Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:18]2C=CC=CC=2)([C:13](OCC)=[O:14])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[H-].[Na+].C([O-])(O)=O.[Na+].[Li].[H-]>C1COCC1>[CH3:18][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:13][OH:14])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C(=O)OCC)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: CC(CO)(CO)c1ccccc1
Temperature: 25 °C

Procedure:
Diethyl diphenylmalonate (10 g, 42.4 mmol) and iodomethane (6.6 g, 46.6 mmol) was mixed in anhydrous THF (200 ml) at room temperature before NaH powder was added in several portions. The reaction finished instantly with release of heat. After cooled down to room temperature, aqueous NaHCO3 solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with water, brine, dried with Na2SO4 and concentrated. A clean NMR spectrum of the crude product identified it as the desired product. 1H NMR (500 MHz, CDCl3) δ ppm 1.26 (t, J=7.17 Hz, 6 H) 4.24 (m, 3 H) 7.34 (m, 5 H). The crude product was then dissolved in anhydrous THF (200 ml) and cooled to −20° C. Lithium aluminun hydride (42.4 mmol) was added via dropping funnel within 10 minutes. The reaction mixture was warmed up naturally to room temperature and quenched with ethyl acetate and water. The orgamic layer was washed with brine and dried with Na2SO4 before being concentated in-vacuo. The crude product was purified by silica flash chromatography using 50% ethyl acetate in hexanes to yield 4.35 grams (62% in two steps) of the desired product. 1H NMR (500 MHz, CDCl3) δ: 3.85 (m, 3 H) 3.98 (d, J=10.99 Hz, 2 H) 7.27 (m, 1 H) 7.38 (t, J=7.93 Hz, 2 H) 7.44 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:9]/[CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])[CH:3]=1.[CH:17]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH2:18]>C1COCC1.C([O-])(=O)C.[Ag+]>[C:22]1([S:19]([CH:17]2[CH2:18][C:10]3([CH2:14][CH2:13][N:12]([CH3:15])[C:11]3=[O:16])[NH:9][CH:8]2[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(/N=C/c2cc(Br)ccn2)C1=O
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CN1CCC2(CC(S(=O)(=O)c3ccccc3)C(c3cc(Br)ccn3)N2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[(E)-(4-bromo-2-pyridyl)methyleneamino]-1-methyl-pyrrolidin-2-one (which may be prepared as described in Description 1) (564.3 mg, 2 mmol) and phenyl vinyl sulfone (339.8 mg, 2.02 mmol) in THF (10 mL) was treated with silver acetate (333.99 mg, 2 mmol). The mixture was stirred at room temp for 2 hours, filtered through Celite and concentrated to give the title compound as a brown gum;
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]2[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:27]=1)(=[O:5])=[O:4]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cccc(N2CCOCC2)c1)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.18 ml (12.9 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 1.54 g (8.6 mmol) of 3-(4-morpholinyl)-phenol and 3.59 ml (25.8 mmol) of triethylamine in 10 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 2.41 g (90.1% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[NH:20][C:19](=[O:21])[CH:18]=[N:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]([CH3:23])[C:19](=[O:21])[CH:18]=[N:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cncc(=O)[nH]1
Reactant: CI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cncc(=O)n1C

Procedure:
The title compound, yellow cristalline solid, MS: m/e=326.1, 328.2 (M+H+), was prepared in accordance with the general method of example 3 from 6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-1H-pyrazin-2-one and methyl iodide, along with the O-alkylation product from which it was separated by flash chromatography (gradient: EtOAc to EtOAc/MeOH 95:5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>C1COCC1.CCOC(C)=O.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#CCO)c2)c1F)c1[nH]cnc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (100 mg, 0.203 mmol), dichlorobisthiphenylphosphinepalladium(II) (14.22 mg, 0.020 mmol), copper(I) iodide (1.929 mg, 10.13 μmol) and TEA (0.141 ml, 1.013 mmol) in THF (5 ml) was added propargyl alcohol (22.72 mg, 0.405 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(3-hydroxy-1-propyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (18 mg, 0.038 mmol, 19% yield).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].N.C([N:38](CC)CC)C>O1CCOCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH2:38])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Agent: N
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(N)(=O)=O)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 7 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. dioxane (5 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 60 mg, 75 μmol) was added and the solution was cooled to 7° C. Dry ammonia gas was then introduced for 15 min, and the mixture was then cooled to 0° C. Triethylamine (11 μl, 75 μmol, 1 eq.) was added, and the reaction was then stirred for 12 h, during which time the mixture gradually warmed to RT. The solvent was then distilled off under reduced pressure, and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (33 mg, 90% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6])[CH3:2].ClCCl.Cl[CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl.CCCCCC>CCCCCC.C(OCC)(=O)C>[CH3:8][CH:7]([CH3:9])[C@H:5]([N:6]1[CH2:18][CH:17]=[CH:16][CH2:15]1)[C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: ClC/C=C\CCl
Reactant: CCOC(=O)[C@@H](N)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C(C)C)N1CC=CC1
Yield: 52 %

Procedure:
From L-valine ethyl ester (1.0 g, 6.9 mmol), dichloromethane (1 ml) and cis-1,4-dichloro-2-butene (250 mg, 2.0 mmol). Flash chromatography: silica gel, gradient neat hexane to hexane:ethyl acetate (1:2) afforded the product (205 mg, 52%) as yellow oil.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].CC(C)([O-])C.[K+].[N+:38]([C:41]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:42]=1[CH:43]=O)([O-:40])=[O:39].Cl>C1COCC1>[N+:38]([C:41]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:42]=1[CH:43]=[CH:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:11][CH:10]=1)([O-:40])=[O:39]
Reactant: COC(=O)c1ccc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=Cc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a solution of 4-methoxycarbonylphenylmethyltriphenylphosphine bromide (4.83 g) in THF (20 ml), potassium t-butoxide (600 mg) was added. The mixture was stirred for 1 hour at room temperature. To the reaction solution, 2-nitro-5-chlorobenzaldehyde (742 mg) was added at 0° C. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into diluted HCl. The mixture was extracted with hexane-AcOEt. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) and recrystallization from the mixture solvent of hexane-AcOEt to give the title compound (680 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S:11][CH3:12].ClN1C(=O)CCC1=O>C(Cl)Cl>[CH3:10][S:11]([CH3:12])=[N:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CSC
Reactant: Cc1cc(C)nc(N)n1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(N=S(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of 12.3 g (0.10 mole) of 2-amino-4,6-dimethylpyrimidine and 8 ml (0.109 mole) of methylsulfide in 100 ml of methylene chloride at -20° C. was added dropwise a solution of 13.3 g (0.10 mole) of N-chlorosuccinimide in 300 ml of methylene chloride. After addition, the resulting solution was warmed to room temperature and was kept at room temperature for one hour with stirring. The solution was then washed with 400 ml of 2.5% sodium hydroxide aqueous solution and then 400 ml of water. This solution was dried over sodium sulfate and filtered. The filtrate was washed with ethyl ether, and dried under vacuum at ambient temperature to afford 4 g of the title compound as a white solid, m.p. 117°-120° C.
Reaction SMILES: [F:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[C:9]2[CH:10]=[N:11][C:2]([F:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)ncc12
Product: Fc1cc2ncnc(Cl)c2cn1

Procedure:
A suspension of 7-fluoro-4-oxo-3H-pyrido[4,3-d]pyrimidine (0.23 g, 1.39 mmol) in POCl3 (10 mL) is stirred under reflux for 3.5 h, and is then concentrated under vacuum. The resulting oil is ice-cooled, diluted with CH2cl2 (100 mL), saturated aqueous Na2CO3 (40 mL) and ice, and stirred at 20° C. for 2 h. The CH2Cl2 extract is separated and the aqueous portion further extracted with CH2Cl2 (2×100 mL), and then the combined extracts are dried (Na2SO.) and filtered to give crude 4-chloro-7-fluoropyrido[4,3-d]pyrimidine. 3-Bromoaniline (1.26 g, 7.35 mmole), 3-bromoaniline hydrochloride (20 mg) and dry isopropanol (5 mL) are added, then the resulting solution is concentrated under vacuum to remove the CH2Cl2 and stirred at 20° C. for 1 h. Upon addition of dilute NaHCO3 and water, the product crystallises. Filtration, washing with water and CH2Cl2, gives pure 4-(3-bromoanilino)-7-fluoropyrido[4,3-d]pyrimidine (297 mg, 67%) as a cream solid. 1H NMR (DMSO) δ 10.38 (1H, brs), 9.59 (1H, s), 8.72 (1H, s), 8.17 (1H, s), 7.85 (1H, m), 7.38 (3H, m)
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.O1CCCC1>O>[CH:10](/[CH:7]1[CH2:6][CH2:5][CH:4]([CH:3]=[O:2])[CH2:9][CH2:8]1)=[CH:11]\[CH2:12][CH2:13][CH3:14]
Reactant: CCC/C=C/C1CCC(=COC)CC1
Solvent: C1CCOC1
Solvent: O
Product: CCC/C=C/C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
2.75 g of 1-(methoxymethylene)-4-(trans-1-pentenyl)cyclohexane [crude product from paragrah (a)] were heated to reflux for 30 minutes with 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) and then stirred at room temperature overnight. The mixture was subsequently treated with 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The extracts were washed with dilute sodium hydrogen carbonate solution and water and the aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting, yellowish liquid (2.5 g) on silica gel with petroleum ether and ethyl acetate/petroleum ether (vol. 3:97) gave 1.65 g (76%) of 4-(trans-1-pentenyl)cyclohexanecarboxaldehyde.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[C:27]([O:33]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:41]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].CO>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[C:27]([OH:33])=[CH:26][C:25]=2[OH:41])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(C(C)C)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in an. DCM and under a nitrogen atmosphere, was cooled to 0° C. 1 MBCl3 in DCM was added drop wise and the solution was stirred under these conditions for 30 minutes. Methanol (2 ml) was added and the reaction mixture was concentrated in vacuo. Purification of the sample by preparative LC/MS gave 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([OH:17])[CH:10]=1>CCO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10][C:11]=1[OH:17])#[N:14]
Reactant: Clc1ncccn1
Reactant: N#Cc1ccc(N)cc1O
Solvent: CCO
Product: N#Cc1ccc(Nc2ncccn2)cc1O
Temperature: 90 °C
Yield: 5 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloropyrimidine (209 mg, 1.8 mmol) and 4-amino-2-hydroxybenzonitrile (123 mg, 0.9 mmol) in 10% aqueous EtOH (5 mL) was heated at 90° C. for 18 h. The title compound was obtained in 5% yield a (10 mg) and used for the next step without additional purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13]CCCC)=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C>CO.C(O)=O.[C].[Pd]>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH2:9][CH2:10][C:11](=[O:13])[NH:1]2)=[N:4][CH:5]=1
Reactant: CCCCOC(=O)/C=C/c1ncc(F)cc1N
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CCc2ncc(F)cc2N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a suspension of 9.1 g of butyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate and 0.9 g of 10% palladium carbon in 30 mL of methanol, 4 mL of formic acid was added, and 15 mL of triethylamine was added dropwise thereto under ice cooling. The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtered out, and the filter residue was washed using 30 mL of toluene. The filtrate and the wash liquid were combined and the solvent was evaporated under reduced pressure. To the obtained residue, 30 mL of toluene was added, the mixture was stirred at 100° C. for 2 hours and 30 minutes. To the reaction mixture, 30 mL of water was added dropwise at 45° C. and the mixture was cooled to 5° C. The solid product was obtained by filtration and washed in the order of water and toluene to give 5.7 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1.N([O-])=O.[Na+].[BrH:19]>O>[Br:19][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C(F)(F)C(F)(F)O2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC1(F)Oc2ccc(Br)cc2C1(F)F
Temperature: 3 °C

Procedure:
A stirred mixture of 5-amino-2,2,3,3-tetrafluorobenzofuran (5.0 g, 0.024 mole) and hydrobromic acid (7.3 ml of a 48% aqueous solution) and water (10 ml) was cooled to 3° C. in an ice bath. While maintaining a temperature of less than 5° C., a solution of sodium nitrite (1.7 g, 0.024 mole) in water was added. After complete addition this mixture was stirred for a brief period, then was added slowly to a stirred, refluxing mixture of cuprous bromid (6.9 g, 0.024 mole) in hydrobromic acid (10 ml of a 48% aqueous solution). After complete addition the mixture was stirred at reflux for 20 minutes, then allowed to cool to room temperature. The reaction mixture was poured into a separatory funnel and diluted with ice water. This mixture was extracted several times with diethyl ether. The extracts were combined and washed first with 100 ml of an aqueous saturated sodium chloride solution, then with two 100 ml portions of a 2 N aqueous sodium hydroxide solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated at atmospheric pressure, yielding 5.9 g of 5-bromo-2,2,3,3-tetrafluorobenzofuran as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:14].Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1
Reactant: Fc1cc(-c2ccncc2)ccc1Br
Reactant: CCOC(=O)[C@H]1CCCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CCCN(c2ccc(-c3ccncc3)cc2F)C1
Temperature: 25 °C

Procedure:
A mixture of 4-(4-bromo-3-fluorophenyl)pyridine (190 mg, 0.00075 mol), ethyl (3S)-piperidine-3-carboxylate hydrochloride (180 mg, 0.00090 mol), sodium tert-butoxide (140 mg, 0.0015 mol), palladium acetate (5 mg, 0.00002 mol) and 2-(di-tert-butylphosphino)biphenyl (7 mg, 0.00002 mol) was evacuated and charged with nitrogen and 1,4-dioxane (5 mL, 0.06 mol). The resulting mixture was refluxed overnight. After cooling to ambient temperature, the mixture was filtered and the filtrate was adjusted with TFA to pH=7.0 and purified by CombiFlash (ethyl acetate in hexanes: 60%) to afford the desired product. LCMS: m/z 329.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[NH:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[NH:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c([nH]1)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2[nH]ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:24])[CH:18]=1)=O.[NH3:35]>CO>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([N:23]([CH3:24])[C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][NH:15][C:10]2[C:9]3[C:14](=[C:5]([C:3]([NH2:35])=[O:2])[CH:6]=[CH:7][CH:8]=3)[N:13]=[CH:12][N:11]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: COC(=O)c1cccc2c(NCc3cccc(N(C)C(=O)c4ccc(OC)cc4)c3)ncnc12
Reactant: N
Solvent: CO
Product: COc1ccc(C(=O)N(C)c2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid methyl ester from step d was dissolved in 1 ml 7N NH3 in methanol in a sealed vessel and stirred for 24 h at room temperature. The reaction mixture was evaporated and purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][S:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:21][S:22][CH2:23][CH2:24][CH2:25][NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CSCCCN
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Product: CSCCCNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Yield: 93.3 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (5.3 g, 18.8 mmol) and 3-methylsulfanyl-propylamine (2.17 g, 20.6 mmol) were combined and treated according to the general procedure described in Part E of Example 1. Recrystallization from isopropanol afforded 6.2 g of (3-methylsulfanylpropyl)-(3-nitro-7-phenylquinolin-4-yl)amine as gold plates.