Azzindani/Open_Reaction_Data huggingface dataset:
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.[NH:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([O:23][CH3:24])=[O:22].Cl>C(Cl)Cl>[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]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([O:23][CH3:24])=[O:22])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Z-Pro-OH (1 equivalent), H-Pro-OMe hydrochloride (1 equivalent) and TEA (1 equivalent) were dissolved in dry methylene chloride, and WSCD (1 equivalent) was added under cooling with ice. Thereafter, the mixture was stirred at room temperature for 20 hours, and the reaction mixture was washed successively with IN HCl, water, saturated aqueous sodium bicarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel to obtain the end compound. Z-Pro-Pro-OMe (1 equivalent) thus obtained was dissolved in ethanol, and boron trifluoride-ether complex (1 equivalent) and palladium on carbon (a small amount) were added. The mixture was subjected to catalytic reduction in a hydrogen atmosphere to remove the Z grup, and the solvent was distilled off under vacuum to obtain the end compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Cl[C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ncc(Cl)cn1
Product: COc1cc(-c2cnc(C(F)(F)F)nc2)ccn1
Yield: 46.1 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (1.0 g, 46%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 2H), 8.35 (d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 4.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][C:17]1[C:18]([CH3:25])=[C:19]([CH:23]=O)[NH:20][C:21]=1[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:23][C:19]1[NH:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][CH2:14][N:13]([CH3:12])[CH3:26])[C:18]=1[CH3:25]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1CCCN(C)C
Yield: 52.7 %

Procedure:
5-Chloro-1,3-dihydroindol-2-one (167 mg, 1.0 mmol) was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 188.7 mg (53%) of 5-chloro-3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](/[CH:15]=[N:16]/[OH:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].ClN1C(=O)CCC1=O.[CH2:26]=[C:27]1[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:26][C:27]3([CH2:30][CH2:29][CH2:28]3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(/C=N/O)c1
Reactant: C=C1CCC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NOC3(CCC3)C2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl 3-bromo-5-[(E)-(hydroxyimino)methyl]benzoate (5.26 g, 17.5 mmol) in N,N-dimethylformamide (80 mL)) was added N-chlorosuccinimide (2.57 g, 19.3 mmol). The reaction mixture was heated to 50° C. After 1 h, the reaction was cooled to ambient temperature and methylenecyclobutane (6.49 mL, 70.1 mmol) was added. Triethylamine (12.2 mL, 88.0 mol) was added. The mixture was stirred at ambient temperature. After 10 min, saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→90% hexanes/ethyl acetate) gave the title compound (2.86 g). MS 366 (M).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (S)-1,1-diethoxypropan-2-amine (Compound XIV-1) 682 mg (3.55 mmol) in tetrahydrofuran 2 ml, benzaldehyde 337 mg (3.55 mmol) was added and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 3 ml and sodium triacetoxyborohydride 829 mg (3.91 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate aq. 50 ml twice, water 50 ml twice and brine 50 ml twice. The organic phase was dried over magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 826 mg (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15](OC)=[O:16])=[CH:12][N:11]=[C:10]1[S:19][CH2:20][CH2:21][CH3:22].CO.C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH2:15][OH:16])=[CH:12][N:11]=[C:10]1[S:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCSc1ncc(CC(=O)OC)n1Cc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCSc1ncc(CCO)n1Cc1ccccc1Cl
Yield: 83 %

Procedure:
A solution of methyl 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]acetate (2.1 g, 6.2 mmol) in dry tetrahydrofuran (150 mL) was cooled to -78° C. for 1.5 hours and at ambient temperature for 18 hours. Methanol was added followed by 5% aqueous acetic acid. The mixture was concentrated in vacuo, the residue was extracted with methylene chloride, and the organic extract was washed with 5% aqueous sodium carbonate solution, dried, and concentrated to give 2.33 g of crude product. This was chromatographed over silica gel with ethyl acetate to give 1.6 g (84%) of 1-[(2-chlorophenyl)methyl]-5-(2-hydroxy)ethyl-2-propylthio- 1H-imidazole as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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>[CH:14]([N:12]1[CH:13]=[C:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([CH3:17])[CH:19]=[CH:20]4)[N:3]=2)[N:10]=[N:11]1)([CH3:16])[CH3:15]
Reactant: CC(C)n1cc(-c2nc(Br)cnc2N)nn1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2nc(-c3ccc4c(ccn4C)c3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyrazin-2-ylamine (750 mg, 2.65 mmol) and N-methylindole-5-boronic acid (556 mg, 3.18 mmol) in 1,4-dioxane (15.0 mL)/water (5.0 mL) was added Cs2CO3 (1.29 g, 3.97 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(PPh3)4 (153 mg, 0.13 mmol) was added and allowed to stir at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude product. The crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 70-80% EtOAc in Hexane to afford the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-:10]#N.[Na+].[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:10][CH2:14][C:13]([OH:16])=[O:15])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:10][CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1
Product: O=C(O)CCCc1ccc(Cl)cc1

Procedure:
4-(4-Chlorophenyl)-n-butyric acid was prepared by reacting 4-chlorobenzaldehyde with ethyl acetate and sodium cyanide to provide ethyl 4-(4-chlorophenyl)-4-oxo-butyrate, hydrolyzing the ethyl butyrate derivative to afford 4-(4-chlorophenyl)-4-oxobutyric acid, and then reducing the 4-oxo-group of said acid by reaction with zinc and hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1.[H-].[Na+]>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:23])=[O:22])=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: N#Cc1ccc(N)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2[N+](=O)[O-])c2ncccc12
Yield: 30.9 %

Procedure:
In a similar fashion using route 14 general procedure 58, 8-aminoquinoline-5-carbonitrile (Intermediate 472) (100 mg, 0.5 mmol), 4-chloro-2-nitrobenzenesulfonyl chloride (Intermediate 454) (166 mg, 0.65 mmol), NaH (60% dispersion in mineral oil, 26 mg, 0.65 mmol) and THF (2 ml) gave the title compound (60 mg, 26%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([N:45]2[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]2)[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH:42]6[CH2:44][CH2:43]6)[CH2:46][CH2:47]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(C2CC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C3CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.038 g (0.25 mmole) of 1-cyclopropyl-piperidin-4-ylamine in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate and three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.081 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopropyl-piperidin-4-yl)-3-methoxy-benzamide (I-66) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=1.[CH3:26]N(C)CCN(C)C.C([Li])(C)(C)C.CI.[Cl-].[NH4+]>O1CCCC1.CCCCC>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH3:26])[N:6]=1
Reactant: COc1cc(OC)nc(Cc2ccccc2NC(=O)OC(C)(C)C)n1
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(OC)nc(C(C)c2ccccc2NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The product of stage (a) above (1 g) was dissolved in dry tetrahydrofuran (20 ml) and tetramethyl ethylenediamine (1.1 ml) was added under nitrogen. The solution was cooled to -70° C. and 1.7M t-butyllithium in pentane (4.3 ml) was added dropwise. The mixture was then stirred at about -20° C. for 1 hour. It was then cooled to -70° C., and methyl iodide (0.45 g) was added. The reaction mixture was allowed to warm to 0° C. and saturated ammonium chloride solution (25 ml) was added. The mixture was extracted with tetrahydrofuran (3×50 ml) and the combined extracts were dried and evaporated to give a pale brown solid which was triturated with hexane to give 0.73 g of the desired product, mp 119°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:25]1([NH:29][C:20]([CH:17]2[CH2:18][CH2:19][N:14]([CH:9]3[CH2:10][CH:11]4[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([CH2:13][CH2:12]4)[CH2:8]3)[CH2:15][CH2:16]2)=[O:22])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(C(=O)O)CC1)C2
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCOC(=O)N1C2CCC1CC(N1CCC(C(=O)NC3(C)CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 34 %

Procedure:
1-[8-(Ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxylic acid (0.50 g assumed 1.62 mmol) was dissolved in DMF (8 mL) and (1-methylcyclobutyl)amine hydrochloride (0.295 g, 2.44 mmol), HATU (0.926 g, 2.44 mmol) and DIPEA (1.05 g, 1.41 mL, 8.12 mmol) were added. The reaction mixture was stirred at rt for 60 h and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and passed through a phase separator cartridge. The solvents of the organic filtrate were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-6 3 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate isomer 1 (0.208 g, 34%) as a light yellow gum.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:18])[C:9](=[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][NH:13]2)[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.C(O)(=[O:23])C>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[S:18]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[NH:7][C:8]1=[C:9]([C:12]1[N:13]=[CH:14][CH:15]=[CH:16][N:17]=1)[C:10]#[N:11].[S:18]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[NH:7][C:8]1=[C:9]([C:12]1[N:13]=[CH:14][CH:15]=[CH:16][N:17]=1)[C:10]([NH2:11])=[O:23]
Reactant: CC(=O)O
Reactant: N#CC(C(=S)Nc1ccccc1)=C1N=CC=CN1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: BrBr
Agent: [K+]
Product: N#CC(=C1Nc2ccccc2S1)c1ncccn1
Product: NC(=O)C(=C1Nc2ccccc2S1)c1ncccn1

Procedure:
In the first step of the synthesis, the phenyl isothiocyanate 14 (which may be readily prepared by reaction of an aniline with thiophosgene) is coupled with a 2-(pyrimidin-2-yl)acetonitrile 11 or 2-(pyrimidin-2-yl)acetamide 12 in the presence of a base to give a 3-(phenylamino)-2-(pyrimidin-2(1H)-ylidene)-3-thioxo-propionitrile 15 or 3-(phenylamino)-2-(pyrimidin-2-yl)-3-thioxopropanamide 16. In the second step, ring closure of the compound of formula 15 or 16 is achieved by reaction with an agent such as bromine/acetic acid or potassium ferricyanide, to give a 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile 6 or 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide 8. If the compound of formula 6 has been prepared, it is then hydrolyzed to a compound of formula 8, as in Reaction Scheme 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([CH2:22][NH2:23])[OH:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:21][CH2:20][CH2:22][NH:23][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCO)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Ethanolamine (39.9 mg; 0.65 mmol; 2 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, Compound (11) is obtained as white-off solid (36.5 mg; 30%). 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.43 (s, 3H), 2.91 (m, 2H), 3.41 (m, 2H), 4.72 (t, J=6 Hz, 1H), 7.21 (d, J=4.5 Hz, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.88 (br s, 1H), 12.25 (br s, 1H). M−(ESI): 360.11; M+(ESI): 362.06. HPLC, Rt: 2.36 min (purity: 97.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cncc(Br)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A mixture of (5-bromo-pyridin-3-yl)-acetic acid (2.0 g, 9.3 mmol), benzyl alcohol (1.0 g, 9.2 mmol), DCC (1.9 g, mmol), and DMAP (1.0 g, mmol) in DCM (30 mL) is stirred at room temperature for 16 h. The mixture is filtered and the filtrate is concentrated to give the crude product. Purification by flash column chromatography affords 1.2 g of (5-bromo-pyridin-3-yl)-acetic acid benzyl ester.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]([F:16])([F:15])[C:12](O)=O>>[F:10][C:11]([F:16])([F:15])[CH:12]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][NH:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCc1ccccc1
Product: FC(F)(F)C1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 25 ml of phenethylamine(0.2M) and 30 ml of anhydrous trifluoroacetic acid(0.21M) were used as starting materials, 5.4 g of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C.ClC1[S:45][C:46]([CH3:54])=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:48]=1.Cl>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:45][C:46]([CH3:54])=[C:47]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:48]=3)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1nc(Cl)sc1C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (80 mg, 0.21 mmol) was dissolved in methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for one hour. Following concentration under reduced pressure, the residue was dissolved in DMF (2 mL). Diisopropylethylamine (0.16 mL, 0.92 mmol) and ethyl 2-chloro-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (38a) (70 mg, 0.34 mmol) were added, and the mixture was stirred using a microwave reactor at 160° C. for three hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, ethyl acetate) to obtain 15.3 mg of the title compound as a pale yellow solid (16%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2].[C:11]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:16])([CH3:14])([CH3:13])[CH3:12].CN(C)C1C=CC=CC=1>C(#N)C>[C:11]([C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:4]([CH2:3][C:1]#[N:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:21]=[CH:22][CH:23]=1)=[O:16])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#CCNc1ccccc1
Reactant: CC(C)(C)C(=O)Nc1cccc(OC(=O)Cl)c1
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cccc(OC(=O)N(CC#N)c2ccccc2)c1
Temperature: 0 °C

Procedure:
Into a solution of 13.2 g N-cyanomethylaniline in 150 ml acetonitrile is added 25.57 g chloroformic acid-[3-(tert.-butylcarbonylamino)-phenyl]-ester, then with further stirring 12.1 g N,N dimethylaniline is added dropwise and the mixture heated for an additional 15 minutes to boiling. The mixture is stirred after cooling in 1 l ice water, the substance which separates out is taken up and after drying in vacuum is recrystallized from a little acetonitrile.