Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]C1C=CC(N)=C([N+]([O-])=O)C=1)[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24]2[CH:25]=[CH:26][C:27](C(F)(F)F)=[CH:28][C:23]=2[N:22]=[C:21]1/[CH:33]=[CH:34]/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>C(OCC)(=O)C>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[O:3]([C:27]1[CH:26]=[CH:25][C:24]2[N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[C:21](/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:22][C:23]=2[CH:28]=1)[CH2:1][CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-ethoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 435.05; mp: 215.5-216.0° C.; 1H-NMR (DMSO-d6) δ: 8.78-8.75 (1H. m), 8.17 (1H, td, J=7.7, 1.8 Hz), 7.85 (1H, d, J=15.8 Hz), 7.72 (1H, d, J=8.1 Hz), 7.65-7.59 (3H, m), 7.44-7.33 (4H, m), 7.24 (1H, d, J=2.6 Hz), 7.18 (1H, d, J=15.8 Hz), 6.89 (1H, dd, J=8.8, 2.2 Hz), 4.10 (2H, q, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[NH:13][CH2:12][CH2:11][N:10]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:9]12.Br[CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([N:13]1[CH2:12][CH2:11][N:10]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:9]2[CH2:8]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1cc2n(c1)CCNC2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCCCN1CCn2cc(C(=O)OCC)cc2C1
Yield: 20.9 %

Procedure:
To a solution of ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate trifluoroacetate (2.6 g, 13.4 mmol) and 1-bromobutane (3.67 g, 26.8 mmol) in acetonitrile (26 mL) was added potassium carbonate (2.45 g, 17.7 mmol). The resulting mixture was refluxed overnight. The solvent was then evaporated to give a solid residue. Purification via flash chromatography (petroleum ether:EtOAc, 10:1) afforded ethyl 2-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate Intermediate 11 (0.7 g, 21%). 1H NMR (CDCl3, 300 MHz) δ7.11 (s, 1 H), 6.18 (s, 1 H), 4.25 (m, 2 H), 3.99 (m, 2 H), 3.53 (s, 2 H), 2.82 (t, J=5.6 Hz, 2 H), 2.46 (t, J=7.4 Hz, 2 H), 1.46 (m, 2 H), 1.30 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H), 0.87 (t, J=7.3 Hz, 2 H).
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.CON(C)[C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[CH3:37]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:30]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:38])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][C:14]=1[C:19]([F:21])([F:22])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1cccnc1C
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 29 using N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide and N-methoxy-2,N-dimethyl-nicotinamide. 1H NMR: (400 MHZ, CDCl3) δ 8.61 (m, 1H), 8.26 (m, 1H), 8.20 (m, 1H), 8.17 (m, 1H), 8.04-8.01 (m, 1H), 7.67 (d, 1H), 7.50 (m, 1H), 7.18 (m, 1H), 2.41 (s, 3H). MS: (M+H)/z=490.0.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24]([CH3:26])[CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:27][C:28]1[N:36]=[CH:35][C:34]([I:1])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24]([CH3:26])[CH3:25]
Reactant: NC(=O)CCC(=O)NI
Reactant: CC(C)COc1ncccc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)COc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (25 mL) were added to 2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was refluxed for 2.5 h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[NH2:7]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](O)CN(N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
(R)-3-(N-biphenyl-4-ylmethyl-N′-t-butoxycarbonylhydrazino)-2-hydroxypropionic acid methyl ester (300 mg, 749 μmol, 1.0 eq.) was dissolved in DCM (3.0 mL). TFA (3.0 mL) was added and the mixture was stirred at room temperature until the reaction was complete (approximately 1 hour). The mixture was concentrated to yield the title compound, which was used without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH2:21].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O>[O:26]1[CH2:27][CH2:28][N:23]([CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[NH2:21])[CH2:24][CH2:25]1
Reactant: Nc1ccc(C(=O)OCCCCl)c(N)c1
Reactant: C1COCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)OCCCN2CCOCC2)c(N)c1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 35 ml of toluene, 4.6 g of (3-chloropropyl)-2,4-diaminobenzoate and 3.5 g of morpholine was refluxed for 10 hrs, cooled to room temperature, and poured into 70 ml of water with stirring. The precipitate was filtered, washed with hexane and dried. Recrystallization from toluene gave 2.6 g (3-morpholinopropyl)-2,4-diaminobenzoate, a white solid, mp 96° C.
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[C:13]3[CH:19]=[CH:20][CH:21]=[N:22][C:12]2=3)(=O)=O)=CC=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[N:22]1[C:12]2[NH:11][CH2:17][CH2:16][CH2:15][C:14](=[O:18])[C:13]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3cccnc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1CCCNc2ncccc21
Temperature: 0 °C
Yield: 78 %

Procedure:
A solution of 5.00 g of 6,7,8,9-tetrahydro-9-[(4-methylphenyl)sulfonyl]-5H-pyrido[2,3-b]azepin-5-one in 60 ml of 40% (v/v) sulfuric acid in acetic acid is heated at 60° C. for 11 hours. The mixture is chilled and poured into 350 ml of ice water (cooled in an ice bath) with thorough stirring. To the cold mixture is added solid NaOH until the pH is 8 while keeping the temperature below 30° C. The mixture is filtered and the solid washed with ethyl acetate. The organic layer of the filtrate is separated and the aqueous layer extracted with ethyl acetate. The organic layer and extracts are combined and treated with activated carbon. The mixture is filtered through MGSO4 and the solvent removed under vacuum to Give 2.0 g of yellow crystals.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10]O.S1C2C(=[N:16]C=CC=2)C=C1CN>>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10][NH2:16]
Reactant: NCc1cc2ncccc2s1
Reactant: OCc1cc2cccnc2s1
Product: NCc1cc2cccnc2s1

Procedure:
Intermediate E was prepared from thieno[2,3-b]pyridine-2-ylmethanol (E-2) following similar procedures for synthesizing intermediate C from C-4, as described above. MS (m/z): 165 (M+1)+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[OH:10][C@H:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:12]([N:14]([CH3:26])[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=1)[CH3:13].C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:55][CH:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=N2)C=1)(C)(C)C.O>O1CCCC1>[CH:56]1([CH2:55][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:15]([N:14]([C@H:12]([CH3:13])[C@H:11]([OH:10])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])=[O:25])[CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: CSc1cccc(CC(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CSc1cccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 1,1,1,3,3,3-Hexamethyldisilazane (1.81 g, 11.19 mmol) in tetrahydrofuran (15 mL) cooled to −20° C. under nitrogen was added n-butylithium (6.4 mL of a 1.6 M solution, 10.21 mmol) slowly keeping the temperature at −20° C. for 30 min. N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-acetamide (1.60 g, 4.86 mmol) in tetrahydrofuran (15 mL) was added slowly to the reaction maintaining the temperature at −20° C. After the addition was complete the reaction was warmed to 0° C. and stirred for 30 min. A solution of 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.31 g, 10.21 mmol) and iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 1.23 g, 5.84 mmol) were added to the reaction at 0° C. and stirring continued for 3 h. The reaction was poured into water (60 mL) and extracted with ethyl acetate. The ethyl acetate fractions were washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-propionamide (1.16 g, 58%) as a clear sticky solid.
Reaction SMILES: OP([O-])(O)=O.[Na+].[C:7]1([S:13]([CH2:16][C:17]2[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([OH:30])[C:20]([C:31]3[CH:35]=[CH:34][O:33][C:32]=3[CH:36]=[O:37])=[CH:19][CH:18]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:39].[Na+]>O.C(#N)C.OO>[C:7]1([S:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:31]3[CH:35]=[CH:34][O:33][C:32]=3[C:36]([OH:39])=[O:37])=[C:21]([OH:30])[C:22]=2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(=O)O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
A solution of sodium phosphate monobasic (0.039 g) in water (1 mL) was added to a solution of tert-butyl 6-(benzenesulfonylmethyl)-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (Intermediate 27, 0.105 g) in acetonitrile (2 mL) at 0° C. Hydrogen peroxide (50% wt. in water, 0.078 mL) and sodium chlorite (0.029 g) were added and the reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was cooled to 0° C. and further sodium phosphate monobasic (0.028 g) in water (0.5 mL), hydrogen peroxide (50% wt. in water, 0.038 mL) and sodium chlorite (0.052 g) were added and the mixture was warmed to room temperature and stirred for 18 hours. The mixture was poured onto sodium sulfite (10% in water) at 0° C., extracted into ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and 1% acetic acid in methanol with a gradient of O-100%. The resultant product was triturated in cyclohexane and ethyl acetate and the solid was collected by filtration and dried in vacuo to give 3-[4-(benzenesulfonylmethyl)-3-tert-butoxycarbonyl-2-hydroxy-phenyl]-furan-2-carboxylic acid (0.028 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C[Si]([N:15]=[C:16]=[N:17][Si](C)(C)C)(C)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:10][C:6]1[CH:5]=[C:4]([C:2](=[N:17][C:16]#[N:15])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=NC#N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Following the procedure of Cuccia, S. J.; Fleming, L. B.; France, D. J. Synth. Comm. 2002, 32 (19), 3011-3018: 3-Bromoacetophenone (2.0 g, 10 mmol, 1 eq), was dissolved in 20 mL DCM. A 1.0 N solution of titanium tetrachloride in DCM (20 mL, 20 mmol, 2 eq) was added dropwise over 15 min and the resulting mixture was stirred at 25° C. for 1 h. Bis-trimethylsilylcarbodiimide (5.0 mL, 22 mmol, 2.2 eq) in 5 mL of DCM was added over 15 min and the reaction was stirred for 16 h under argon. The reaction was poured onto 200 mL of an ice/water mixture and extracted with 3×200 mL of DCM. The combined organic phase was dried over MgSO4, filtered, and concentrated to give 2.3 g (100%) of (1-(3-bromophenyl)ethylidene)cyanamide (DB1, R4=Me) as a white solid: 1H NMR (CDCl3) δ 8.16 (t, J=1.8 Hz, 1H), 7.94 (dd, J=1.7, 1.1 Hz, 1H), 7.76 (dd, J=1.7, 1.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 2.82 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[C:7]([NH:10][NH2:11])(=[O:9])[CH3:8]>C1C=CC=CC=1>[C:7]([NH:10][NH:11][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:9])[CH3:8]
Reactant: CC(=O)NN
Reactant: C=CCN=C=O
Solvent: c1ccccc1
Product: C=CCNC(=O)NNC(C)=O

Procedure:
Allyl isocyanate (25 g, 0.30 mol) was added slowly to a boiling solution of acethydrazide (22.2 g, 0.30 mol) in dry benzene (300 ml). The mixture was heated for 1 hour whereupon 2 layers formed. The benzene was then evaporated off and the residue triturated with ether to yield the title compound as a white solid. (m.p. 71°-74° C.).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][NH:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:20][N:21]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: CNC1CCCC1
Product: CN(c1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12)C1CCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with N-methylcyclopentylamine to obtain 4-(N-methylcyclopentylamino)-7-nitro-5-cyano-2-trifluoromethylbenzimidazole, m.w., 353.3.
Reaction SMILES: [NH2:1]/[C:2](=[N:24]\C(=O)OC(C)(C)C)/[C:3]1[S:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:19]=[C:18]([CH:20]4[CH2:22][CH2:21]4)[NH:17][N:16]=3)[C:11]([Cl:23])=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[Cl:23][C:11]1[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22]3)[NH:17][N:16]=2)=[N:13][C:8]([C:5]2[S:4][C:3]([C:2](=[NH:1])[NH2:24])=[CH:7][CH:6]=2)=[N:9][CH:10]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CC(C)(C)OC(=O)/N=C(\N)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (Z)-tert-butyl amino(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)methylenecarbamate (Compound 328) (60 mg, 0.13 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1 h. The solvent was distilled and recrystallized with ether (2 mL) to afford get 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboximidamide (Compound 205) as TFA salt (55 mg, 72%). LC-MS (m/z)=360 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.77-0.81 (m, 2H), 0.97-1.01 (m, 2H), 1.97-2.01 (m, 1H), 6.43 (s, 1H), 7.90 (d, J=4.0 Hz, 1H), 8.01 (d, J=4.0 Hz, 1H), 8.50 (s, 1H), 9.34 (s, 2H), 9.44 (s, 2H), 9.56 (s, 1H).
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[OH-].[NH4+:19]>>[Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:19])=[O:10])=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: [OH-]
Product: NC(=O)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Yield: 99 %

Procedure:
4-(2-Bromo-tetrafluoroethoxy)benzoic acid prepared as in Example 1 (26.6 g, 0.083 mol) is transferred to a 250 mL round-bottomed flask along with 150 mL of methylene chloride. Oxalyl chloride (11.64 g, 0.92 mol) is added and the mixture is stirred under nitrogen overnight to form a turbid solution which is concentrated by rotary evaporation and distilled at 80°-90° C./0.1 mmHg to yield 20.88 g of 4-(2-bromotetrafluoroethoxy)benzoyl chloride as a colorless liquid, leaving 6.16 g of unreacted acid (76.8% conversion, 96.5% yield). The benzoyl chloride is added slowly with stirring to 8 mL of cold ammonium hydroxide (0.12 mol). The product amide precipitates as fine white needles which are filtered and dried under vacuum to yield 14.74 g of 4-(2-bromotetrafluoroethoxy)benzamide (75% conversion, 99% yield, m.p. 150.5°-151.5° C.), along with 4.8 g of 4-(2-bromo-tetrafluoroethoxy)benzoic acid which is recovered from the mother liquor (24.3% recovery).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].[NH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1>CC#N>[C:4]([CH2:3][CH2:2][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][CH2:11]1)#[N:5]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#CCCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Temperature: 60 °C
Yield: 31.6 %

Procedure:
3-Bromopropionitril (0.74 g, 5.49 mmol) was added to a solution of tert-butyl piperidin-4-ylcarbamate (1.00 g, 4.99 mmol) and TEA (0.56 g, 5.49 mmol) in MeCN (15 mL), and the mixture was heated at 60° C. for 5 h and then evaporated. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 40:60 and then 15:85-10:90 mixture of heptane and EtOAc as eluant, to give the title compound (0.40 g, 32%). 1H NMR (500 MHz, CDCl3): δ 4.44 (br s, 1H), 3.54-3.42 (br m, 1H), 2.88-2.79 (m 2H), 2.69 (t, 2H), 2.51 (t 2H), 2.24-2.16 (m, 2H), 1.99-1.92 (m 2H), 1.47 (s 9H), 1.49-1.41 (m 2H); 13C NMR (125 MHz, CDCl3): δ 155.4, 119.0, 53.6, 52.2, 47.7, 32.7, 28.6, 16.4.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:25][C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>C(Cl)Cl>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([CH:2]([NH:1][S:31]([C:29]2[S:30][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:33])=[O:32])[CH2:3][OH:4])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H](N)CO)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(CO)NS(=O)(=O)c2ccc(Cl)s2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a stirred mixture of tert-butyl 4-[(1S)-1-amino-2-hydroxyethyl]-1-piperidinecarboxylate (0.107 g, 0.44 mmol), triethylamine (0.046 g, 0.46 mmol) and methylene chloride (5 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (0.095 g, 0.44 mmol) as a solution dissolved in 2 mL methylene chloride, dropwise by pipet. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. and stir overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil that was flash chromatographed using ethyl acetate-hexane, 1—1 as eluent. This produced the title compound as a solid (0.109 g, 58%). MS (+APCI) 442.18 ([M+NH4]+); 386.08; 357.01; 325.07; 307.01; 285.06. Anal. Calc'd for C16H25ClN2O5S2: C, 45.22; H, 5.93; N, 6.59; Found: C, 45.31; H, 5.87; N, 6.4
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][C@H:13]([C:22](OC)=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:11])=[CH:6][CH:5]=1>CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([NH:12][C@H:13]([CH2:22][OH:23])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[O:11])=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(COC(=O)N[C@H](CO)Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
In 150 ml of 50% aqueous methanol, 13.1 g of sodium borohydride was added with stirring while cooling with ice. To the mixture was added dropwise 250 ml of a methanol solution containing 26.5 g of methyl N-(4-methylbenzyloxycarbonyl)-tyrosinate. The mixture was stirred while cooling with ice for two hours and at room temperature for four hours. After neutralization with 10% hydrochloric acid, the mixture was concentrated in vacuo and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 17.9 g of N-(4-methylbenzyloxycarbonyl)-tyrosinol: yield 74%; mp. 128°-129° C. Analysis, calculated for C18H21O4N: C, 68.55; H, 6.72; N, 4.44; found C, 68.51; H, 6.84; N, 4.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][Mg]Br>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH3:11])[CH:9]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(Br)ccc1F
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde 101 (100 g, 0.492 mol.) in ether (500 mL), cooled in an ice bath, was added a 3 M solution of methyl magnesium bromide in ether (i.e., diethyl ether) (173 mL, 0.516 mol.) in a dropwise manner. The reaction mixture was stirred for 30 minutes in the ice bath. The reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes. The reaction mixture was cooled in an ice bath and the reaction was quenched by addition of water in a dropwise manner. The reaction mixture was acidified with dilute hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with ether for two times. The combined organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford 1-(5-bromo-2-fluoro-phenyl)-ethanol 102 (106 g, 0.484 mol.) which was used in the next step without further purification.