Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(CC)C(C)C)(C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (3.2 g, 6.08 mmol) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (1.11 mL, 6.38 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (1.18 g, 6.38 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (2.23 g, 63%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)=[O:10].[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:11]1[N:15]([C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[N:13][CH:12]=1)[OH:10]
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Solvent: ClCCl
Product: Cc1cccc(C(O)(c2ccccc2)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2,3-dimethylphenyl)(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 3) (1.2 g, 2.7 mmol) in dichloromethane (30 mL) was treated with phenyl-magnesium bromide (1.35 mL, 4.05 mmol, 3 M in THF) 0° C. and then stirred for 16 h at rt. The mixture was quenched with water (10 mL) and a saturated solution of ammonium chloride (10 mL). The residue was isolated in a typical aqueous workup to give (2,3-dimethylphenyl)(phenyl)(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 4), (crude).
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([N+:9]([O-])=[O:10])[C:6]([Br:12])=[CH:5][C:4]=1[F:13].[C:14](O)(=O)C.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[Br:12][C:6]1[CH:5]=[C:4]([F:13])[CH:3]=[CH:8][C:7]=1[NH:9][O:10][CH3:14]
Reactant: CC(=O)O
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1F
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CONc1ccc(F)cc1Br
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-nitrophenyl methyl ether (25.5 g, 102 mmol), acetic acid (250 mL), ethanol (250 mL) and iron powder (22.7 g, 408 mmol) was heated to 100 C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralised by addition of potassium carbonate and filtered through Celite. The aqueous layer was extracted thrice with DCM. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (15 g, 67%) as a white solid. LC-MS (ES) (M+H)+ m/z=220.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([CH2:11][OH:12])[CH:7]=2)=[CH:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([CH:11]=[O:12])[CH:7]=2)=[CH:2]1
Reactant: OCc1cc(-c2ccsc2)on1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1cc(-c2ccsc2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a solution of 30 mg of (5-(3-thienyl)isoxazol-3-yl)methanol in 5 mL of dichloromethane, 84 mg of Dess-Martin periodinane was added under cooling with ice, and the mixture was stirred at room temperature for 1 hour 30 minutes. Thereto was further added 40 mg of Dess-Martin periodinane, and the mixture was stirred at room temperature for 1 hour 30 minutes. Diethyl ether was added to the reaction mixture, the insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 30 mg of 5-(3-thienyl)isoxazole-3-carbaldehyde as a yellow solid.
Reaction SMILES: CO[C:3](=[O:11])[C@@H:4]([CH2:9][OH:10])[NH:5][C:6](=[O:8])[CH3:7].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC)(C)(C)C>[C:6]([NH:5][C@H:4]([CH2:9][OH:10])[C:3]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:8])[CH3:7]
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H](CO)NC(C)=O
Solvent: COC(C)(C)C
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reaction time: 12 h
Yield: 81.9 %

Procedure:
N-Acetyl-D-serine methyl ester (25 g, 0.155 mole) was dissolved in benzylamine (33.2 g, 0.3101 mole) at 0-5° C. The reaction mixture was allowed to room temperature and stirred for 12 hr. To the thick colorless precipitate formed was added 300 ml methyl tert-butyl ether and stirred for 6 hr. The product was filtered and dried under vacuum to obtain (R)-2-acetamido-N-benzyl-3-hydroxy-propionamide (30.0 g, Yield: 82%, HPLC: 98.9, Chiral HPLC: 96.2%).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cccc(OC)c1I
Reactant: COC(=O)CCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of 2-iodo-1,3-dimethoxybenzene (13.798 g; 52.25 mmol) in anh. THF (200 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (32.66 ml; 52.25 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 15 min. A yellow solution of methyl 4-((tert-butylsulfinyl)imino)butanoate (7.640 g; 34.83 mmol) in anh. THF (50 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting yellow reaction mixture was treated successively with aq. sat. NH4Cl (20 ml), Et2O (250 ml) and water (75 ml). The separated yellow organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded methyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)butanoate as a yellow oil. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 358.34 g/mol.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:25][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (30.3 mg) obtained in Step A of Example 286 in DMF (2 mL) was added N-chlorosuccinimide (13.0 mg) at 0° C., and the mixture was stirred overnight at 80° C. To the reaction mixture was added N-chlorosuccinimide (6.0 mg), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added N-chlorosuccinimide (6.0 mg), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound (19.5 mg).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(#N)C.N1C=CC=CC=1>[C:21]1([C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: OCCOCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
25 g of hexaethyleneglycol was dissolved in a mixture of 100 mL of acetonitrile and 30 mL of pyridine, to which 12.5 g of trityl chloride was added at 0° C., and then the solution was stirred overnight at room temperature. The reaction solution was mixed with iced water and subjected to extraction with ethyl acetate, and then the organic layer washed with water and concentrated under reduced pressure after drying. The residue was purified with silica gel column chromatography to obtain 15.7 g of the objective compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:14]=1[CH2:15]Br>S1(CCCC1)(=O)=O.C(OCC)(=O)C>[Br-:12].[Br:12][C:13]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:14]=1[CH2:15][N+:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:2]1[O:3][CH2:4][CH2:5][O:1]1
Reactant: BrCc1cc(Br)ccc1Br
Reactant: c1ccc(C2OCCO2)nc1
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: Brc1ccc(Br)c(C[n+]2ccccc2C2OCCO2)c1
Product: [Br-]
Yield: 78.6 %

Procedure:
A mixture of 25.03 g (0.165 mol) of 2-(1,3-dioxolan-2-yl)-pyridine and 2,5-dibromobenzyl bromide (54 g, 0,165 mol) in 60 mL of sulfolane was heated on a steam-bath for 6 h. The mixture was diluted with 600 mL of ethyl acetate, cooled, and the resulting solid product was isolated by filtration. The above solid was triturated in 300 mL of ethyl acetate, the mixture was cooled, filtered and dried to afford 62.24 g (79%) of 1-(2,5-dibromobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide (Formula VI: R1 =R2 =H;R7 =2,5-Br2 ;Z- =Br-), as a yellow solid, m.p.135°-139° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][C:29]([OH:31])=[O:30])=[CH:35][CH:36]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Product: CC(c1ccc(-c2ccc(CCC(=O)O)cc2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 4-(2-carboxyethyl)benzeneboronic acid to give the title compound as a colorless solid. MS (m/e)=548.2 [M+H+].
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[C:22]1([NH:32][NH2:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:33][N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNc1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3cccc4ccccc34)nc(O)c12
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.00 g, 6.80 mM) and 1-naphthylhydrazine hydrochloride (9.26 g, 47.6 mM) in ethanol (72 mL) was added triethylamine (7.60 mL) to give a brown solution. After refluxing for 4 days, the solution was cooled to room temperature and diluted with ethyl acetate (0.35 L) to give a tan suspension. This suspension was filtered to remove the solids which were discarded. The filtrate was then poured into ethyl acetate (500 mL) which was washed with hydrochloric acid (3×500 mL, 1N). The washed solution was diluted with ether (250 mL) to give a tan suspension. The solids were collected to give the 1-naphthylhydrazine salt of the title compound as a tan powder (2.09 g). This material was refluxed in glacial acetic acid (50 mL) for 2 hours, cooled to room temperature and filtered. The collected solids were washed with glacial acetic acid and ether to give the title compound (1.44 g, 54%) as a tan powder, mp 368° C. (decomp.); MS(CI): 390 (M+H).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:11][C:10]=2[F:24])[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:35])(=O)C>C(OCC)(=O)C.CO>[ClH:35].[F:24][C:10]1[CH:11]=[C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH:13]=[CH:14][C:9]=1[C@@H:6]1[NH:5][C@H:4]([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2F)CC[C@H]1C(N)=O
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: NC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2F)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(2-fluoro-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate (D47, 130 mg, 0.300 mmol) in a mixture of ethyl acetate (2.3 ml) and methanol (0.230 ml) was added acetyl chloride (64 μl, 2.5 eq) at 0° C. The mixture was shaken for 2 h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (101 mg, 92%); Rt (HPLC): 3.66 min; MS: (ES/+) m/z: 333 [MH+], C18H18F2N2O2 requires 332; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.36 (br. s., 1H), 8.35 (br. s., 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.51-7.64 (m, 2H), 7.40-7.49 (m, 1H), 7.20-7.32 (m, 2H), 7.05 (dd, 1H), 6.98 (dd, 1H), 5.19 (s, 2H), 4.81 (dd, 1H), 4.31 (dd, 1H), 2.22-2.42 (m, 2H), 2.01-2.22 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16]CC)=[CH2:15])CCC.[Br:27]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:27][CH2:16][C:14]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1)=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1ccnc(Cl)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CBr)c1cc(F)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Tetrakis(triphenylphosphine) palladium(0) (0.439 g, 0.380 mmol) was added to a solution containing 2-chloro-4-fluoropyridine (1 g, 7.60 mmol) and tributyl(1-ethoxyvinyl)tin (2.59 ml, 7.60 mmol) in Toluene (15.21 ml). In a capped vial, the reaction was heated to 110° C. for overnight. LC/MS verified that the vinyl enolate intermediate formed. The reaction was cooled to room temperature, filtered thru a plug of Celite and the filtrate concentrated. The resulting residue was diluted with THF (20 mL) and water (2 mL). The reaction mixture was cooled to 0° C. and N-bromosuccinimide (1.624 g, 9.12 mmol) was added. The reaction was stirring for 1 hour and warmed to room temperature. The reaction was diluted with ethyl acetate and washed with water. Separated organics, dried with MgSO4, filtered and concentrated. Purified using Combiflash using 0% to 20% ethyl acetate in hexanes to afford 2-bromo-1-(4-fluoropyridin-2-yl)ethanone (1.4 g, 6.42 mmol, 84% yield) as a light purple oil. 1H NMR (CDCl3, 400 MHz), δ: 4.81 (s, 2H), 7.24 (m, 1H), 7.79 (m, 1H), 8.65 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[N:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:13][CH2:12]2)=[N:2]1
Reactant: O=C1CCC(Oc2nsc3ccccc23)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3nsc4ccccc34)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[d]isothiazol-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([O:8][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1[nH]c(=O)ccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(C#N)n1
Reaction time: 8 h

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from step 2) (1.0 eq.), tert-butyldimethylsilylchloride (TBSCl) (1.8 eq.), and imidazole (2.5 eq.) in DMF (0.2 M) was heated to 60° C. and stirred overnight. The reaction mixture was diluted with water and extracted with ether. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The residue was purified by a COMBIFLASH® system (ISCO) using 0-20% ethyl acetate in hexane to give 3-bromo-6-(tert-butyldimethylsilyloxy)picolinonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH:15]([CH:17]1[CH2:19][CH2:18]1)=O.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH:17]2[CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Temperature: 20 °C
Reaction time: 14 h
Yield: 79.7 %

Procedure:
To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (10 ml) were added water (0.15 ml), acetic acid (3.60 ml), formylcyclopropane (1.35 ml, 18.1 mmol), and sodium cyanoborohydride (18 ml of a 1M solution in THF, 18 mmol). The mixture was stirred at 20° C. for 14 hours. The mixture is concentrated under reduced pressure, and the residue is mixed with water (80 ml) and 1 N aqueous hydrochloric acid (40 ml). After washing with ethyl acetate (20 ml) the aqueous phase is made basic by addition of potassium carbonate (approx. 20 g) and extracted with ethyl acetate (4×30 ml). The combined extracts were dried with magnesium sulphate and concentrated under reduced pressure, to yield 2.3 g (80%) of the title compound as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].CCN(C(C)C)C(C)C.[Br:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:21][CH2:22][C:23]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:24]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
3-Trifluoromethylaniline (1.6 g, 10 mmol) was dissolved in dichloromethane with DIEA (3.4 mL, 20 mmol), cooled to 0° C., and to this solution bromoacetyl chloride was added as a neat liquid (exothermic). After 1 hour the reaction mixture was washed with 1N HCl, dried and concentrated to a brown oil which was purified by column chromatography (10 to 40% EtOAc/hexanes) to give a light brown oil, 1.8 g, 6.4 mmol, 64% yield. 1H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.75 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.35 (d, J=7.8 Hz, 3.96 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:12][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[C:14](O)=[O:15])(=[O:11])[CH3:10].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[C:9]([O:12][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[C:14]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:15])(=[O:11])[CH3:10]
Reactant: Cc1ccc(N)nc1
Reactant: COCC[C@H](OC(C)=O)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COCC[C@H](OC(C)=O)C(=O)Nc1ccc(C)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
5-Methylpyridin-2-amine (CAS no. 1603-41-4) (460 mg, 4.26 mmol) was added to (S)-2-acetoxy-4-methoxybutanoic acid (Intermediate F3) (500 mg, 2.84 mmol), in THF (8 mL) under nitrogen. The resulting suspension was stirred at 23° C. for 30 minutes. 4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (CAS no. 3945-69-5) (1.18 g, 4.26 mmol) was added and the suspension stirred for 40 hrs. The reaction mixture was concentrated and purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (S)-4-methoxy-1-(5-methylpyridin-2-ylamino)-1-oxobutan-2-yl acetate (410 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 2.13-2.28 (5H, m), 2.30 (3H, s), 3.31 (3H, s), 3.48-3.53 (2H, m), 5.37-5.40 (1H, m), 7.50-7.53 (1H, m), 8.09-8.11 (2H, m), 8.52 (1H, s); m/z (ESI+) (M+H)+=267; HPLC tR=1.22 min.