Fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (31.1 g) was dissolved in pyridine (150 mL), and the mixture cooled to −20° C. Trifluoromethanesulfonic anhydride (14.0 mL) was added dropwise over 30 min and the reaction was allowed to warm to 0° C. After stirring for 2 h, the reaction was quenched by the addition of ammonium chloride (sat., aq., 400 mL) and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (2% to 30% EtOAc/hex) to obtain the title compound (18.50 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (dd, J=13.9, 3.5 Hz, 1 H), 3.25 (d, J=13.6 Hz, 1 H), 3.61 (br. s., 1 H), 4.00-4.10 (m, 1 H), 4.66 (d, J=8.8 Hz, 1 H), 4.78-4.87 (m, 1 H), 7.12-7.60 (m, 6 H), 7.68-7.73 (m, 1 H), 7.99-8.16 (br. s., 2 H), 8.62-8.66 (m, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([NH:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CC(C)(CO)Nc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nccc(NC(C)(C)CO)n2)ccc1-n1cnc(C)c1
Yield: 62 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-(2-chloro-pyrimidin-4-ylamino)-2-methyl-propan-1-ol, using potassium carbonate as a base. The title compound was isolated as a slightly orange solid in a yield of 62%. MS ISP (m/e): 369.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.91 (d, 1H), 7.62 (d, 1H), 7.43 (d, 1H), 7.20-7.10 (m, 2H), 6.87 (s, 1H), 6.79 (s, 1H), 5.88 (d, 1H), 4.74 (s, 1H), 3.84 (s, 3H), 3.69 (s, 2H), 2.29 (s, 3H), 1.42 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.Cl[Sn:13]([CH3:16])([CH3:15])[CH3:14]>C(OCC)C>[CH3:1][C:2]1[S:3][C:4]([Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][N:6]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ncc([Sn](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2-methylthiazole (1.0 g, 10 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of nitrogen was added n-butyllithium (2.5M solution in hexanes, 5.2 mL, 13 mmol) dropwise over 10 minutes. The reaction mixture was stirred for 1 h and then allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was then cooled to −78° C. and a solution of chlorotrimethylstannane (1.8 g, 9.0 mmol) in anhydrous diethyl ether (10 mL) was added dropwise over 10 minutes. The reaction mixture was stirred for 30 minutes and then allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a yellow oil which was used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:9])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1([N:9]2[CH2:22][CH2:21][N:13]([C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])[CH2:12][CH2:11]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: CCOC(=O)C1(N)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-aminocyclopropane-1-carboxylic acid ethyl ester (440 mg, 2.6 mmol) was suspended in diisopropylethylamine (2 ml). Tert-Butyl bis(2-chloroethyl)carbamate (610 mg, 2.5 mmol, prepared according to Evans et al. J. Med. Chem. 1992, 35, 3919) was added at room temperature. The suspension was stirred at room temperature for 10 minutes before being heated to 100° C. for 18 h. The resulting biphasic mixture was cooled to room temperature. Brine was added and the mixture was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 20% EtOAc/hexanes) to give tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate as a colorless oil (60 mg, 8% 2 steps). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.91 (m, 2 H), 1.22 (t, J=7.2 Hz, 3 H), 1.25 (m, 2H), 1.43 (s, 9 H), 2.87 (bs, 4 H), 3.27 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H); 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.0, 28.4, 45.7, 49.0, 60.2, 79.4, 154.8, 174.0; ESI-MS: m/z 299.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][C:4]([NH:6][NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([N:18]([CH2:20][CH:21]2[CH2:23][CH:22]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:19])[CH:11]=[CH:10][N:9]=1)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:22]2[CH2:23][CH:21]2[CH2:20][N:18]([CH3:19])[C:12]2[CH:11]=[CH:10][N:9]3[C:4]([CH2:3][C:2]([F:32])([F:31])[F:1])=[N:6][N:7]=[C:8]3[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:25][CH:26]=1
Reactant: CN(CC1CC1c1ccc(F)cc1)c1ccnc(NNC(=O)CC(F)(F)F)c1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC1CC1c1ccc(F)cc1)c1ccn2c(CC(F)(F)F)nnc2c1C(F)(F)F
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
A mixture of 3,3,3-trifluoro-N′-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide (0.5 g, 1.077 mmol) and Burgess reagent (0.513 g, 2.153 mmol) in THF (10 mL) was heated to reflux stirring for 90 min. The reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL), dried with brine (20 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-100% EtOAc/hexane as the eluent to give N-((2-(4-fluorophenyl)cyclopropyl)methyl)-N-methyl-3-(2,2,2-trifluoroethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine as a yellow solid (0.14 g, 26.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (d, J=7.8 Hz, 1H), 7.03-6.91 (m, 4H), 6.83 (d, J=7.8 Hz, 1H), 4.02 (q, J=9.8 Hz, 2H), 3.48 (dd, J=14.1, 6.0 Hz, 1H), 3.33 (dd, J=14.1, 7.3 Hz, 1H), 3.16 (s, 3H), 1.77 (dd, J=9.0, 4.8 Hz, 1H), 1.34-1.23 (m, 1H), 1.05 (dt, J=8.5, 5.4 Hz, 1H), 0.91 (dt, J=8.8, 5.5 Hz, 1H). LCMS: M+1=447.12.