Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)OC(C)(C)C)CC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)O)CC3)cc12
Reaction time: 0.33 h

Procedure:
A solution of Example 226A (0.43 g, 0.983 mmol) and trifluoroacetic acid (1.817 mL, 23.59 mmol) in dichloromethane (9.83 mL) was stirred at ambient temperature for 24 hours. The mixture was concentrated, dissolved in 5 mL dichloromethane and 2N hydrogen chloride in ether (20 mL) was added. The suspension was stirred for 20 minutes, treated with ether (50 mL), and filtered. The solid was washed with ether and dried under vacuum to afford the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 2.84-2.92 (m, 2H), 3.50-3.63 (m, 2H), 3.74 (s, 3H), 4.03-4.11 (m, 2H), 4.14 (s, 2H), 6.40 (s, 1H), 6.46-6.56 (m, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.16-7.29 (m, 3H), 8.26 (d, J=5.1 Hz, 1H), 12.07 (bs, 1H). MS (ESI+) m/z 382.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[CH2:7][N:8]([CH3:10])[CH3:9].[CH2:14]([O:18]C=C)[CH2:15]CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:9][N:8]([CH2:7][C:6]1[CH:11]=[C:2]([C:14](=[O:18])[CH3:15])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13])[CH3:10]
Reactant: COc1ccc(Br)cc1CN(C)C
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1CN(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
(5-Bromo-2-methoxy-benzyl)-dimethyl-amine (29 mmol), Butoxy-ethene (100 mmol), Palladium acetate (0.9 mmol), 1,3-Bis(diphenylphosphino)propane (1.8 mmol), and potassium carbonate were suspended in DMF (50 ml) and H2O under argon. Heated at 80° C. overnight. Poured into hydrochloric acid (2 M) and stirred for 1 hour. The mixture was adjusted to basic pH and extracted with CH2Cl2. The organic phase was evaporated on celite and the residue was purified by flash chromatography to give the title product as orange oil in 42% yield.
Reaction SMILES: [CH:1]([CH:4]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]([O:7]CC)=[O:6])([CH3:3])[CH3:2].[OH-].[K+].CO>O>[CH:1]([CH:4]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C=Cc1ccc(F)cc1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of the above ester (0.46 g), potassium hydroxide (2.5 mmol), 3 ml methanol and 0.5 ml water is stirred at about 45° overnight. Methanol is removed by evaporation and then 5% NaOH-ether is added. After adjusting to about pH 3 by addition of dilute HCl, the mixture is extracted with ether. The ether phase is washed with water and brine, dried over sodium sulfate, and solvent evaporated to yield 2-isopropyl-4-(4-fluorophenyl)-3-butenoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH2:7][CH2:8]Cl)=[CH:4][CH:3]=1.[CH2:12]([NH:16][CH3:17])[CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[Na+].[Na+].[OH-].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH2:7][CH2:8][N:16]([CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCCNC
Reactant: ClCCNc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN(C)CCNc1ccc(Cl)cc1
Yield: 72.2 %

Procedure:
5.70 g of 2-(4-chloroanilino)ethylchloride, 5.28 g of n-butylmethylamine and 6.36 g of Na2CO3 were refluxed while stirring for approximately 24 hours in toluene as a solvent. After the addition of a solution of 1.80 g of 90% KOH in 15 ml of water the reaction mixture was extracted with diethyl ether. The ether layer was washed with water, dried and filtered. After evaporating the solvent approximately 6 g of product were obtained which was identified by means of thin layer chromatography. The product was purified via the HCl salt, after which 5.21 g of a light-brown oil were obtained; identification by means of N.M.R. spectrum.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:35](=[O:36])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:26][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Glycine ethyl ester.hydrochloride in an amount of 20.6 g was dissolved in 500 ml of chloroform and 20 ml of triethylamine was added thereto. Then, 57.2 g of carbobenzoxyphenylalanine p-nitorphenyl ester was added to the resulting mixture and the reaction was carried out overnight at room temperaure. The resulting mixture was washed with IN-NaHCO3, water, IN-HCl and water in this order and the chloroform layer was dried over magnesium sulfate MgSO4). After removing the solvent by distillation, the residue was recrystallized from ethyl acetate and petroleum ether to give carbobenzoxy-phenylalanyl-glycine ethyl ester having a melting point of 110°-112° C. in yield of 40.5 g (81%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][O:36][CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: COCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (153 μl, 1.1 mmol) was added followed by methoxyacetic acid (31 μl, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) and the product was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.BrN1C(=[O:30])CCC1=O.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O1CCOCC1.O.C(O)(=O)C>[O:30]1[C@@H:17]2[C@:18]31[C@H:7]([C@H:8]1[C@:15]([CH3:23])([CH2:16]2)[C@@H:11]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:9]1)[CH2:6][CH2:5][C@@H:4]1[C@:19]3([CH3:22])[CH2:20][CH2:21][C@@H:2]([OH:1])[CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@@]34O[C@H]4C[C@]12C
Reaction time: 0.08 h
Yield: 25.5 %

Procedure:
3α-Hydroxy-5α-pregn-9(11)-en-20-one (500 mg.) was dissolved in dioxan (50 ml.) and water (12.5 ml.) under nitrogen; N-bromosuccinimide (325 mg.) was added followed by perchloric acid (60% w/v; 0.175 ml.) in water (5 ml.) and the reaction was allowed to stand at room temperature for 5 min. The pH was adjusted to 11.7 with 2N sodium hydroxide and the reaction mixture was allowed to stand at room temperature for a further 15 mins. The pH was adjusted to 6 with glacial acetic acid and the mixture was poured into water. The steroid was extracted with chloroform and triturated with ether to give a white solid; crystallisation from ether followed by crystallisation from methyl acetate-petrol gave the title compound (134 mg.), m.p. 160°-162°, [α]D + 101°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6].[C:18]([O:21][CH2:22][C:23](Cl)=O)(=[O:20])[CH3:19]>O1CCOCC1>[C:18]([O:21][CH2:22][C:23]1[N:11]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc(C(=O)O)ccc1NC1CCOCC1
Solvent: C1COCCO1
Product: CC(=O)OCc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.6 %

Procedure:
A 4-neck flask (1 L) equipped with a reflux condenser was charged with 3-amino-4-((tetrahydropyran-4-yl)amino)benzoic acid (14.53 g, 45.65 mmol) and anhydrous 1,4-dioxane (226 mL) and this was refluxed. Acetoxyacetyl chloride (12.57 g, 92.07 mmol) in 1,4-dioxane solution (100 mL) was added dropwise to this over approx. 15 minutes. This was stirred under these conditions for 13 hours. This was allowed to cool to room temperature, and after the precipitated crystals were filtered off, they were washed with distilled water, and dried under reduced pressure with heating to yield the title compound (13.46 g, 92.6% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C:11]1[S:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C:11]1[S:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])s1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(N)s1)NC(=O)OC(C)(C)C
Yield: 93.9 %

Procedure:
A solution of Ethyl N-(tert-butoxycarbonyl)-3-(5-nitro-2-thienyl)-DL-alaninate (4.92 g, 14.3 mmol) in ethanol (75 ml) was hydrogenated over 10% palladium/Charcoal (2.0 g) at 25 psi for 6 hours using a Parr hydrogenation apparatus. The mixture was filtered through a pad of celite. The solvent was removed at reduced pressure to give Ethyl N-(tert-butoxycarbonyl)-3-(5-amino-2-thienyl)-DL-alaninate (4.22 g, 94%) as a dark yellow solid. Melting point=132° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][CH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][CH2:14][NH:13][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)#[N:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1ccc(CCN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice bath cooling, 5.82 ml (15.57 mmol) of benzyl chloroformate (45% in toluene) were added to a solution of 2.37 g (12.98 mmol) of 4-(2-aminoethyl)benzonitrile hydrochloride and 4.34 ml (31.14 mmol) of triethylamine in 95 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 2:1 to 1:1).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[NH:5][C:6]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)=[N:7]2.[CH3:21][O-:22].[Na+].CO.O>CN(C=O)C.C(O)(=O)C>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:20])[NH:5][C:6]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7]2)=[C:2]([O:22][CH3:21])[CH:11]=1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cc(F)cc2nc(-c3ccnc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5,7-difluoro-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one (0.30 g, 1.09 mmol) in anhydrous DMF (8 mL) was added a solution of sodium methoxide in methanol (25 wt %, 0.59 g, 10.9 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Water was added, the mixture was acidified to pH approximately 5 with acetic acid, and the precipitated solid was filtered and dried under vacuum to give 7-fluoro-5-methoxy-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.24 g (76%).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: C1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCCCC2)nc1

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and piperidine. MS calcd. for C27H25ClN4O2 [(M+H)+] 473.2, obsd. 473.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Reaction time: 2 h

Procedure:
113.4 g (0.387 mol) of 4-chloro-3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added a little at a time at -40° C. to 500 ml of 98% strength nitric acid. The mixture was stirred at this temperature for 2 hours and then the solution was stirred into ice. The product was extracted from the aqueous phase with dichloromethane. The dichloromethane phase was subsequently washed a number of times with water and then with saturated sodium chloride solution. Drying over magnesium sulfate and removal of the dichloromethane gave 119.6 g of the target product.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]>C(O)(C)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH3:17])[CH2:15][C:14]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)OCC
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CC(C)O
Product: CCOC(=O)CC(C)N1CCC(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
A solution of 4-benzyl piperidine (0.50 mL, 2.8 mmol) and ethyl crotonate (0.46 mL, 3.4 mmol) in isopropanol (10 mL) was refluxed for 24 h and was concentrated in vacuo. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as solvent to afford the title compound as a pale yellow oil (0.64 g, 74%): 1H NMR (CDCl3) δ1.09 (d, J=6.6 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 1.20-1.40 (m, 2H), 1.45-1.61 (m, 1H), 1.68 (bd, J=12.3 Hz, 2H), 2.10-2.35 (m, 3H), 2.57 (d, J=6.9 Hz, 2H), 2.50-2.70 (m, 1H), 2.82 (bd, J=10.8 Hz, 2H), 3.15-3.30 (m, 1H), 4.18 (q, J=6.9 Hz, 2H), 7.18 (d, J=7.2 Hz, 2H), 7.24 (m, 1H), 7.32 (t, J=6.9 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([C:31]2[CH:36]=[CH:35][C:34]([S:37][CH:38]3[CH2:40][CH2:39]3)=[CH:33][CH:32]=2)=[CH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[N:13][C:14]=1[O:15][CH3:16]>ClCCl>[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[N:13][C:12]([C:17]([C:31]2[CH:32]=[CH:33][C:34]([S:37][CH:38]3[CH2:39][CH2:40]3)=[CH:35][CH:36]=2)=[CH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: COc1nc(C(=C[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(SC3CC3)cc2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C(=C[C@H]2CCNC2)c2ccc(SC3CC3)cc2)ccc1Cl
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl (3R)-3-{2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(cyclopropylsulfanyl)phenyl]ethenyl}pyrrolidine-1-carboxylate (EZ mixture) (296 mg) in dichloromethane (3 mL) under ice-cooling, followed by stirring for three hours. The reaction solution was concentrated under reduced pressure to give 3-chloro-6-{1-[4-(cyclopropylsulfanyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]ethenyl}-2-methoxypyridine (EZ mixture) as a crude product (235 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.O.O.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C2(C)SC(N[C@@H](C)c3ccc(F)cc3)=NC2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)O)cc2)S1)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoate (0.64 g, 1.7 mmol) in THF (3 mL), MeOH (1 mL), and H2O (1 mL) was added lithium hydroxide monohydrate (0.10 g, 2.5 mmol), and the mixture was stirred at ambient temp. overnight. The mixture was then heated to reflux for 5 h. The mixture was neutralized with 1N HCl, and then extracted with CH2Cl2 five times. The organic extracts were dried over Na2SO4, concentrated in vacuo, and the product was dried on vacuum. MS: 373 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[CH:19]=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[CH3:25])[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
0.072 g (0.23 mmol) of 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde are dissolved in 10 ml of tetrahydrofuran under a stream of nitrogen. The medium is cooled to 0° C. for slow addition of 0.23 ml (0.68 mmol) of a methylmagnesium bromide solution (3M in ethyl ether). The medium is subsequently brought back to ambient temperature and stirred for 1 hour 30 minutes. Neutralization is carried out by adding, under cold conditions and dropwise, a saturated aqueous ammonium chloride solution and then dilution is carried out with dichloromethane and water. The pH of the medium is adjusted to 9-10 by addition of a saturated aqueous sodium carbonate solution. The medium is filtered through a hydrophobic cartridge (70 ml liquid/liquid extraction column, Radleys®) and the organic phase is recovered and concentrated under reduced pressure after having added 0.8 g of silica. The residue obtained is purified by chromatography on silica gel, elution of the solid deposit being carried out with a mixture of cyclohexane and ethyl acetate (8/2). 0.056 g (74%) of the expected product is obtained in the form of a white powder.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:11]([NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[O:12])=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NS(=O)(=O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-benzenesulfonyl-3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=12)=[O:4].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[C:26]([Cl:31])[N:25]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([O:14][C:28]3[CH:27]=[C:26]([Cl:31])[N:25]=[C:24]([NH2:23])[N:29]=3)[CH:11]=[CH:10][C:9]=12)=[O:4]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COC(=O)c1cnn2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnn2cc(Oc3cc(Cl)nc(N)n3)ccc12
Temperature: 70 °C
Reaction time: 20 h

Procedure:
58.9 mg Product from Step 15.6 (0.31 mMol) are dissolved in 8 ml NMP and treated with 268 mg (1.2 mMol) K3PO4 and 75 mg (0.46 mMol) 2-amino-4,6-dichloropyrimidine at rt. The reaction mixture is warmed to 70° C. and stirred for 20 h at rt. It is worked up by addition of EtOAc and washed with H2O. The organic layer is dried and concentrated to give the crude product which is purified by recrystallization from EtOAc to give the title compound as a white powder: MS: [M+1]+=320; 1H MNR (DMSO-d6): δ ppm 9.18 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H), 7.60 (d, 1H), 7.21 (bs, 2H, NH2), 6.42 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([CH3:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[CH3:34])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cc(N2C(=O)CC[C@H]2CO)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 33.8 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (153 mg) and (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 124 and by the reaction and treatment in the same manner as in Example 1, the title compound (183 mg) was obtained.