Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O.[OH-].[Li+:30]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O-:9])=[O:8].[Li+:30]
Reactant: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 123.1 %

Procedure:
To a mixture of methyl 5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinate (D91) (220 mg, 0.548 mmol) in a mixture 1,4-dioxane/water (2 ml/1 ml), lithium hydroxide monohydrate (34.55 mg, 0.823 mmol) was added and the resulting mixture was stirred at 150° C. under microwave irradiation for 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo to afford the title compound (D136) 265 mg
Reaction SMILES: [C:1]([O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][N:9]([CH2:25][CH2:26][CH2:27][Cl:28])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1OC(C)(C)C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)Oc1ccccc1CN(CCCCl)CCNC(=O)C(C)(C)C
Reaction time: 48 h
Yield: 55 %

Procedure:
Compound 14 (1 g, 4.1 mmol), 1-bromo-3-chloropropane (9.7 g, 60 mmol) and K2CO3 (0.56 g, 4.09 mmol) were added to 50 mL CH3CN, and the solution was stirred for 48 h. The solvent was evaporated to dryness and the residue was purified on a silica gel TLC plate that was developed in 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2 yield the desired product as a pale yellow oil (55%). 1H NMR (CDCl3) δ 7.341 (d, 1H, Ar), 7.139 (dd, 1H, Ar), 7.029 (m, 1H, Ar), 6.995 (m, 1H, Ar), 3.592 (s, 2H, —CH2—), 3.539 (t, 2H, —CH2—), 3.167 (m, 2H, —CH2—), 2.583 (ddd, 2H, —CH2—), 2.519 (ddd, 2H, —CH2—), 1.900 (p, 2H, —CH2—), 1.425 (s, 9H, —C(CH3)3), 1.385 (s, 9H, —C(CH3)3). Mass Spec.=399.96 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[NH:11][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:9][C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]1[CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([OH:27])=[O:26].[CH3:31]O>>[O:5]=[C:6]1[NH:11][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:9][C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]1[CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([O:27][CH3:31])=[O:26]
Reactant: CO
Reactant: CCCC(C(=O)O)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution cold solution of methanol (20 mL) was added thionyl chloride (2.90 mL; 40 mmol) dropwise. The acidic solution was added to a flask containing 2-(6-oxo-4-phenyl-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoic acid (1.67 g; 4.71 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and neutralized with a saturated solution of sodium hydrogen carbonate. The suspension was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The product was used as such in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[CH2:10][C:11]1([C:16]([NH:18][CH:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[CH2:10][C:11]1([C:16]([NH:18][CH:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 1 h
Yield: 114.2 %

Procedure:
Next, to the solution of the crude tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoate (38 mg) in DCM (0.7 ml), TFA (0.263 ml, 3.42 mmol) is added. After stirring for 1 hour, the reaction mixture is concentrated to give crude 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoic acid (39 mg).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cccc(Cl)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (2.86 g, 17.2 mmol) and 2-amino-3-chlorobenzonitrile (2.62 g, 17.2 mmol) in DCM (60 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (7.2 mL, 51.6 mmol) was added, followed by dropwise additiona of titanium (IV) chloride solution (1 N in DCM, 10.3 mL, 10.3 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue obtained was used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1N
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1nc(-c2c(F)cccc2F)ccc1N
Yield: 47 %

Procedure:
A solution of methyl 3-amino-6-bromopicolinate (1.0 equiv.), 2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3:1 DME/2M Na2CO3 (0.5 M) was subjected to microwave irradiation at 120° C. for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H2O (25 mL), was further washed with NaCl(sat.) (25 mL), was dried over MgSO4, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difluorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC Rt=2.70 min
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[NH2:20]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH3:16])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:15]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (228 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (40 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=90/10→0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (191 mg) as a colorless transparent oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:6]1[C:5]2=[O:19].[OH-:20].[Na+]>O>[C:5]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=1[NH:8][C:7]1[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:6]=1)([OH:19])=[O:20]
Reactant: [OH-]
Reactant: Cc1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ccc(C(=O)O)cn2)c(C(=O)O)c1

Procedure:
A solution of 10.0 g (39.4 mmol) of 2-methyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid and 78.8 ml of 1 N. NaOH in 500 ml of H2O was heated at reflux for 16 hours. The reaction mixture was evaporated to give a white powder which was triturated with hot EtOH giving the analytical sample upon filtration and drying; yield, 8.25 g (66.5%) mp 348.5° dec.
Reaction SMILES: [CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8].Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8]
Reactant: CO[C@]1(c2csc(Sc3ccc(C(C)=O)cc3)c2)CCO[C@@H]1C
Reactant: NO
Agent: Cl
Product: CO[C@]1(c2csc(Sc3ccc(/C(C)=N/O)cc3)c2)CCO[C@@H]1C
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}acetophenone oxime in 87% yield, m.p. 89°-90° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2Br)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2[N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1-n1cccn1
Temperature: 140 °C

Procedure:
A mixture of 2-amino-N-(4-bromo-3-methyl-isothiazol-5-yl)-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.05388 mmol), 1H-pyrazole (7.339 mg, 0.1078 mmol), Cut (21 mg, 0.1103 mmol), Cs2CO3 (71 mg, 0.2179 mmol) in DMF (2 mL) was degassed with nitrogen and heated at 140° C. in a microwave for 1 h. The insoluble material was filtered off and the filtrate was purified by fractionlynx. The clean fractions were freeze-dried yielding 2-amino-6-fluoro-N-(3-methyl-4-(1H-pyrazol-1-yl)isothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid. (0.63 mg, 1.9%). MS (ES+) 359.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(Cl)Cl)nc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-amino-5-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.830 g, 6.3 mmol) and the mixture stirred at 0° C. To the reaction mixture 2,2-dichloroacetyl chloride (0.923 g, 6.3 mmol) was added dropwise and the mixture was stirred at 0° C. for about 1 hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 25-30% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N:15]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21]
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: O=C1COCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
1.00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen atmosphere and 36.6 mg (40 μmol) tris-(dibenzylideneacetone)-dipalladium(0), 67.1 mg (116 μmol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95° C. for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1.31 g (quantitative)
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=[C:31]5[NH:25][C:26](=[O:27])[NH:28][C:29]5=[O:30])=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cn4ccnc4)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cn5ccnc5)c4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74 mg, 0.233 mmol) in EtOH was added hydantoin (23 mg, 0.233 mmol) and piperidine (23 μL, 0.233 mmol). The mixture was heated at 70° C. for 48 hr and then purified by HPLC to yield 5-((5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=401)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:7]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([OH:24])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCCBr
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCCCC(=O)O)Cc1ccccc1
Yield: 30 %

Procedure:
N-benzylglycine ethyl ester (1.87 ml) and 5-bromovaleric acid ethyl ester (1.92 ml) are dissolved in dimethylformamide (100 ml) and stirred in the presence of potassium carbonate (1.66 g) for 2 days at room temperature. The reaction is quenched with saturated aqueous ammonium chloride solution, and extraction is carried out with ethyl acetate. After drying over sodium sulphate the combined organic phases are concentrated by evaporation. From the obtained residue, 5-(benzyl-ethoxycarbonylmethyl-amino)-pentanoic acid is isolated in a yield of 30% by chromatography using silica gel (ethyl acetate/heptane 1:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:17][C:16]([C:15]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18]
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Temperature: 25 °C
Yield: 87 %

Procedure:
A 2 L 3-neck round bottom flask is charged with 1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone (215 g, 0.88 mol) and dimethylformamide dimethylacetal (1.1 L). The mixture is refluxed for 5 hours and then cooled to room temperature. Solvent is removed under vacuum, and the resulting solid is filtered and washed with MTBE (methyl tert-butyl ether) to give the desired product (229.0 g) in 87% yield as light yellow solid. M.p.=187-189° C.; 300 MHz 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.72-7.64 (m, 3H), 7.46 (s, 1H), 7.13-7.10 (m, 2H), 5.19 (d, J=12.5 Hz, 1H), 3.07 (bs, 3H), 2.55 (bs, 3H). LCMS: 300 [M+H]. Calc. for C16H14FN3O2: C, 64.21; H, 4.71; N, 14.04; found. C, 64.22; H, 4.31; N, 14.10.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:16])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)c1cc(C(C)C)c(OC)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (331 mg, 2.4 mmol) in acetonitrile (10 ml) was treated with dimethyl sulphate (0.2 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (440 mg, 98%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:30](=[O:32])[CH3:31])[CH2:14][CH2:13]1
Reactant: Clc1ccc(Oc2ccccc2NC2CCNCC2)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To an ice cooled solution of [2-(2,4-dichlorophenoxy)phenyl]piperidin-4-ylamine (AMR01040, 132 mg, 0.39 mmol) in dry DCM (5 mL) were added triethylamine (0.137 mL, 0.98 mmol) and acetyl chloride (0.031 mL, 0.43 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-{4-[2-(2,4-dichlorophenoxy)phenylamino]piperidin-1-yl}ethanone (95.3 mg, 64%) as a white solid after, mp 145-146° C. Rf: 0.22 (EtOAc) LC/MS (APCI) tr=1.44 min, m/z 381.29 (63), 379.34 (M++H, 100) HPLC tr=3.10 min (99.31%) 1H NMR (270 MHz, CDCl3) δ 1.36 (2H, m, CH2), 2.06 (2H, m, CH2), 2.08 (3H, s, CH3), 2.89 (1H, m), 3.20 (1H, m), 3.53 (1H, m), 3.74 (1H, m), 4.05 (1H, m), 4.37 (1H, m), 6.63 (1H, m, ArH), 6.74 (1H, dd, J=7.9, 1.5 Hz, ArH), 6.75 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.80 (1H, d, J=8.9 Hz, ArH), 7.03 (1H, m, ArH), 7.12 (1H, dd, J=8.9, 2.5 Hz, ArH) and 7.43 (1H, d, J=2.5 Hz, ArH). Anal. Calcd. for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.90; H, 5.47; N, 7.13%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13][CH2:14][NH:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:8][CH2:7][C:6]=2[CH:29]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:21]=3)[CH2:8][CH2:7][C:6]=2[CH:29]=1
Reactant: Fc1ccc2c(c1)CC[C@H](CN(CCNc1ncccn1)Cc1ccccc1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2c(c1)CC[C@H](CNCCNc1ncccn1)O2
Yield: 54.1 %

Procedure:
A mixture of 8.4 g of (-)-(R)-N-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl) methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,2-ethanediamine and 150 ml methanol was hydrogenated in the presence of 2 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.5 g (55.1%) of (-)-(R)-N-[(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)methyl]-N'-(2-pyrimidinyl)-1,2-ethanediamine; mp. 103.2° C. [α]D 20 =-76.58° (conc.=1% in CH3OH) (comp. 46).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.FC(F)(F)S(O[C:37]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49]([O:51][CH3:52])=[O:50])[CH:38]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:37]2[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49]([O:51][CH3:52])=[O:50])[CH:38]=2)=[CH:6][C:7]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])=[C:10]([F:21])[CH:9]=1
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)cnc2N)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C=C(c2cnc(N)c(-c3ccc(C(=O)OC(C)(C)C)c(F)c3)c2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 95 %

Procedure:
A mixture of tert-butyl 4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-fluorobenzoate (400 mg, 0.966 mmol), (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (1.087 g, 2.90 mmol, Pd(PPh3)4 (112 mg, 0.097 mmol) and cesium carbonate (1.258 g, 3.86 mmol) in THF (10 mL) and water (2 mL) was degassed, then microwave heated to 90° C. for 10 min. At completion, the reaction was diluted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate and concentrated. The crude mixture was purified by flash chromatography over silica gel (20-90% ethyl acetate/heptane) to provide (S)-1-tert-butyl 2-methyl 4-(6-amino-5-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyridin-3-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (470 mg, 95%). LCMS (m/z): 514.3 (MH+), 0.92 min.