Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([C:17]#[C:18][Si](C)(C)C)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[F-].[K+].C(Cl)(Cl)Cl.O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([C:17]#[CH:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C#C[Si](C)(C)C)c2c1=O
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
1 g of the product of Example E and 0.45 g of potassium fluoride are stirred for 1 hour at room temperature in a mixture of 20 ml of dimethylformamide, 10 ml of chloroform and 1 ml of water. After chloroform has been added, the organic phase is separated off, extracted by shaking with water, dried over sodium sulphate and concentrated. The residue is boiled briefly in 20 ml of methanol. When the mixture has cooled to 0° C., the solid obtained is filtered off with suction and dried. 0.63 g of the title compound is obtained (77% of theory).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[CH2:20][C:21](=[O:23])[CH3:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[O:23]=[C:21]([CH3:22])[CH2:20][O:4][C:3]([C@@H:2]1[CH2:6][CH2:7][CH2:8][N:1]1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 2.0 g Z-Pro-OH n 20 ml dichloromethane were added 0.58 ml hydroxyl-acetone and 10 mg DMAP. The solution was cooled to 0° C. and a solution of 1.7 g DCC in 20 ml dichloromethane was added dropwise. The suspension was allowed to warm to RT for 16 h before being filtered over a short plug of Celite. The reaction mixture was washed with dichloro-methane and the combined wash solutions evaporated. The residue thus obtained was purified by chromatography on silica using heptane/ethyl acetate 1:1 as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:27]=1)=[O:25]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:33][NH:32][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:35][CH:34]=3)[CH3:16])[C:11]([C:18]([F:19])([F:20])[F:21])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1c(C(F)(F)F)nn(-c2ccc(C)c(C)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C(F)(F)F)cc1
Yield: 62 %

Procedure:
1-(1-(3,4-Dimethylphenyl)-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-yl)-ethanone (0.189 mmol, 56.5 mg) and 4-methoxycarbonylbenzhydrazide (0.189 mmol, 36.8 mg) were stirred in DMF at 100° C. for 2.2 hours and at 120° C. for 17 hours. After the solvent was removed by evaporation, the residue was resolved by silica gel thin layer chromatography (CHCl3/MeOH=10/1) to obtain 4-methoxycarbonylbenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide as a yellow solid (55.6 mg, 62%)
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([NH:25]C1CCCCO1)=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2].Cl.[O:33]1CCOCC1>>[C:1]([NH:4][C@H:5]([C:23]([NH:25][OH:33])=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NC1CCCCO1
Agent: Cl
Product: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Reaction time: 1 h
Yield: 32 %

Procedure:
The product from Example 9f (1.0 mmol, 450 mg) was dissolved in dioxane (5 mL). Six normal HCl (0.5 mL) was added, and the mixture was stirred one hour. Concentration followed by chromatography afforded the title compound as a glass (120 mg, 32%). MS MH+ calcd. for C17H18N2O6S 378, found 379.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1
Yield: 64.2 %

Procedure:
A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (2.40 g), 2,4-thiazolidinedione (1.66 g), ethanol (40 ml) and piperidine (0.2 ml) was heated under reflux for 8 hours. The resulting crystals were recrystallized form ethyl acetate to give 2.14 g (64%) of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4thiazolidinedione as colorles crystals. m.p.: 165.5°-167° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14]1.[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26](F)[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26]([CH:16]([CH:13]2[CH2:15][CH2:14]2)[C:17]#[N:18])[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]
Reactant: N#CCC1CC1
Reactant: COc1c(F)ncc(F)c1OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1c(C(C#N)C2CC2)ncc(F)c1OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A −78° C. solution of diisopropylamine (1.3 mL, 9.0 mmol), under a nitrogen atmosphere in dry tetrahydrofuran (20 mL), was treated dropwise with 2.5 N n-butyllithium (3.6 mL, 9.0 mmol) and stirred for 10 minutes. The solution was treated dropwise with cyclopropylacetonitrile (0.8 g, 3.5 mmol) and stirred at −78° C. for 15 minutes. A solution of 4-tert-butoxy-2,5-difluoro-3-methoxypyridine (0.8 g, 3.5 mmol)[Example 7] in dry tetrahydrofuran (5 mL) was added and stirred for 1 hour at −78° C. followed by 1 hour at 0° C. The mixture was quenched with saturated ammonium chloride and extracted with diethylether. The combined extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.98 (s, 3H), 3.77 (d, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.62-0.54 (m, 2H), 0.50-0.42 (m, 1H), 0.35-0.30 (m, 1H). MSCI: m/z=279 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-].[Cs+].[CH2:15](B1OC(C)(C)C(C)(C)O1)[CH:16]=[CH2:17].O>C1COCC1.CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH:16]=[CH2:15]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=CCc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (5 g, 18 mmol) in. THF (500 mL) are added cesium fluoride (11 g, 72 mmol) and Pd(PPh3)4(0.56 g, 48 mmol). The resulting mixture is stirred for 30 min at room temperature. A solution of allylboronic acid pinacol ester (5.6 mL, 33 mmol) in THF (15 mL) is added dropwise. The resulting mixture is refluxed for 24 h then diluted with hexane (100 mL) followed by water (100 mL). The product is extracted with hexane (2×100 mL). The combined organic layers are washed with water (150 mL) then brine (150 mL) and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by column chromatography using hexane as eluent affording 1.8 g (48%) of the title compound as a brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.93-7.91 (m, 1), 7.59-7.50 (m, 1H), 7.04-7.01 (m, 1H), 5.0-4.9 (m, 2H), 3.89-3.85 (m, 1H), 3.81 (s, 3H), 3.53-3.51 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[OH-:14].[Na+]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [OH-]
Reactant: O=Cc1ccc(Br)c2cccnc12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromoquinoline-8-carbaldehyde (10 g, 0.039 mol) in THF (300 ml) was added aqueous NaOH (30 g) and followed by silver nitrate (10.79 g, 0.0635 mol) lot wise at RT for 10 min and this reaction mixture was stirred at RT for 30 min. The reaction completion was confirmed by TLC. After completion of reaction the reaction mixture was filtered. The black solid was wanded with THF, MeOH and DMF (50 ml each). (Note: Product was not soluble in any of these solvents!! The filtrate and washings were discarded). The black solid was dried to afford the title compound (crude −30 g). The crude product was as such taken for the next step. 1H NMR (DMSO-d6, 400 MHz): δ 8.92-8.91 (dd, J=4.12, 5.8 Hz, 1H), 8.49 (s, 1H), 8.46-8.44 (dd, J=8.56, 10.2 Hz, 1H), 7.83-7.81 (dd, J=7.6, Hz, 1H), 7.63-7.6 (dd, J=8.52, 12.68 Hz, 1H), 7.46-7.44 (d, J=7.6 Hz, 1H).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(I)cc1
Reactant: COc1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3ccc(OC)cc3)cn2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
10 mg cupper (I) iodide, 20 mg trans-N,N′-dimethyl-1,2-cyclohexyldiamine was added to 1.1 g 4-(4-methoxy-phenyl)-1H-imidazole, 1.5 g 1-iodo-4-methoxy-benzene and 1.95 g cesium carbonate in 5 mL DMF under argon. The reaction was stirred 48 h at 120° C. in a closed microwave bottle under argon. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by chromatography on Alox (50 kg, Merck (Darmstadt), Bestell-Nr. 1.01097.9050 activity: II-III) (gradient: dichlormethane/EtOAC 9:1-8:2) to yield 1 g of the desired compound.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:5]1[C:6]2[CH:7]=[N:8][S:9][C:10]=2[C:2]([CH3:13])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Br)c2sncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C)c2sncc12
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A solution of 7-bromo-4-methoxy-benzo[d]isothiazole (460 mg, 1.88 mmol), K2CO3 (780 mg, 5.64 mmol), and Pd(PPh3)4 (217 mg, 0.188 mmol) in 1,4-dioxane (5 mL) was added trimethylboroxine (290 μL, 2.07 mmol) and the solution was heated to 110° C. for 18 h. The reaction was cooled to rt and diluted with water and dichloromethane. The organic phase was separated and the aqueous phase was extracted with 2×30 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:10] to yield 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 26%). A method similar to that described for the preparation of benzo[d]isothiazol-4-ol (above) using 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 0.491 mmol) and pyridine hydrochloride (567 mg, 5 mol) gave the title compound (30 mg, 37%): δH (300 MHz, CDCl3): 8.99 (1H, s), 7.15 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 2.45 (3H, s).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.O=P(Cl)(Cl)[Cl:15].CN(C)[CH:20]=[O:21]>>[Cl:15][C:4]1[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[O:1][CH2:7][CH2:6][C:5]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: O=C1CCCOc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)c2ccccc2OCC1

Procedure:
Scheme 2 shows a general method of preparation of N,N-disubstituted 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide intermediates 69. 3,4-Dihydrobenzo[b]oxepin-5(2H)-one intermediates 66 are formylated with phosphorus oxytrichloride and dimethylformamide (DMF) to give 5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde intermediate 70. Cyclization of 70 with a mercapto acetate ester (HSCH2CO2R where R is alkyl or aryl) in potassium carbonate and DMF gives the 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate ester intermediate 71. Saponification of 71 with lithium hydroxide in THF and water gives the acid (R═H) which is treated with thionyl chloride at reflux followed by a secondary amine (HNR5R6), such as N-methyl-2-chloroaniline, with a catalytic amount of DMAP (4,4-dimethylaminopyridine), triethylamine, and dichloromethane to give 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide intermediates 69. Alternatively, the acid is treated with oxalyl chloride and a catalytic amount of DMF to generate the acid chloride, followed by reaction with the amine and potassium carbonate in acetonitrile to give amides such as 69. Where one of R1, R2, R3, or R4 is bromo, the bromine of 69, or of another intermediate such as 66, 70, 71, may be displaced by: (i) carbonylative amination to give amide (—NR12C(═O)R10, (ii) formylation (—CHO) followed by reductive amination to —CH2NR10R11, (iii) Suzuki coupling with aryl or heteroaryl, (iv) Sonagoshira coupling to give alkynyl (—C═CR10), or (v) amination (—NR10R11).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1>>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:28][CH:29]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: N#Cc1cc(-c2ccc(N)nc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, brown solid (46 mg, 58%), MS (ISP) m/z=318.5 [(M+H)+], mp 314.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1.91 g, 9.53 mmol), 3-fluoroaniline (1.06 g, 9.53 mmol) and acetic acid (0.55 ml, 9.53 mmol) in 1,2-DCE (50 ml) was stirred at room temperature overnight. Sodium tri(acetoxy)borohydride (2.82 g, 13.3 mmol) was then added and the reaction mixture was stirred for 8 h, then allowed to stand at room temperature. The reaction mixture was diluted with DCM and washed with NaHCO3 solution, dried over MgSO4 and then concentrated to give the product which was purified by column chromatography. Elution with 0-40% EtOAc/pentane gave the title compound as a white solid (2.3 g). δH (CDCl3, 250 MHz) 7.08 (1H, q), 6.35 (3H, m), 4.04 (1H, br s), 3.65 (1H, br s), 3.38 (1H, m), 2.92 (2H, m), 2.02 (2H, m), 1.47 (9H, s), 1.34 (2H, m).
Reaction SMILES: [Li]CCCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C@:32]1([OH:38])[C:33]2[N:34]([CH:35]=[N:36][CH:37]=2)[C@@H:30]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[F:21])[CH2:31]1
Reactant: c1ccc2scnc2c1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc([C@H]2C[C@](O)(c3nc4ccccc4s3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a 1.6 M solution of n-BuLi in hexane (0.29 mL, 0.46 mmol) cooled to −78° C. was added a solution of benzo[d]thiazole (56 mg, 0.42 mmol) in THF (1 mL). The crude was stirred at −78° C. for 1 hr. This solution was then cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) cooled at −78° C. After stirring at −78° C. for 2 hrs, the crude was warmed to room temperature. The crude was stirred at room temperature for 1 hr. The crude was quenched with sat. NH4Cl. The crude was diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 18 mg of the entitled product as the major diastereomer. MS 377.0 (M+H); LCMS condition A, retention time 1.23 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.09 (dd, 1H), 3.84 (dd, 1H), 5.96 (d, 1H), 7.02 (s, 1H), 7.24-7.53 (m, 6H), 7.85 (d, 1H), 7.93 (d, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][C@@H:34]([CH3:38])[CH2:33]2)=[CH:28][CH:27]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][C@@H:34]2[CH3:38])=[O:48])[C:44]=1[CH3:45]
Reactant: C[C@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)C[C@@H]1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-3-(S)-methylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H), 3.80–3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm; MS (ES) M+H expected=435.1, found=435.0.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: BrCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCBr)cccc21
Reaction time: 2 h
Yield: 281.4 %

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,5-dibromopentane (3.72 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. After 2 hours, water was added and the solution was repeatedly extracted with ether. The collected organic phases were washed with water, dried on Na2SO4 and evaporated under reduced pressure to give a solid (4.50 g), which was purified by chromatography on silica gel (Etp/Et2O 8:2) yielding 2.38 g of a white solid. Yield 68%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C
Temperature: 2 °C
Reaction time: 48 h
Yield: 99.4 %

Procedure:
A mixture of 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.0 g, 5.4 mmol) in N,N-dimethylformamide at 25° C. was treated with triethylamine (1.89 mL, 13.5 mmol) and triphenylmethylchloride (1.66 g, 5.94 mmol). The reaction was stirred at 2° C. for 2 days. At this time, the reaction was concentrated in vauco. The residue was dissolved in dichloromethane (100 mL) and was washed with a 1N aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL), and a saturated aqueous sodium chloride solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid ethyl ester (2.3 g, quant.). The product was used without further purification: LR-MS for C26H24N2O2S (M−H)+ at m/z=427.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:15]([CH2:16]O)=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=S(Cl)[Cl:22]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:15]([CH2:16][Cl:22])=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2cc(=O)[nH]c(C)c2CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2cc(=O)[nH]c(C)c2CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of intermediate 15 (275 mg; 1 mmol) in dichloromethane (10 ml) became homogeneous by addition of SOCl2 (2.3 ml) at room temperature. After 2 hours of stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected intermediate 16 in quantitative yield (294 mg).