Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH2:14][C:15]3[CH:26]=[CH:25][C:18]4[CH:19]=[C:20]([C:22](O)=[O:23])[S:21][C:17]=4[CH:16]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].[Cl-].C(N=C=NCCC[NH+](C)C)C>CN(C=O)C>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:34][C:22]([C:20]1[S:21][C:17]2[CH:16]=[C:15]([CH2:14][C:12]3[O:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:10][N:11]=3)[CH:26]=[CH:25][C:18]=2[CH:19]=1)=[O:23]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(-c2nnc(Cc3ccc4cc(C(=O)O)sc4c3)o2)cc1
Agent: CCN=C=NCCC[NH+](C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Cc3ccc4cc(C(=O)Nc5ccccc5N)sc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1-benzothiophene-2-carboxylic acid (20 mg, 0.055 mmol) and 1,2-phenylenediamine (15 mg, 0.14 mmol) in 1 mL DMF was added 3-{[(ethylimino)-methylene]amino}-N,N-dimethylpropan-1-aminium chloride (16 mg, 0.082 mmol). The reaction was stirred at ambient temperature for 12 hours. Purification by reverse phase mplc gave the title compound as a white solid (TFA salt). 1H NMR (CD3OD) δ 8.19 (s, 1H), 8.00 (s, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.93 (m, 2H), 7.48 (dd, J=8.2, 1.5 Hz, 1H), 7.37 (m, 1H), 7.32 (m, 1H), 7.24 (m, 2H), 7.07 (m, 2H), 4.48 (s, 2H), 3.86 (s, 3H). LC/MS (EI): cal'd 457.1 (MH+), exp 457.1 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[S:33])[NH:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34]I>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([S:33][CH3:34])=[N:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:21][CH2:22]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: Cc1ccc(C)c(NC(=S)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Solvent: ClCCl
Product: CSC(=Nc1cc(C)ccc1C)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 14-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarbothioamide (i.e. the product of Step C) (476 mg, 1.0 mmol) and methyl iodide (0.25 mL, 4.0 mmol) in dichloromethane (2 mL) was agitated at room temperature for 3 h. The reaction mixture was then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give a foamy white solid (480 mg). The solid was crystallized from methyl acetate/petroleum ether to give the title compound, a compound of the present invention, as a white powder (320 mg) melting at 114-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([N:20]([CH2:28][CH2:29][CH3:30])C(=O)OC(C)(C)C)=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:12]=[CH:13][N:14]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([NH:20][CH2:28][CH2:29][CH3:30])=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCCN(C(=O)OC(C)(C)C)c1c(CC)nc2c(-c3ccc(Cl)cc3Cl)nccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCNc1c(CC)nc2c(-c3ccc(Cl)cc3Cl)nccn12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-propylcarbamate was dissolved in ethyl acetate (1 mL), then a 4N hydrochloric acid-ethyl acetate solution (1.9 mL, 7.4 mmol) was added thereto at room temperature, and the mixture was stirred at room temperature for 20 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added thereto, which was extracted with ethyl acetate. The organic layers were combined, which was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:4) to give the title compound (151 mg) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M62) (0.36 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (234 mg, 86%).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(OC)c2)[nH]c1=O
Reaction time: 17 h
Yield: 31.8 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 3-methoxyaniline (8.5 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (4.3 g). M.p. 233°-234° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:27]5[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(SC)cc5)cn4)CC3)nc2)cc1
Yield: 43.7 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-methylthiophenylboronic acid (202.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as pale yellow needles (melting point: 252.0-255.0° C.) (109.0 mg, yield: 43%).
Reaction SMILES: C(S)CCCCCCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19][C:20](=[O:35])[CH2:21][C:22]1[C:26]2[C:27]([Cl:33])=[CH:28][C:29]([O:31]C)=[CH:30][C:25]=2[S:24][C:23]=1[CH3:34]>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:35])[CH2:21][C:22]1[C:26]2[C:27]([Cl:33])=[CH:28][C:29]([OH:31])=[CH:30][C:25]=2[S:24][C:23]=1[CH3:34]
Reactant: COC(=O)Cc1c(C)sc2cc(OC)cc(Cl)c12
Agent: CCCCCCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C)sc2cc(O)cc(Cl)c12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 87.6 %

Procedure:
To a solution of 1-dodecanethiol (3.38 mL) in toluene (5.0 mL) was added aluminum chloride (627 mg) at 0° C. After being stirred at 0° C. for 50 min, to the solution was added a mixture of methyl(4-chloro-6-methoxy-2-methyl-1-benzothiophen-3-yl)acetate (670 mg) in toluene (10 mL) at 0° C. The mixture was stirred at 80° C. for 14 h. To the suspension was added aluminum chloride (627 mg) again. The mixture was stirred at 80° C. for 5 h. The mixture was quenched with water and 1N HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in MeOH (2.0 mL), and to the solution was added conc.H2SO4 (0.025 mL). The mixture was stirred at 80° C. for 2 h. The mixture was concentrated and the residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was washed with hexane to give the title compound (557.8 mg).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13].Cl>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]2[CH2:16][CH2:15][O:14][C:12]2=[O:13])=[CH:5][CH:4]=1
Reactant: O=C1OCCC1Br
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1OCCC1Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Sodium (23 g, 1 mol) is added in pieces to a reactor containing ethanol (1 l). The temperature of the reaction medium is stabilised at 70° C. (exothermic) before adding a solution of 4-bromophenol (173 g, 1 mol) in ethanol (150 ml). After cooling to room temperature, α-bromo-γ-butyrolactone (83 ml, 1 mol) is added slowly. The reaction medium is stirred for ten hours and is then treated by adding 1N hydrochloric acid solution (600 ml). The aqueous phase is extracted with ethyl acetate (2×1 l) and the combined organic phases are washed with water (1 l), dried over sodium sulphate, filtered and concentrated. The residue obtained is recrystallised from isopropanol (2.2 l) to give the expected compound in the form of a white powder (80.1 g, 31%).
Reaction SMILES: I[C:2]1[C:3]([CH3:19])=[N:4][C:5]([NH2:18])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[C:3]([CH3:19])[N:4]=[C:5]([NH2:18])[N:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 3.0 g (7.7 mmol) 5-iodo-4-methyl-6-(4-methanesulfonyl-phenyl)-pyrimidin-2-ylamine (A-33) and 1.6 mL (12 mmol) trimethylsilylethyne using 147 mg (0.77 mmol) CuI, 541 mg (0.77 mmol) PdCl2(PPh3)2 and 11 mL (7.7 mmol) triethylamine in 18 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica (DCM/MeOH gradient). Yield: 2.45 g (71%, approximately 80% pure).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][NH:25][C:26](=[O:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([NH:25][CH3:24])=[O:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:10][CH2:11]1
Reactant: CNC(=O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CNC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 45.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (9.45 g) and N-methyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (6.26 g) in 2-propanol (80 mL) was added piperidinium acetate (4.05 g). The reaction mixture was stirred at 80° C. for 3.5 hr and concentrated. Water and THF were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/heptane to give the title compound (6.50 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13].N1CCCCC1.C(O)(=O)C>C(Cl)Cl.CN(C=O)C.CCCCCCC>[CH2:10]([O:9][C:1](=[O:8])[C:2](=[CH:25][C:22]1[CH:21]=[N:20][C:19]([NH:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:27])=[CH:24][CH:23]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cn1
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a solution of diethyl malonate (710 μL, 4.7 mmol) and (5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.04 g, 4.7 mmol) in methylene chloride/DMF (1:1, 5 mL) was added piperidine (46 μL, 0.47 mmol) and acetic acid (27 μL, 0.47 mmol). The reaction mixture was stirred for 72 h at room temperature and then for 16 h at 45° C. Heptane was added slowly to give 2-(6-tert-butoxycarbonylaminopyridin-3-ylmethylene)-malonic acid diethyl ester (0.69 g, 40%) as grey crystals.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[F:29][C:26]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][CH:10]=[C:9]3[NH2:8])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccnc3c(Nc4cccc(C(F)(F)F)c4)cccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc2c(Nc3cccc(C(F)(F)F)c3)cccc12
Yield: 93.1 %

Procedure:
A solution of N4-(4-methoxybenzyl)-N8-(3-(trifluoromethyl)phenyl)quinoline-4,8-diamine (180 mg, 0.425 mmol) in TFA (2 mL) was stirred at 80° C. for 2 h. Then the reaction mixture was quenched with a saturated solution of NaHCO3 and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated. The residue was triturated with Et2O to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.86 (s, 1H), 8.30 (d, J=4.5 Hz, 1H), 7.66-7.43 (m, 4H), 7.38 (t, J=7.8 Hz, 1H), 7.21-7.18 (d, J=7.8 Hz, 1H), 6.83 (m, 3H), 6.60 (d, J=5.1 Hz, 1H).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])[CH3:6].C(O[C:18](=O)[CH2:19][C:20]1[S:24][CH:23]=[N:22][C:21]=1[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)C>C(Cl)Cl>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:21]1[N:22]=[CH:23][S:24][C:20]=1[CH2:19][C:18]1[N:7]([CH2:5][CH3:6])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]=1
Reactant: CCOC(=O)Cc1scnc1-c1nccs1
Reactant: CCNc1ccncc1N
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCn1c(Cc2scnc2-c2nccs2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (2M in toluene)(2.2 mL, 4.4 mmol) is added dropwise under N2 yo a solution of N4-Ethyl-pyridine-3,4-diamine (237 mg, 1.73 mmol) in DCM (5 mL). The mixture is stirred at room temperature for 1 hour. A solution of [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester (440 mg, 1.73 mmol mmol) in DCM (2 mL) is added. The mixture is reluxed for 3 days. On cooling, the reaction is quenched with water added dropwise and DCM (40 mL) is added. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 2-[2,4′]bithiazolyl-5′-ylmethyl-1-ethyl-1H-imidazo[4,5-c]pyridine as a solid. 1H NMR (CDCl3) δ 9.05 (s, 1H0), 8.76 (s, 1H), 8.41 (d, 1H), 7.88 (d, 1H), 7.41 (d, 1H) 7.25 (d, 1H), 5.35 (s, 2H), 4.26 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]3[C:20]([C@@H:21]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=4[Cl:31])[CH3:22])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH:9]=[N:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:31][C:24]1[C:25]([F:30])=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C@H:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:4]([CH3:5])([CH3:6])[CH2:3][OH:2])[CH:11]=3)[CH:13]=2)[NH:18][CH:19]=1)[CH3:22]
Reactant: COC(=O)C(C)(C)n1cc(-c2cnc3[nH]cc([C@H](C)c4c(Cl)ccc(F)c4Cl)c3c2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C(C)(C)CO)c3)cc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-{3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridin-5-yl}-pyrazol-1-yl)-2-methylpropionic acid methyl ester (64.0 mg, 0.135 mmol) in THF (3.0 mL) was added 2 M of LiAlH4 in THF (0.20 mL, 0.40 mmol) under N2 at −78° C. The reaction mixture was stirred for 1 h at −78° C., quenched by adding water, warmed to rt, filtered, and concentrated in vacuo. Purification of the residue by HPLC afforded the title compound. A crystal structure of the title compound bound to cMet confirmed the absolute configuration as shown. 1H NMR (400 MHz, CD3OD): δ=1.58 (s, 6 H), 1.88 (d, J=7.2 Hz, 3 H), 3.75 (s, 2 H), 5.28 (q, J=7.2 Hz, 1H), 7.18 (t, J=8.6 Hz, 1 H), 7.35 (d, J=1.3 Hz, 1 H), 7.37-7.39 (m, 1H), 7.41 (brs, 1H), 7.58 (s, 1 H), 7.91 (s, 1 H), 8.32 (d, J=1.8 Hz, 1H). MS (ES+): m/z 447.09/449.04 (100/70) [MH+]. HPLC: tR=3.50 min (ZQ3 polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[C:8](OCC)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][N:1]=[C:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: NCCNCCO
Product: CCCCCCCCCCCC1=NCCN1CCO
Yield: 69.3 %

Procedure:
58.7 g (564.4 mmoles) of 2-(2-aminoethylamino)ethanol and 122.8 g (538.6 mmoles) of ethyl dodecanoate were heated at 125° C. and ethanol was removed by distillation. 100 ml of toluene was cautiously added and water was removed azeotropically on further reflux. The reaction mixture was fractionally distilled to give 100.2 g (69.5%) of pure product, m.p. 40°-42° C.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C@H:13]([OH:26])[CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH3:12])C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:10][C@H:11]([CH3:12])[C@H:13]([OH:26])[CH2:14][O:15][Si:16]([CH:17]([CH3:19])[CH3:18])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[Si](OC[C@@H](O)[C@@H](C)NC(=O)OCc1ccccc1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[Si](OC[C@@H](O)[C@@H](C)N)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
Benzyl{(2R,3S)-3-hydroxy-4-[(tripropan-2-ylsilyl)oxy]butan-2-yl}carbamate (3.70 g, 9.35 mmol) synthesized in Example (89d) was dissolved in ethanol (30 mL), and palladium carbon (1.00 g) was added, followed by stirring at room temperature for 8 hours under hydrogen atmosphere. After Celite filtration, the solvent was distilled off under reduced pressure to afford the desired compound (2.65 g, yield ˜100%) as a pale yellow liquid.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])=[CH:26][C:25]=1[F:36].FC1C=C(I)C=CC=1N.O1CCNC1=O.C(N)CN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:36][C:25]1[CH:26]=[C:27]([N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH:28]=[CH:29][C:24]=1[NH:23][C:4]([CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)=[O:22]
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: Nc1ccc(N2CCOC2=O)cc1F
Agent: Nc1ccc(I)cc1F
Agent: O=C1NCCO1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: NCCN
Product: CO[C@H]1CN(CC(=O)Nc2ccc(N3CCOC3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 25.3 {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 3-(4-amino-3-fluoro-phenyl)-oxazolidin-2-one (prepared from 2-fluoro-4-iodoaniline and 2-oxazolidinone in the presence of Cu(I)I, ethylenediamine and potassium phosphate in dioxane at 110° C.) to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-1-{[2-fluoro-4-(2-oxo-oxazolidin-3-yl)-phenylcarbamoyl]-methyl}-4-methoxy-pyrrolidin-3-yl)-amide as yellow solid. MS 497.5 ([M+H]+)
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][CH2:9][C:10]1[C:11]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:13]2[N:14]([C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)[N:15]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][C:11]1[C:10]([CH2:9][O:8][CH2:7][C:6]([OH:37])=[O:5])=[N:15][N:14]2[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:13]2[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1)[CH3:36]
Reactant: CCOC(=O)CCCCc1c(COCC(=O)OC(C)(C)C)nn2c(CC)ccc2c1-c1cncc(C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCc1c(COCC(=O)O)nn2c(CC)ccc2c1-c1cncc(C)c1
Yield: 103 %

Procedure:
A solution of ethyl 5-[2-[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (60 mg) in trifluoroacetic acid (2 mL) was stirred at ambient temperature for 2 hours, and evaporated in vacuo to give {[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}acetic acid as brown oil (55 mg).
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)OCC[O:18]2)[CH:12]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7].Cl>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:18])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1)([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(C2(c3ccccc3)OCCO2)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Yield: 95 %

Procedure:
Methanol (10 ml) and 1 ml of water was added to 2.52 g of methyl α-methylthio-α-[m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl]propionate, and 0.2 ml of conc. hydrochloric acid was added. The mixture was heated for 20 minutes under reflux. After cooling, 20 ml of water was added, and the mixture was extracted with 50 ml and 10 ml respectively of methylene chloride. The extract was washed twice with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel using methylene chloride as an eluent to afford 2.10 g of methyl α-methylthio-α-(m-benzoylphenyl)-propionate as a colorless oil in a yield of 95%.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].FC1C=CC([I:26])=C(C=1)C(O)=O>>[I:26][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1cc(I)ccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting 2-bromo-5-iodobenzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 8.09 (d, J=2.0, 1H), 8.03-7.97 (m, 1H), 7.95-7.86 (m, 3H), 7.53 (d, J=8.4, 1H).