Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[O:21]1[CH2:25][CH2:24][C@H:23]([O:26][C:27]2[CH:28]=[C:29]([C@@H:33]([NH2:35])[CH3:34])[CH:30]=[CH:31][CH:32]=2)[CH2:22]1.CS(C)=O.CCN(C(C)C)C(C)C>O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:35][C@H:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C@H:23]3[CH2:24][CH2:25][O:21][CH2:22]3)[CH:28]=2)[CH3:34])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1cccc(O[C@H]2CCOC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cccc(O[C@H]2CCOC2)c1
Temperature: 110 °C

Procedure:
To a microwave vial with a stir bar was added (R)-4-((R)-1-tert-butoxyethyl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (43.6 mg, 0.145 mmol) and (S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethanamine (25.1 mg, 0.121 mmol), followed by DMSO (605 uL) and DIEA (63.5 ul, 0.363 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 110° C. for 21 hr. The mixture was diluted with water and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one, as a brown solid film, (yield assumed quantitative). LCMS m/z 471.4 (M+H)+, Rt 0.85 min.
Reaction SMILES: [Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5]([N:7](C(OCC(Cl)(Cl)Cl)=O)[C:8]1[C:12]([Br:13])=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:9]=1)=[O:6].OP([O-])(O)=O.[K+]>C1COCC1.[Zn]>[Br:13][C:12]1[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:29])([Cl:1])[Cl:30])=[O:6])=[N:9][N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH:11]=1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)n1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-{bis[(2,2,2-trichloroethoxy)carbonyl]amino}-4-bromo-1H-pyrazole-1-carboxylate (12.7 g, 20.73 mmol) in THF (200 mL) was added activated zinc powder (13.5 g, 207.3 mmol) followed by an aqueous solution of KH2PO4 (1.0 M, 41.5 mL, 41.5 mmol) dropwise and the reaction was stirred for 3 hours at rt. The zinc powder was filtered off, rinsed with Et2O and water, the aqueous phase extracted with Et2O (2×), and the combined organics dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford tert-butyl 4-bromo-3-{[(2,2,2-trichloroethoxy)carbonyl]amino }-1H-pyrazole-1-carboxylate.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([N:22]1[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[C:26](=[O:32])[NH:25][CH2:24][CH2:23]1)[CH3:21].C(O[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)(C)C.Cl>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([N:22]1[C:28]2[CH:29]=[C:30]([B:37]3[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]3)[S:31][C:27]=2[C:26](=[O:32])[NH:25][CH2:24][CH2:23]1)[CH3:21]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(c1ccccc1Cl)N1CCNC(=O)c2sccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
HNiPr2 (246 μL, 1.74 mmol, 3.0 Eq) was dissolved in anhydrous THF (10 mL) and cooled to −78 ° C. under nitrogen. 2.5 M BuLi in hexanes (700 μL, 1.74 mmol, 3.0 Eq) was added dropwise and the reaction stirred at −78 ° C. for 15 minutes then warmed to 0° C. for 30 minutes. The reaction was cooled to −78 ° C. and 1-[1-(2-chloro-phenyl)-ethyl]-1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (178 mg, 0.58 mmol, 1.0 Eq) was in anhydrous THF (5 mL) was added dropwise. The reaction was stirred at −78 ° C. for 2 hours. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (355 μL, 1.74 mmol, 3.0 Eq) in anhydrous THF (5 mL) was added and the reaction stirred at −78 ° C. for 20 minutes them warmed to ambient temperature for 1.5 hours. 1M HCl (20 mL) was added and the mixture extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and concentrated in vacuo. The yellow oil obtained was used without further purification; 1H NMR (DMSO D6) 1.28 (12H, s), 1.51 (3H, d), 2.93-2.99 (1H, m), 3.03-3.13 (2H, m), 3.20-3.26 (1H, m), 5.32 (1H, dd), 6.19 (1H, br s), 7.20-7.28 (3H, m), 7.33-7.36 (2H, m); LC/MS M+1 (obs.) 433.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][C@H:10]([CH2:15][C:16](OCC)=[O:17])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC[C@@H]1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 255D (9.2 g, 33.3 mmol) in tetrahydrofuran (150 mL) at 0° C. was added lithium aluminum hydride (2 M, tetrahydrofuran, 50 mL) dropwise. The solution was allowed to warm to room temperature and stirred for 16 hours. Water (3.8 mL) in tetrahydrofuran (25 mL) was added dropwise to the solution followed by 3.8 mL NaOH (15% aqueous) and more water (11.4 mL). The solids were removed via filtration. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:27][C:28]#[N:29]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:27][C:28]#[N:29])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(O)cc1
Reactant: N#CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCC#N)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid tert-butyl ester 31 (0.365 g, 1.37 mmol) and Cs2CO3 (0.672 g, 2.06 mmol) in anhydrous DMF (8 mL) was heated at 65° C. for 30 min. Iodoacetonitrile (0.276 g, 1.651 mmol) was then added to the mixture in one portion. The mixture was stirred at 65° C. overnight, and then cooled to room temperature. The precipitated solid was filtered, and the filtrate was partitioned between water and dichloromethane (each 50 mL). The organic layer was separated, washed with brine (3×50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with a mixture of diethyl ether/dichloromethane (6:94, v/v), to afford the desired product 40 (0.109 g, 38% yield) as a colorless viscous oil. 1H NMR (300 MHz, CDCl3): δ 1.43 (s, 9H), 1.57 (m, 4H), 2.60 (t, 2H), 3.15 (m, 2H), 4.49 (br, 1H), 4.75 (s, 2H), 6.91 (d, 2H), 7.13 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:11])[O:15][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1ccc(CC#N)cc1
Agent: Cl
Product: CCOC(=N)Cc1ccc(OC)cc1

Procedure:
A solution of 4-methoxyphenylacetonitrile (50 g, 0.34 mol) in absolute ethanol (200 ml) was treated with dry HCl gas with ice cooling for 1 hour. The solvent was evaporated in vacuo, and the residual oil triturated with ether. The solid was filtered off, washed with ether and dried (66 g, 84%), then used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=O)[C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([NH:22][CH3:23])[CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[C:17]([F:20])([F:19])[F:18])[N:22]([CH3:23])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Cl)c(F)cc1NC(=O)c1cnccc1C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: Cn1c(-c2cnccc2C(F)(F)F)nc2cc(F)c(Cl)cc21
Temperature: 140 °C

Procedure:
To the solution of compound N-(4-chloro-5-fluoro-2-(methylamino) phenyl)-4-(tri-fluoromethyl) nicotinamide (0.1 g, 0.0028 mol) in DMA (5 ml) was added DBU (0.05 g, 0.0037 mol). Reaction mixture was heated at 140° C. for 24 h. Reaction mass was quenched with ice water and layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic extracts were washed with brine dried over Na2SO4 and concentrated to get crude product which was purified by column chromatography to provide 6-chloro-5-fluoro-1-methyl-2-[4-(trifluoromethyl)pyridin-3-yl]-1H-benzimidazole 335; as a white colored solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.11-9.09 (d, J=5.2 Hz, 1H), 9.03 (s, 1H), 8.07-8.04 (m, 2H), 7.82-7.79 (d, J=10 Hz, 1H), 3.65 (s, 3H). MS (M+1): 330.12, Purity 99.52%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][C@@H:27]([NH:30]C3CC3)[CH2:26]2)=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>O1CCOCC1.[NH4+].[OH-].O.C(Cl)Cl.[Cu]I>[NH2:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:23]=[CH:24][C:19]([N:13]3[CH:14]=[CH:15][C:10]4[CH:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[S:17][C:11]=4[C:12]3=[O:16])=[CH:20][CH:21]=2)[CH2:26]1
Reactant: Brc1ccc(N2CC[C@@H](NC3CC3)C2)nc1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H]1CCN(c2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)C1
Temperature: 100 °C
Yield: 63.5 %

Procedure:
Degass a mixture of 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (374 mg, 1.43 mmol), [(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-cyclopropyl-amine (404 mg, 1.43 mmol) and cesium carbonate (932 mg, 2.86 mmol) in 1,4-dioxane (20 mL). Add copper (I) iodide (162 mg, 851 μmol) and sym-dimethylethylene diamine (150 mg, 1.70 mmol). Heat the mixture at 100° C. overnight. Dilute with concentrated NH4OH (5 mL) and water (50 mL) and CH2Cl2. Separate the organics and dry with Na2SO4, filter, and concentrate. Purify using chromatography (0 to 10% MeOH/CH2Cl2) to afford 0.384 g (64%) of 6-[6-((R)-3-amino-pyrrolidin-1-yl)-pyridin-3-yl]-2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)[CH:10]=1.O[Li].O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([OH:24])=[O:7])=[CH:10][C:11]=1[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: COC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
A mixture of THF (15 mL) and water (1 mL) containing 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.7 g, 5.4 mmol) and LiOH.H2O (0.68 g, 16.1 mmol) was stirred at room temperature for 12 hrs. The mixture was acidified and extracted with ethyl acetate. The organic layer was washed with brine and water and was dried. Filtration and concentration gave 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid as a white solid (1.4 g). MS (M+H)+: 301.6, tR=7.048 min (method 2)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]([C:7](=[O:9])[C:4]3[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=3)[C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(Cl)cs1
Reactant: NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2ccc(Cl)cc21
Yield: 53 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 463 mg (2.85 mmole) portion of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem., 13, 393 (1976)) was transformed into the acyl imidazole by reaction with 500 mg (3.09 mmole) of to 1,1'-carbonyldiimidazole. The intermediate 4-chloro-2-thiophene-(l-imidazo)carboxamide coupled directly with 500 mg (2.37 mmole) of 6-chloro-2-oxindole-1-carboxamide in the presence of 783 mg (6.41 mmole) of 4-(N,N-dimethylamino)pyridine to give 665 mg of crude greenish-yellow solid. Recrystallization gave 450 mg (1.27 mmole, 53% yield) of pure title compound as a yellow solid, m.p. 231°-3° C. (acetic acid).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.[NH4+].[Cl-]>CC(O)(C)C.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)c1cc(N)no1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 5-t-butyl-isoxazol-3-ylamine (10.0 g, 71.33 mmol) in t-BuOH (500 mL) at 20° C. was added NaOt-Bu (17.1 g, 178.3 mmol) in 3 portions over 10 min. The solution turned pale yellow with the appearance of a thick, white precipitate. The mixture was stirred at 20° C. for 1 h, then 2,4-dichloropyrimidine (15.9 g, 107.0 mmol) was added. The mixture was stirred for an additional 90 min. at 20° C., accompanied by the dissolution of the white precipitate and appearance of an orange color. NH4Cl (aq., sat., 100 mL) and H2O (1 L) were added, and the mixture was extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with H2O (300 mL), brine, and dried with MgSO4 before being filtered and concentrated under reduced pressure. Purification by chromatography of the crude reaction mixture (96:4 CH2Cl2:MeOH) provided the title compound.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH3:4]>C(OCC)C.C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([OH:5])([CH3:1])[CH3:4])[CH:7]=1
Reactant: [Li]C
Reactant: CC(=O)c1cccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1cccnc1
Yield: 45.9 %

Procedure:
The method followed that of Example 4a, but using methyllithium (1.4 M; 14 ml, 20 mmol) in diethyl ether and 3-acetylpyridine (2.2 ml, 20 mmol) in dry THF (40 ml). Work-up and chromatography, on elution with ether-petrol-triethylamine 30:10:1, afforded the title compound (1.26 g, 46%) as an oil. 1H-NMR (CDCl3) δ1.58 (6H, s, CMe2), 7.22 (1H, m, Py 5-H), 7.85 (1H, m, Py 4-H), 8.32 (1H, m, Py 6-H), 8.65 (1H, m, Py 2-H); MS m/z 137 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:5]=[CH:6][C:7]=1F.ClC1C=C(C2SC(C(O)=O)=NC=2C2C=CC=C(Cl)C=2)C=CC=1[F:36]>>[Cl:28][C:24]1[CH:23]=[C:22]([C:10]2[N:11]=[C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[S:13][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:27]=[C:26]([F:36])[CH:25]=1
Reactant: O=C(O)c1nc(-c2cccc(Cl)c2)c(-c2ccc(F)c(Cl)c2)s1
Reactant: O=C1CN(C(=O)c2nc(-c3cccc(Cl)c3)c(-c3ccc(F)c(Cl)c3)s2)CN1
Product: O=C1CN(C(=O)c2nc(-c3cc(F)cc(Cl)c3)c(-c3cccc(Cl)c3)s2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 4 starting with the compound from Example 11A. 4.5 mg (19% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:5]([O:19][Si](C(C)(C)C)(C)C)[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.C([O:44][C:45](=O)[C@@H:46]1[CH2:50][CH2:49][CH2:48][NH:47]1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:45](=[O:44])[C@@H:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(N=C2N(c3ccccc3Br)C(=O)[C@@H]3CCCN23)c(O)c1
Yield: 67.3 %

Procedure:
The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (54 mg, 0.13 mmol), diisopropylethylamine (32 μL, 0.29 mmol), L-proline benzylester hydro chloride (34 mg, 0.14 mmol) and TBAF (0.16 mL, 0.16 mmol) in THF (2 mL) and methanol (0.1 mL) to give 36 mg (67%) of 4-[[(7aS)-2-(2-bromophenyl)-hexahydro-1-oxo-3H-pyrrolo[1,2-c]imidazol-3-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. 1H NMR (400 MHz, MeOD) δ 7.6 (2H, m), 7.35 (3H, m), 7.15 (1H, m), 7.0 (1H, m), 4.5 (1H, t), 3.0 (1H, m), 2.4 (1H, m), 2.2 (1H, m), 2.05 (2H, m); MS(EI) m/e 412 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.CO>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:24][C:23]#[CH:22])[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CO
Product: C#CCN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (800 mg, 2.6 mmol) in acetone (20 ml) was added propargyl bromide (80% solution, 0.290 ml, 2.6 mmol) and potassium carbonate (720 mg, 5.2 mmol). The solution was heated to reflux and stirred for 5 hours. Thin layer chromatography (10:1 dichloromethane:methanol) showed formation of product. The solution was cooled and filtered. The filtrate was concentrated and purified by preparative chromatography (dichloromethane:methanol) to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ynylpiperazinyl)propan-2-ol (500 mg, M+1=346.2). B. Preparation of a Compound of Formula I
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[O:22][C:23]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[C:24]=5[C:25]=4[CH3:26])=[CH:15][C:13]=3[CH:14]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:43][C:44]1C2C(OCCCNCC3C=NC=CC=3)=CC=CC=2OC=1COC1C=CC2OC(C(N3CCNCC3)=O)=CC=2C=1.[BH4-].[Na+].C([BH3-])#N.[Na+].[CH2:90]([O:92][C:93]([C:95]1[O:96][C:97]2[CH:103]=[CH:102][C:101]([O:104][CH2:105][C:106]3[O:107][C:108]4[CH:115]=[CH:114][CH:113]=[C:112]([O:116][CH2:117][CH2:118][CH2:119][NH:120][CH2:121][C:122]5[CH:123]=[N:124][CH:125]=[CH:126][CH:127]=5)[C:109]=4[C:110]=3[CH3:111])=[CH:100][C:98]=2[CH:99]=1)=[O:94])[CH3:91].NO.NN>[O-2].[O-2].[Mn+4]>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[O:22][C:23]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[C:24]=5[C:25]=4[CH3:26])=[CH:15][C:13]=3[CH:14]=2)=[O:9])[CH2:6][CH2:7]1.[CH2:90]([O:92][C:93]([C:95]1[O:96][C:97]2[CH:103]=[CH:102][C:101]([O:104][CH2:105][C:106]3[O:107][C:108]4[CH:115]=[CH:114][CH:113]=[C:112]([O:116][CH2:117][CH2:118][CH2:119][NH:120][CH2:121][C:122]5[CH:123]=[N:124][CH:125]=[CH:126][CH:127]=5)[C:109]=4[C:110]=3[CH:111]3[CH2:44][CH2:43]3)=[CH:100][C:98]=2[CH:99]=1)=[O:94])[CH3:91]
Reactant: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Reactant: Cc1c(COc2ccc3oc(C(=O)N4CCNCC4)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Agent: [Mn+4]
Agent: Cc1c(COc2ccc3oc(C(=O)N4CCC(O)CC4)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Agent: NN
Product: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C3CC3)ccc2o1

Procedure:
Aldehyde 34 can be obtained from compound 13 by the reaction using an oxidizing agent such as manganese dioxide. Aldehyde 34 can be the starting material for compounds 35, 36, 37, 38, 39, 40, 41, 42, 43 and 44. Amine 35 can be prepared by the reaction of compound 34 with an amine followed by reduction with a reducing agent such as sodium borohydride and sodium cyanoborohydride. Compounds 36 and 37 can be prepared by the reaction of compound 34 and a hydroxylamine derivative (NH2OR8) and a hydrazine derivative (NH2NR9R10) respectively. Wittig reaction (A. Maercker, Organic Reactions. Vol. 14, PP. 270-490) of compound 34 gives compound 38 and the hydrogenation of compound 38 gives compound 39. Wittig-Honor reaction (J. Boutagy and R. Thomas, Chem. Rev. Vol. 74, PP. 87-99, 1974) of compound 34 gives compound 40. Compound 40 can be converted into compound 41 by hydrogenation over a catalyst such as Palladium on carbon. Compound 41 can be converted into alcohol 42 by reducing compound 41 with a reducing agent such as lithium aluminium hydride. When compound 42 is treated with a base such as sodium hydride and halogen-R61a, compound 43 is obtained. When methanesulfonyl derivative of compound 42, which can be obtained by the reaction of compound 42 and methanesulfonyl chloride in the presence of a base such as triethylamine, is treated with HO—R61b in the presence of a base such as cesium carbonate, compound 44 is prepared.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: OB(O)c1cccc(F)c1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2cccc(F)c2)cc1

Procedure:
Compound (104) was prepared from compound (20) and (3-fluoro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.83 mins, m/z (ES)=325 (M−H for C19H15FO4).