Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20]>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Oc1ccc(F)cc1F
Product: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1F
Yield: 98 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2,4-difluorophenol, the titled compound was obtained as yellow solid. (Yield: 98%)
Reaction SMILES: [NH2:1][C:2]([CH:17]([F:19])[F:18])([CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O)[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:22])[CH3:21].Cl>[OH-].[Na+]>[C:20]([NH:1][C:2]([CH:17]([F:18])[F:19])([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCC(N)(C(=O)O)C(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(CCCN)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.9 g of 2-amino-5-tert-butoxycarbonylamino-2-difluoromethylpentanoic acid in 10.5 ml of 1M sodium hydroxide is added at 0° C. simultaneously 0.19 g of acetylchloride and 5 ml of 2M aqueous sodium hydroxide. The reaction mixture is stirred for 3 hours at room temperature. The alkaline aqueous solution is then adjusted to a pH of 2 with hydrochloric acid and extracted with ethylacetate. After usual work-up the solvent is evaporated and the residue taken up in trifluoroacetic acid. After concentration and purification by ion exchange chromatography on a resin 5-amino-2-acetylamino-2-difluoromethylpentanoic acid is obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[Cl:23][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.6g (93.5 mmoles) of 2-(3-hydroxymethylphenoxy)methylquinoline is dissolved in 30 ml of methylene chloride and 3 drops of dimethylformamide is added. 60.7 ml of a 2.0M solution of thionyl chloride in methylene chloride is then added dropwise at 0° C. The mixture is allowed to warm to room temperature and stirred for 5 hours. The solution is worked with sodium bicarbonate solution, dried, concentrated in vacuo and the crude product purified by silica gel HPLC to yield 12.1 g 2-(3chloromethylphenoxy)methylquinoline as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CCO>[OH:14][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A suspension of 7-nitro-1-tetralone (2.00 g, 10.5 mmol) in EtOH (15 mL) was cooled by an ice water bath and treated with NaBH4 (0.40 g, 10.6 mmol) . The mixture was stirred at room temperature for 2 h and then poured into ice water (50 mL) and extracted with EtOAc (3×20 mL). The extract was washed with NaCl solution, dried (MgSO4), filtered and concentrated to give a white solid (1.92 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:13]1[C:14](=[O:27])[NH:15][C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:13]2[C:14](=[O:27])[NH:15][C:16]3[C:21]([N:22]=2)=[CH:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: Fc1ccc2c(c1)NCCC2
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of 7-fluoro-1,2,3,4-tetrahydroquinoline (1 g, 6.61 mmol) in NMP (30 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (900 mg, 3.77 mmol) and then stirred for 2 h at 150° C. The resulting solution was diluted with water ((900 ml). The solids were collected by filtration to afford methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a brown solid (900 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[C:16](=[O:27])[NH:17][N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:20]=1)=O.O1CCCC1.[OH-].[Li+].Cl>O.CO>[O:27]=[C:16]1[C:15]([C:13]2[NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=3[N:12]=2)=[CH:20][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:18][NH:17]1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2cc(-c3ccncc3)n[nH]c2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture consisting of 500 mg of methyl 4-amino-3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]benzoate, 6 ml of tetrahydrofuran (THF), 6 ml of methanol, 6 ml of water and 173 mg of lithium hydroxide is stirred at 50° C. for 5 hours. After cooling to room temperature, the pH is adjusted to 4-5 with 1N HCl, whereupon a precipitate separates out and is filtered off with suction and then washed with water and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(OC([N:49]1[CH2:52][CH:51]([C:53](O)=[O:54])[CH2:50]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:49]1[CH2:52][CH:51]([C:53]([N:22]2[CH2:21][CH2:20][CH:19]([N:14]3[CH2:13][C:12]4[C:16](=[CH:17][C:9]([NH:8][C:5]5[N:4]=[C:3]([NH:29][C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=5)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=4)[C:15]3=[O:18])[CH2:24][CH2:23]2)=[O:54])[CH2:50]1
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCN(C(=O)C3CNC3)CC1)C2
Reaction time: 1 h

Procedure:
To a solution of 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one C (41 mg, 0.07 mmol) in DMF (1.0 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (14 mg, 0.07 mmol), HATU (39 mg, 0.104 mmol), and DIEA (0.138 mmol, 24 μL) sequentially. The reaction mixture was stirred for 1 h, then partitioned between EtOAc and water. The organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was stirred in a solution of DCM (1 mL) and TFA (1 mL) at room temperature for 1 h. The resulting solution was concentrated and then purified by preparative RP-HPLC to afford 2-(1-(azetidine-3-carbonyl)piperidin-4-yl)-6-(5-chloro-4-(2-(isopropylsulfonyl)phenyl-amino)pyrimidin-2-ylamino)-5-isopropoxyisoindolin-1-one.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37](CCC3C=C(C=CC=3)N)[CH2:36][CH2:35]2)[N:25]=1.[N:49]1([C:54]2[CH:55]=[C:56]([CH2:60][C:61]([OH:63])=O)[CH:57]=[CH:58][CH:59]=2)[CH:53]=[CH:52][CH:51]=[N:50]1>CN(C)C=O>[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37]([C:61](=[O:63])[CH2:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([N:49]4[CH:53]=[CH:52][CH:51]=[N:50]4)[CH:55]=3)[CH2:36][CH2:35]2)[N:25]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(O)Cc1cccc(-n2cccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)Cc4cccc(-n5cccn5)c4)CC3)cccc2n1
Yield: 74 %

Procedure:
EDC•HCl (1.5 eq), HOBt (2 eq) and 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq) were added sequentially to a stirred solution of [3-(1H-pyrazol-1-yl)phenyl]acetic acid (D19) (1.1 eq) in dimethylformamide at room temperature under an inert atmosphere. The solvent was removed by means of an SCX cartridge. The crude material was purified on SPE cartridge (Silica) eluting with a gradient from dichloromethane/MeOH 99/1 to dichloromethane/MeOH 98/2 affording the title compound in 74% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 43.1 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(methylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (85 mg, 0.24 mmol) in methanol (4.6 mL) and 1N sodium hydroxide aqueous solution (3.6 mL, 3.6 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and back-dissolved in aqueous sodium hydroxide solution, then was acidified with 1 M hydrochloric acid solution again to pH=7. The white precipitated solid was collected by filtration and dried in vacuo to afford 35 mg of 3,3-dimethyl-2-(3-(methyl carbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 42.9%. LC-MS (M+1)=339.2.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]N(C)C(=O)CCC)=[C:20]([F:33])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][CH:3]([CH2:2][CH3:12])[C:4]([NH:6][CH3:7])=[O:5])=[C:20]([F:33])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: Cc1ccccc1
Product: CCC(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 127 %

Procedure:
A solution of 2,6-difluorobenzoylisocyanate (2.0 g) in a 1:1 mixture of toluene and petroleum ether (5 ml) was added at room temperature over 30 minutes to a stirred solution of the compound of Example 3 (4.4 g) in the same solvent (20 ml). After stirring at room temperature for 2 hours, the solid product was filtered off and recrystallised from a mixture of diethyl ether and petroleum ether to give 4.3 g of the desired product, melting point 136°-138° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1.[OH:24]OS([O-])=O.[K+]>CO.O.O>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])(=[O:24])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)=O)[nH]2)ncc1Br
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)(=O)=O)[nH]2)ncc1Br

Procedure:
35 mg (0.086 mmol) of (R)-2-[5-bromo-2-(5-methanesulfinyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is dissolved in 4 ml of MeOH/water (4:1) and stirred with 25 mg of oxone (0.25 mmol) at room temperature. The batch is diluted with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is digested with ethyl acetate. 19 mg (0.045 mmol, 52% of theory) of the product (R)-2-[5-bromo-2-(5-methanesulfonyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is obtained.
Reaction SMILES: [SH2]=N.C(O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([NH:16][C:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH3:15].C1(O)C=CC=CC=1.[Na]>O>[CH2:12]([NH:16][C:17](=[O:18])[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CCCCNC(=O)O
Agent: N=[SH2]
Agent: [Na]
Solvent: O
Solvent: Oc1ccccc1
Product: CCCCNC(=O)Oc1ccccc1
Reaction time: 3 h

Procedure:
5 g. N-butyl-carbamic acid benzoic acid sulfimide are suspended in the mixture of 1.67 g. phenol and 50 ml water, then while stirring (5 hours) a solution of 0.71 g. sodium hydroxyd in 50 ml water is added. After stirring another 3 hours the mixture is extracted with 2×30 ml ether. The ethereal extracts dried with sodium sulfate, then the solvent evaporated in vacuum at a temperature not above 30° C. 2.15 g. phenyl N-butyl-carbamate are obtained, which can be distilled at 146°-148° C. at 2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O1CCC[CH2:18]1>CN>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH3:18])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: C1CCOC1
Agent: CN
Product: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.0 g) in tetrahydrofuran (100 ml), methylamine was introduced over a period of 15 min. The reaction mixture was stirred for 2 hr at room temperatur and evaporated. The residue was triturated with cold aqueous sodium carbonate solution and the solid was washed and dried to give 1.769 g of 2-chloro-4-methylamino-6,7-dimethoxyquinazoline. A portion of this compound was crystallized from methylene chloride-hexane to mp 216°-217° C.; ir (nujol mull) 3470 cm-1 ; nmr (DMSO-d6) δ 3.0 (d, 3H), 3.9 (s, 6H), 7.05 (s, 1H), 7.55 (s, 1H) and 8.3 (broad s, 1H); and Anal. Calcd for C11H12ClN3O2 : C, 52.07% H, 4.77% N, 16.56% and Found: C, 51.95% H, 4.70% N, 16.45%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH2:13]([O:15][C:16]1[N:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:22][C:19]2[CH:20]=[N:21][C:16]([O:15][CH2:13][CH3:14])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CCOc1ncc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (90 mg, 0.386 mmol) in DCM (10 mL) was added 6-ethoxy-5-(trifluoromethyl)pyridin-3-amine (88 mg, 0.425 mmol), DIEA (0.135 mL, 0.772 mmol) and HATU (220 mg, 0.579 mmol). The mixture was stirred at 25° C. for 16 h. The mixture was diluted with H2O and extracted with DCM. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1:1, Rf=0.6) to yield a light yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)acetamide (120 mg, 0.228 mmol, 59.0% yield): 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.39-7.34 (m, 3H), 4.47 (m, 2H), 1.21 (t, J=6.5 Hz, 3H); ES-LCMS m/z 421.0 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=O)=[N:7][CH:8]=1.[C:15]([O:19][C:20](=[O:43])[NH:21][C@H:22]([CH2:27][NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:31][CH:30]=1)[C@@H:23]([CH3:26])[CH2:24][CH3:25])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[C:15]([O:19][C:20](=[O:43])[NH:21][C@H:22]([CH2:27][N:28]([C:29]1[CH:30]=[CH:31][C:32]([O:35][Si:36]([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38])=[CH:33][CH:34]=1)[C:12]([C@@H:10]1[CH2:11][C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][N:7]=1)=[O:14])[C@@H:23]([CH3:26])[CH2:24][CH3:25])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC[C@H](C)[C@@H](CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of trans-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid HCl salt (217 mg, 1 mmol) in thionyl chloride (2 mL) was heated at reflux for over night. The mixture was concentrated and dried under high vacuum for 3 h. Then the residue was dissolved in DCM (4 mL) and added dropwise to a solution of ((1S,2S)-1-{[4-(t-butyl-dimethyl-silanyloxy)-phenylamino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (422 mg, 1 mmol) and triethyl amine (409 uL, 3 mmol) in DCM (4 mL). The resulting mixture was stirred at rt for overnight. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column, 0-40% EtOAc in hexane over 40 min.) to give the titled compound (486 mg, 83%). MS (MH+ 586).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C1C=CC2N(O)N=NC=2C=1.[CH3:18][C:19]1[CH:20]=[C:21]([C:36]2[CH:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=2)[CH:22]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:24]=1>CN(C=O)C>[CH3:18][C:19]1[CH:20]=[C:21]([C:36]2[CH:37]=[CH:38][C:39]([C:42]([N:4]3[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]3)=[O:43])=[N:40][CH:41]=2)[CH:22]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:24]=1
Reactant: O=C1CNCCN1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)O)nc2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)N3CCNC(=O)C3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperazin-2-one (80.0 mg, 0.801 mmol), silica-bound carbodiimide (1.08 mmol/g load, 989 mg, 1.07 mmol), and HOBT (123 mg, 0.801 mmol) were added to a solution of 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxylic acid (200 mg, 0.534 mmol) in DMF (5.30 mL) and the reaction mixture was stirred at room temperature overnight. Macroporous-carbonate (3.17 mmol/g load, 1.01 g, 3.21 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was filtered, washed with DMF and was concentrated under reduced pressure. The residue was triturated with dichloromethane and was isolated by filtration (cold ether wash) to yield 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]carbonyl}piperazin-2-one. MS APCI calc'd for C22H20F3N6O2 [M+H]+ 457. found 457. 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.84 (d, J=5.5 Hz, 2H), 8.14 (s, 2H), 8.00 (s, 1H), 7.76 (t, 1H), 7.60 (s, 1H), 7.32-7.13 (m, 2H), 4.16 (d, J=12.2 Hz, 2H), 3.92-3.77 (m, 1H), 3.72 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C([O:12][C:13](=[O:27])[C:14](=[C:24]([CH3:26])[CH3:25])[N:15]1[C:18](=[O:19])[C:17]([Br:21])([Br:20])[CH:16]1[O:22][CH3:23])C1C=CC=CC=1.C1(OC)C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[Br:21][C:17]1([Br:20])[C:18](=[O:19])[N:15]([C:14](=[C:24]([CH3:26])[CH3:25])[C:13]([OH:27])=[O:12])[CH:16]1[O:22][CH3:23]
Reactant: COC1N(C(C(=O)OCc2ccccc2)=C(C)C)C(=O)C1(Br)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: COC1N(C(C(=O)O)=C(C)C)C(=O)C1(Br)Br
Temperature: 25 °C

Procedure:
To an ice-cooled suspension of aluminum trichloride (0.400 g; 0.003 mole) in methylene chloride (15 mL) in a nitrogen stream a solution of 2-methoxy-3,3-dibromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (0.447 g; 0.001 mole) and anisole (0.648 g; 0.65 mL, 0.006 mole) in methylene chloride (15 mL) was added and then it was stirred for half an hour at room temperature. Ethyl acetate (15 mL) and 0.1N hydrochloric acid (5 mL) were added to the reaction mixture and the layers were separated. The ethyl acetate layer was extracted with a 5% sodium hydrogen carbonate solution (2×20 mL) and the layers were separated. The aqueous layer was acidified with 0.1N hydrochloric acid to pH 1, then fresh ethyl acetate (20 mL) and sodium chloride were added and the layers were again separated. The ethyl acetate layer was washed with a saturated salt solution, dried and evaporated to a dry residue to obtain 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid, which was identical to the one disclosed under 2a.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)CC3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:34].ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:23]3[CH2:24][N:21]([C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])=[O:34])[CH2:22]3)=[CH:13][C:12]2=[O:31])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(Cl)Oc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CN(C(=O)Oc4ccccc4Cl)C3)cc2=O)cc1

Procedure:
Example 22 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)azetidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 2-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.25 Hz, 2 H), 7.62 (d, J=8.25 Hz, 2 H), 7.43 (dd, J=7.97, 1.37 Hz, 1H), 7.32 (d, J=7.70 Hz, 1 H), 7.16-7.31 (m, 3H), 6.28 (d, J=2.20 Hz, 1 H), 6.25 (dd, J=7.70, 2.75 Hz, 1 H), 4.41 (app brs, 1 H), 4.31 (app brs, 1 H), 4.23 (d, J=6.05 Hz, 2 H), 4.20 (app brs, 1 H), 4.04 (app brs, 1 H) 3.15-3.26 (m, 1 H), 3.11 (s, 3 H). MS (ESI) 489 (M+H).