Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(C)(C)C)(C)(C)C.[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH:36]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: C1=CCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CCCC1
Yield: 81 %

Procedure:
A solution of 33.6 g (122 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 23.0 g (157 mmol) of di-t-butyl peroxide, and 70 ml of cyclohexene is heated in a Fischer-Porter bottle at 138° C. for 6.5 hours. The reaction mixture is chromatographed on silica gel (200:1 heptane:ethyl acetate) to afford 35.1 g (81% yield) of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].CCOC(C)=O.O.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:20]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])#[N:21]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(O)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
A mixture of methyl 3-hydroxy-4-iodobenzoate (101 g, 0.36 mol) and zinc(II)cyanide (30 g, 0.25 mol) in 400 mL of dry DMF was degassed by bubbling argon through the solution for 20 minutes. Tetrakis(triphenylphosphine)palladium (8.5 g, 7.2 mmol) was added, and the solution was heated to 80° C. for 4 hours. The solution was cooled to room temperature, then stirred for an additional 36 hr. The reaction was poured into EtOAc/water, and the organic layer was washed with brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the crude product. Purification by column chromatography through silica gel (30%-50% EtOAc/hexane) provided the title compound. 1H NMR (CDCl3 /CD3OD, 400 MHz): d 7.53-7.56 (m, 3H, 3ArH) and 3.93 (s, 3H, OCH3).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]CC1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.CSC.O>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCCCOCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Solvent: O
Product: N#Cc1ccc(O)c(OCCCCO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
4-Benzyloxy-3-(4-benzyloxybutoxy)benzonitrile (4.0 g) was dissolved in a mixed solvent of trifluoroacetic acid (9 mL), dimethyl sulfide (0.5 mL) and water (5 mL), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (1.0 g).
Reaction SMILES: [Cl:1]C1CC(=O)NC1=O.[F:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[CH:12][CH:11]=1.O.C(Cl)Cl>C(#N)C>[Cl:1][C:11]1[CH:12]=[CH:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:15][C:10]=1[F:9]
Reactant: O=C1CC(Cl)C(=O)N1
Reactant: Fc1cccc(N2CCOCC2)n1
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Fc1nc(N2CCOCC2)ccc1Cl
Temperature: 70 °C
Yield: 22.4 %

Procedure:
Chlorosuccinimide (10.29 g, 77 mmol) was added to a solution of 4-(6-fluoropyridin-2-yl)morpholine (11.7 g, 64.2 mmol) in ACN (15 mL). The reaction mixture was heated to 70° C. for 30 min. Water and DCM were added. The organic phase was separated, washed with aqueous NaHCO3, brine and subsequently dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes) to afford 3.11 g of 4-(5-chloro-6-fluoropyridin-2-yl)morpholine.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[C:4]=1[CH3:23])[CH3:2].S(OC)(O[CH3:28])(=O)=O>>[CH2:1]([C:3]1[N:8]([CH3:28])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[C:13]([Cl:20])=[CH:12][C:11]=2[F:21])[C:5](=[O:22])[C:4]=1[CH3:23])[CH3:2]
Reactant: CCc1[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c1C
Reactant: COS(=O)(=O)OC
Product: CCc1c(C)c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-methyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 6-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 88°-91° C.;
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[CH:6]([S:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.[C:29]1([C:35]2[O:36][C:37]([C:43]([F:46])([F:45])[F:44])=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][S:16][CH:6]([C:5]([O:4][CH2:3][C:2]([Cl:27])([Cl:1])[Cl:28])=[O:26])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:40]([C:38]3[N:39]=[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:36][C:37]=3[C:43]([F:45])([F:46])[F:44])=[O:41])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: O=C(OCc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2 trichloro-ethyl ester (675 mg, 1.45 mmol) and 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (410 mg, 1.59 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester. The crude product was obtained as an oil which was carried on to the next step without further purification (892 mg, 79.4%). 1H NMR (500 MHz, CDCl3): δ 8.15 (d, 2H), 7.57 (d, 1H), 7.52 (t, 2H), 7.41 (d, 2H), 7.12 (t, 2H), 6.97 (t, 2H), 5.42 (s, 2H), 4.72 (q, 2H), 3.59 (dd, 1H), 3.25 (dd, 1H), 2.78-3.05 (m, 5H). Mass Spectrum: M+H+ 705.89.
Reaction SMILES: [C:1]([Si:5]([CH3:46])([CH3:45])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C@H:14]([NH:26][C:27](=[O:44])[C@@H:28]([NH:32][C:33](=[O:43])[C@H:34]([CH3:42])[C@H:35]([O:40][CH3:41])[CH2:36][CH2:37][CH:38]=[CH2:39])[CH:29]([CH3:31])[CH3:30])[C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23](O)=[O:24])[NH:18]2)=[O:16])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH:48]([C:50]1[CH:51]=[C:52]([C@H:56]([NH2:58])[CH3:57])[CH:53]=[CH:54][CH:55]=1)=[CH2:49].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C.O.C(OCC)(=O)C>[CH:48]([C:50]1[CH:51]=[C:52]([C@H:56]([NH:58][C:23]([C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:15](=[O:16])[C@@H:14]([NH:26][C:27](=[O:44])[C@@H:28]([NH:32][C:33](=[O:43])[C@H:34]([CH3:42])[C@H:35]([O:40][CH3:41])[CH2:36][CH2:37][CH:38]=[CH2:39])[CH:29]([CH3:30])[CH3:31])[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:45])[CH3:46])[CH:8]=3)[NH:18]2)=[O:24])[CH3:57])[CH:53]=[CH:54][CH:55]=1)=[CH2:49]
Reactant: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)O)N1)C(C)C
Reactant: C=Cc1cccc([C@@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C=CCC[C@@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2cccc(C=C)c2)N1)C(C)C
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of (S)-1-{(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-[(S)-2-((2R,3R)-3-methoxy-2-methyl-hept-6-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (480 mg, 0.72 mmol), (R)-1-(3-vinylphenyl)ethylamine hydrochloride (159 mg, 0.86 mmol) and N,N-diisopropylethylamine (372 mg, 0.5 mL, 2.88 mmol) in acetonitrile (20 mL) was stirred at room temperature under nitrogen. 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (380 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. Ethyl acetate and water were added. The aqueous layer was separated and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to neat ethyl acetate to afford the title compound (331 mg, 58%) as a white foam. 1H NMR (300 MHz, CD3CN) δ0.20 (s, 6H), 0.81 (d, J=6.9 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H), 0.99 (m, 9H), 1.03 (d, J=6.9 Hz, 3H), 1.40 (d, J=7.1 Hz, 3H), 1.45-2.20 (m, 7H), 2.50-2.70 (m, 2H), 2.75-2.85 (m, 1H), 2.95-3.15 (m, 2H), 3.30 (s, 3H), 3.30-3.35 (m, 1H), 3.95-4.15 (m, 2H), 4.25-4.35 (m, 1H), 4.93-5.10 (m, 4H), 5.25 (dd, J=10.9, 0.9 Hz, 1H), 5.28 (dd, J=10.9, 0.9 Hz, 1H), 5.49-5.58 (m, 1H), 5.81 (dd, J=17.6, 0.9 Hz, 1H), 5.83 (dd, J=17.6, 0.9 Hz, 1H), 6.54-6.61 (m, 1H), 6.70-6.84 (m, 5H), 7.10 (t, J=7.6 Hz, 1H), 7.24-7.43 (m, 6H). LCMS (m/z) 790 [M+H], Tr=5.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dichloroaniline (8.87 g, 54.8 mmol) in ethanol (40 mL) was added to a solution of 2,4,6-trichloropyrimidine (10.0 g, 54.8 mmol) in ethanol (20 mL) followed by aqueous Na2CO3 (4.61 g, 43.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. The crude mixture was diluted with water (100 mL), and the resulting precipitate was filtered and dried (10.2 g, 61%). ESI-MS m/z: 307 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7](OCC)=[O:8])(=[O:4])=[O:3].[OH-].[Na+].Cl.Cl.[CH:28]1([C:31]2[CH:32]=[C:33]([CH3:43])[C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:35][CH:36]=2)[CH2:30][CH2:29]1.CN1CCOCC1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(O)C.O>[CH:28]1([C:31]2[CH:32]=[C:33]([CH3:43])[C:34]([N:37]3[CH2:38][CH2:39][N:40]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:23])=[O:22])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:8])[CH2:41][CH2:42]3)=[N:35][CH:36]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](C)CCS3(=O)=O)cc2S(C)(=O)=O)CC1
Temperature: 60 °C
Yield: 54.9 %

Procedure:
Ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (361 mg) described in Preparation Example 28 was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added, and the mixture was stirred at 60° C. After completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid (1.5 mL), 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82, N-methylmorpholine (0.2 mL) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (277 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give the title compound (292 mg).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[F:10][C:6]1[C:7]([F:9])=[CH:8][C:2]2[S:15][C:14]([SH:16])=[N:4][C:3]=2[CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(F)c(F)cc1F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc2nc(S)sc2cc1F
Temperature: 95 °C
Yield: 39.8 %

Procedure:
A mixture of 1 g (6.80 mmol) 2,4,5-trifluoroaniline and 1.33 g (8.16 mmol) potassium ethylxanthogenate in 5 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 7 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 0.55 g (40%) of the titled compound as a light yellow solid. MS(m/e): 201.9 (M−H+).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[CH3:24][O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27]>C(#N)C.CCOC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH:2]2[N:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][CH3:24])=[O:27])[CH2:29][CH2:30]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc2c1CCC2Cl
Reactant: COC(=O)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)N1CCN(C2CCc3c2cccc3[N+](=O)[O-])CC1
Temperature: 79 °C
Yield: 69.9 %

Procedure:
To a room temperature solution of 1-Chloro-4-nitro-2,3-dihydro-1H-indene (221 mg, 1.12 mmol, 1.0 equiv) and DIPEA (430 μL, 2.46 mmol, 2.2 equiv) in dry acetonitrile (1.6 mL) was added methylpiperazine carboxylate hydrochloride salt (444 mg, 2.46 mmol, 2.2 equiv) as a solid in one portion. The resulting reaction mixture was heated to 79° C. overnight. The reaction mixture was allowed to cool to RT and diluted with EtOAc. The organic layer was extracted with 1 M HCl (3×20 mL), and the combined aqueous layers were treated with 3 N NaOH until the pH=10. The resulting solution was extracted three times with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a brown oil (239 mg, 78%). LCMS [M+H]+=306.1.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:15])=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(F)c1CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(F)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-difluoro-6-methoxybenzyl alcohol (6.97 g) in toluene (100 mL) was added thionyl chloride (4.4 mL) in a dropwise manner at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine twice, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (7.65 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[Br:13]N1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:10])=[C:8]([Br:13])[CH:9]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid methyl ester (1.0 g) in THF (10 mL) was added N-bromosuccinimide (1.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1, v/v) to give the title compound (1.16 g). (In the above, THF is tetrahydrofuran)
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O[C@@H]1CNC[C@H]1N1CCCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To a solution of trans-3-[4-(4-Chloro-phenyl)-[1,4]diazepan-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.820 g, 2.08 mmol) in methylene chloride (1 mL) was added 4 N HCl/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour, upon which a brown precipitate formed. The reaction was concentrated in vacuo to yield 0.930 g (-100%) of the title compound. ESI-MS m/z: 296 (M+1), FAS method it 0.83 min.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:5]([C:13]([OH:15])=O)[CH2:4][CH2:3]1.[NH2:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19]([NH2:21])=[O:20].O[NH-].O=[N-]>>[NH2:21][C:19](=[O:20])[C:18](=[O:22])[CH:17]([NH:16][C:13]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1c1ccccc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1c1ccccc1

Procedure:
Coupling of (R)-5-Oxo-1-phenyl-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([Cl:43])=[O:42])=[C:39]([C:46]([F:49])([F:48])[F:47])[CH:38]=1>ClCCl>[ClH:43].[C:25]([C:24]1[CH:27]=[CH:28][C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([N:8]3[CH2:7][CH2:6][CH:5]([N:4]([CH3:3])[C:41](=[O:42])[C:40]4[CH:44]=[CH:45][C:37]([F:36])=[CH:38][C:39]=4[C:46]([F:49])([F:48])[F:47])[CH2:10][CH2:9]3)=[N:12][N:13]=2)=[CH:22][CH:23]=1)#[N:26]
Reactant: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccc(C#N)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Charge a 4 mL reaction vial with 4-(4-(4-(methylamino)piperidine -1-yl)phthalazin -1-yl)benzonitrile dihydrochloride (44.7 mg, 0.107 mmol), dichloromethane (1 mL), and triethylamine (0.0598 mL, 0.429 mmol). Flush the reaction vial with nitrogen and add 4-fluoro-2-(trifluoromethyl)benzoyl chloride (033 g. 0.14 mmol). Cap the vial and allow the reaction to stir at room temperature overnight. Evaporate to a residue and purify using silica gel chromatography (40:60, ethyl acetate:hexane, then ethyl acetate). Add 1 N HCl in diethyl ether to a solution of the isolated product in dichloromethane/methanol and remove the solvents by placing under a stream of nitrogen gas. Dry in a vacuum oven at 50° C. to obtain the title compound (36.0 mg. 59%). ES/MS m/z 533.8 (M+1).
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=[O:8])[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:8][C:7]([C@@H:5]1[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)O)O1
Solvent: CC(C)=O
Product: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.2 g of (2S,3R)-5-oxotetrahydrofuran-2,3-dicarboxylic acid was dissolved in 88 ml of acetone, and 6.5 g of 1,1'-dicyclohexylcarbodiimide was added thereto, followed by stirring at room temperature for 2 hours. 3.26 ml of benzyl alcohol was added to the reaction solution, and stirred at the same temperature for 12 hours. Insoluble mattes were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→chloroform/methanol=50/1) to obtain 7.93 g of the above-identified compound as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:32])(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of 4-(benzyloxycarbonylaminomethyl)-1-Boc-piperidine (0.360 g, 1.03 mol) in DMF (10 mL) was treated with sodium hydride (60%, 0.050 g, 1.25 mmol). After 0.5 h, methyl tosylate (0.18 mL, 1.20 mmol) was added and the mixture heated to 60° C. After 12 h, the mixture was poured into EtOAc and saturated aqueous sodium bicarbonate. The combined extracts were washed with water, brine and concentrated to afford 0.300 g (79%) the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]([CH2:21][C:22]#[C:23][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[O:8])[NH:5][CH:6]=1.C([O-])(=O)C.[Na+]>CS(C)=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[CH:21]=[C:22]([CH2:23][C:24]3[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:5]2[CH:6]=1
Reactant: CCOC(=O)c1cccc(C#CCN(Cc2ccc(OC)cc2OC)C(=O)c2cc(Br)c[nH]2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc(Cc2cn(Cc3ccc(OC)cc3OC)c(=O)c3cc(Br)cn23)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 4B (100 mg, 0.2 mmol) in dimethylsulfoxide (3 mL) was added sodium acetate (16 mg, 0.2 mmol), tetra-n-butylammonium chloride (53 mg, 0.2 mmol) and palladium(II) acetate (4.3 mg, 0.02 mmol). The mixture was stirred at 80° C. for 10 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and diluted aqueous HCl solution. The organic phase was washed with water, NaHCO3 solution, and brine, and concentrated. The residue was separated by flash chromatography eluting with ethyl acetate to afford the title compound. MS (DCI/NH3) m/z 526 (M+H)+.