Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C1COCC1.O>[CH2:1]([O:8][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of benzyl alcohol (0.52 mL, 5 mmol) in THF (20 mL) was treated with NaH (60%, 0.2 g, 5 mmol) and succinic anhydride (0.502 g, 5 mmol) and refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic layer was washed H2O and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (1:1) as eluant to give 20 as white solid (0.866 g, 57%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:10][O:11][CH2:12][CH2:13][OH:14])[CH2:8][CH3:9])=[CH:3][CH:2]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7](=[N:10][O:11][CH2:12][CH2:13][O:14][C:22]2[CH:54]=[CH:53][C:25]([CH2:26][CH:27]3[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]3=[O:52])=[CH:24][CH:23]=2)[CH2:8][CH3:9])=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=NOCCO)c1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 539 mg of 2-[1-(4-biphenylyl)propylideneaminooxy]ethanol (prepared as described in Preparation 38), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 1.09 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: Oc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)N1CCC(COc2cnc(Br)cn2)CC1
Temperature: 70 °C

Procedure:
A mixture of 5-bromo-2-pyrazinol (and tautomers thereof) (0.2 g, 1.14 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.51 g, 1.71 mmol) and K2CO3 (0.32 g, 2.29 mmol) in DMF (12 mL) was stirred at ambient temperature for 30 min, then heated at 70° C. overnight. The mixture was cooled to ambient temperature and poured into water, and then extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give crude 1-methylethyl 4-{[(5-bromo-2-pyrazinyl)oxy]methyl}-1-piperidinecarboxylate a brown oil, which was used without further purification.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>CN(C=O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]=1
Reactant: OC1CCCC1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of cyclopentanol (1.42 mL, 15.70 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.39 g, 15.70 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (2.0 g, 10.47 mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (100 mL), washed with water (2×25 mL) and brine (2×25 mL) solution, dried over anhyd. Na2SO4, filtered, and concentrated to give yellow oil, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (1.94 g, 51%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 7.65 (br. s., 1H), 7.03 (d, J=8.2 Hz, 1H), 5.74 (br. s., 1H), 5.70-5.57 (m, 1H), 2.25-1.95 (m, 2H), 1.90-1.66 (m, 6H).
Reaction SMILES: [Br:1][CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[CH:6]=1)=O.[NH:17]1[CH2:21][CH2:20][NH:19][C:18]1=[S:22].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]([C:3]3[N:19]4[CH2:20][CH2:21][N:17]=[C:18]4[S:22][C:2]=3[CH2:15][CH3:16])=[CH:6][C:7]=2[CH:13]=1
Reactant: CCC(Br)C(=O)c1cc2cc(Cl)ccc2s1
Reactant: S=C1NCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: CCC1=C(c2cc3cc(Cl)ccc3s2)N2CCN=C2S1
Yield: 63.6 %

Procedure:
A mixture of 2-bromo-1-(5-chlorobenzo[b]thiophen-2-yl)butan-1-one (1 g), 2-imidazolidinethione (0.32 g), ethanol (30 ml) and acetic acid (15 ml) was heated under reflux for 24 hours, then the solvents were removed in vacuo. The residue was crystallised from ethanol (100 ml) and the resulting solid was collected by filtration, washed with ethanol (10 ml) and dried in vacuo at 60° C. to give 3-(5-chlorobenzo[b]thiophen-2-yl)-2-ethyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.8 g) as a white solid, m.p. 282-284° C.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][CH3:9])(=O)=O.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH3:18]>C1(C)C=CC=CC=1>[CH:10](=[N:18][CH2:6][C:7]#[C:8][CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC#CCOS(C)(=O)=O
Reactant: N
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC#CCN=Cc1ccccc1
Reaction time: 6 h
Yield: 65.9 %

Procedure:
2-Butynyl methanesulfonate (18.7 g, 126 mol) and benzaldehyde (17.8 g, 168 mmol) were dissolved in 64 g of toluene and an aqueous 28% ammonia solution (68.1 g, 1.12 mol) was added dropwise at 23° C. over 3.5 hours to the solution, followed by stirring at the same temperature for 6 hours. After separating, the resulting organic phase was washed with water and concentrated to obtain 24.3 g of a crude product containing 17.4 g (yield: 88%) of N-benzylidene-2-butynylamine. To obtain 10.6 g (purity: 98%) of N-benzylidene-2-butynylamine, 17.3 g of this crude product was distilled off.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC([C:25]2([C:36]3[CH:41]=[CH:40][C:39](F)=CC=3)[CH2:30][CH2:29][CH2:28][N:27](CC(O)=O)[C:26]2=O)=CC=1.C1C2C(=CC=CC=2)CCN1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[CH2:26]1[C:25]2[C:30](=[CH:39][CH:40]=[CH:41][CH:36]=2)[CH2:29][CH2:28][N:27]1[C:14](=[O:16])[CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]1=[O:17]
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.35-6.96 (m, 8H), 4.68 (d, J=27.4, 2H), 4.34 (d, 1H), 4.19 (dd, J=7.4, 15.9, 1H), 3.84 (t, J=6.0, 1H), 3.78-3.52 (m, 4H), 3.02-2.81 (m, 2H), 2.68-2.45 (m, 1H), 2.25-2.06 (m, 1H); MS (DCI) m/z 353.1 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]([C:24](Cl)=[O:25])[CH2:19][CH2:18][C:17]2=[O:27]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]([C:24]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:25])[CH2:19][CH2:18][C:17]2=[O:27]
Reactant: C1CCN(CC2CSCCN2)C1
Reactant: O=C1CCC(C(=O)Cl)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CCC(C(=O)N2CCSCC2CN2CCCC2)c2ccc(Cl)cc21
Yield: 132.8 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.38 ml of triethylamine and 1.5 g of 6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 1.76 g of the title compound, melting at 195°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1.Cl[O-].[Na+].[O-:25]Cl=O.[Na+].[OH-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:14])=[O:25])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1
Reactant: [O-][Cl+][O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of the crude product from Step A (approximately 89%, 56.0 g, 0.18 mole) was dissolved in acetonitrile (400 mL) and a solution of NaH2PO4 (120 g, 0.87 mole) in 520 mL of water was added. Sodium hypochlorite solution (5.25% in water, 128 g, 2.6 mole) was added dropwise over 10-15 minutes. The orange solution was maintained at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and a solution of NaClO2 in 560 mL of water was added dropwise, keeping the temperature below 11° C. Gas evolution was observed and an aqueous sodium hydroxide scrubber was used to quench evolved chlorine. After the addition was complete, the reaction mixture was kept cold for one hour then allowed to reach room temperature overnight. To the reaction mixture was added 80 mL of concentrated hydrochloric acid dropwise to bring the pH below 3. The reaction mixture was extracted twice with ethyl acetate and the combined organic extracts were added dropwise rapidly with stirring to a cooled (<15° C.) solution of 300 g of NAHSO3 in 1-300 mL of water. The mixture was partitioned and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was taken up in chlorobutane and reconcentrated (twice). The resulting brown solid was triturated in 100 mL of ethyl ether in hexane (1%). Small portions of chlorobutane were added to help granulate the solid. The product was collected via filtration, washed with hexanes and dried. The product consisted of 40.8 g of tan solid, which was essentially pure based upon 1H NMR.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][C:5]=1[CH2:6][NH:7][C:8](=[O:11])[O:9][CH3:10].C(O)C.[N:22](OC(C)(C)C)=[O:23]>C(OCC)(=O)C.O>[Cl:3][C:4]1[CH:15]=[CH:14][C:13]([C:16](=[N:22][OH:23])[C:17]#[N:18])=[CH:12][C:5]=1[CH2:6][NH:7][C:8]([O:9][CH3:10])=[O:11]
Reactant: COC(=O)NCc1cc(CC#N)ccc1Cl
Reactant: CC(C)(C)ON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COC(=O)NCc1cc(C(C#N)=NO)ccc1Cl
Reaction time: 72 h
Yield: 68.4 %

Procedure:
0.15 g of sodium hydroxide and 0.60 g of methyl N-(2-chloro-5-cyanomethylbenzyl)carbamate were added to 5 ml of ethanol, and 0.40 g of t-butyl nitrite was added to the mixture at room temperature, followed by stirring for 72 hours. After completion of the reaction, the reaction solution was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=3/1) to obtain 0.46 g of 2-[4-chloro-3-(methoxycarbonylaminomethyl)phenyl]-2-hydroxyiminoacetonitrile as a colorless viscous liquid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][NH:21][C:20](=O)[C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C(=O)NCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1CNCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of intermediate 40a (15.6 g) in anhydrous THF (94 m[), at 0° C., under N2, BH3 THF 1M/THF (154 ml) was added. The solution was heated at reflux for 3 hr. HCl 37% (54 ml) was slowly added maintaining the reaction mixture in an ice-bath and the reaction mixture was stirred at rt for 1 hr. Water was then added (125 ml) and solid NaHCO3 (62.4 g) was added portionwise until a pH of 6.5. The aqueous phase was extracted with Et2O (4×160 ml) and the combined organic extracts were dried over Na2SO4, the solids were filtered and evaporated to leave a colourless oil which was purified by flash chromatography (silica gel, EtOAc/Methanol 7/3). The obtained product was suspended in Et2O (220 ml) and washed with NaHCO3 sat. (2×36 ml). The combined organic phases were dried (Na2SO4) and evaporated to give the title compound as white foam (8.7 g.).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]1)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:7][C@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[CH2:19][CH2:20]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester (3.4 g, 10.5 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature overnight then concentrated to afford 1-((R)-2-amino-3,3-dimethyl-butyryl)-piperidine-4-carbonitrile trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:3]
Reactant: Clc1nc2ccccc2s1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)Cc1cccc(OCCCNc2nc3ccccc3s2)c1

Procedure:
3-[3-(Dimethylaminomethyl)phenoxy]propylamine (2.38 g) and 2-chlorobenzthiazole (1.94 g) were fused at 130° C. for 2 hours. The cooled residue was subjected to column chromatography on silica using chloroform followed by chloroform:methanol (25:1) as eluants to give the title compound as a yellow oil. This was converted to 2-[3-[3-(dimethylaminomethyl)phenoxy]propylamino]benzthiazole dihydrochloride (0.37 g), m.p. 154°-155° C. (recrystallised from ethanol/ether).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O-:15])=[O:14])[CH:2]=1.[CH2:16](O)[CH3:17]>[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=1
Reactant: O=C([O-])C=Cc1cnc2ccccc2c1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)CCc1cnc2ccccc2c1

Procedure:
3-quinolineacrylate (51.68 g) was dissolved in ethanol (170 ml) and hydrogenated at 37° and a pressure of 50 psi using 10% Palladium on charcoal to give ethyl 3-quinolinepropionate. p (iii) Ethyl 3-quinolinepropionate (47.99 g) and ethyl formate (16.3 g) were added over a period of 3 hours to a stirred mixture of sodium wire (4.8 g) and dry ether (150 ml) cooled by an ice-bath. The mixture was stirred for 20 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (15.9 g) and ethanol (130 ml) and refluxed for 7 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic acid added to pH 4. The mixture was filtered to give 5-(3-quinolinemethyl)-2-thiouracil, m.p. 281°-6° (decomp.) (ex. acetic acid-water).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=O)[C:11]3[CH:23]=[C:24](F)[C:25](F)=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[C:38]([F:39])([F:40])[F:41])=[O:16])[C:11]3[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-trifluoromethylbenzonitrile. The compound was purified by preparative HPLC using a Gemini column and a gradient of acetonitrile:water (containing 0.5% formic acid). Light brown foam (42%). MS (ES+): M+H: 537.3.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]#[N:15])[CH:5]=1.O.O.[OH-].[Li+]>O1CCOCC1>[C:14]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)[C:3]([OH:16])=[O:2])#[N:15]
Reactant: COC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyano-5-trifluoromethyl-benzoic acid methyl ester (0.084 g, 0.367 mmol) in dioxane (0.5 mL) was added water (0.5 mL) and lithium hydroxide monohydrate (19.2 mg, 0.458 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated, the residue was taken up in dioxane and 10% aqueous citric acid solution and the layers were separated. The aqueous layer was extracted twice with EtOAc and the organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Light brown solid (0.09 g; 98%). MS (ESI): m/z=214.01 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([NH:21][C:22](=[O:35])[C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[NH2:24])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[O:37]=[C:38](Cl)OC(Cl)(Cl)Cl>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([N:21]2[C:22](=[O:35])[C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)[NH:24][C:38]2=[O:37])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(NC(C)=O)cc3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.9 %

Procedure:
Crude 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (≈0.175 mmol) was dissolved in dichloromethane (10 mL) and diisopropylethyllamine (72 μL, 0.41 mmol) was added. The resulting mixture was added to an ice cooled solution of diphosgene (13 μL, 0.109 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 15 minutes, diluted with ethyl acetate (100 mL) and washed with 0.2M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. The solution was filtered and the solvent removed in vacu. The residue was purified by chromatography over silica gel gradient eluted from 50% to 100% ethyl acetate in hexanes to afford 2-{(2S,3S)-2-[(R)-4-(4-acetylamino-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (70 mg, 74%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[C:33]1([C:32]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]#[C:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#C[Si](C)(C)C)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: C[Si](C)(C)C#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
To a solution of {1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (84 mg, 0.16 mmol) in MeOH (0.8 mL) and CH2Cl2 (1.3 mL) was added a 4 molar solution of HCl in dioxane (0.8 mL, 3.1 mmol, 20 equiv) and the resulting solution was stirred at room temperature for 18 h with monitoring by UPLC-MS and the resulting solution was concentrated under reduced pressure. The remaining material (84 mg) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 1 min., gradient to 95% CH2Cl2: 5% MeOH over 10 min.; 95% CH2Cl2: 5% MeOH for 5.2 min.). The resulting partially purified material (48 mg) was triturated with diisopropyl ether to give 1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (18 mg, 24%). The resulting diisopropyl ether solution was concentrated under reduced pressure. The remaining material was triturated with diisopropyl ether to give 1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (20 mg, 30%, 54% total):