Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:36])[O:33][CH:32]([CH2:34]O)[CH2:31][O:30]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([O:27][CH2:34][CH:32]3[CH2:31][O:30][C:29]([CH3:36])([CH3:28])[O:33]3)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)OCC2COC(C)(C)O2)cn3C2CC2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (8.86 g, 23.70 mmol) was dissolved in anhydrous dichloromethane (370 ml) under argon. 2,2-dimethyl-1,3-dioxolane-4-methanol (4.71 g, 35.60 mmol), triethylamine (9.59 g, 94.80 mmol) and HBTU (9.90 g, 26.10 mmol) were added and the reaction mixture was stirred at room temperature for three days (exclusion of light). The reaction mixture was washed with saturated NaHCO3 solution (500 ml), aqueous (pH 5) hydrochloric acid (500 ml) and water (500 ml) successively. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure, yielding 10.28 g (89%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH3:26])=[CH:4][CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:34][CH2:26][C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:23])[N:12]([CH3:24])[C:11]=2[S:25][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CCn1c(=O)c2c(CBr)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of methyl 3-(6-(4-chlorophenyl)-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (25 mg, 0.0636 mmol) in CCl4 (1 mL) was added NBS (11.3 mg, 0.0636 mmol) followed by benzoyl peroxide (2 mg). The reaction was heated at reflux for 4 h, cooled to RT then diluted with DCM (10 mL). The mixture was washed with aq. NaHCO3 (5 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated to give methyl 3-(5-(bromomethyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (30 mg, 100% yield). LCMS: MH+ 473 and TR=1.907 min. Used without further purification.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CCCC(=O)O
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 91%), MS (ISP) m/z=401.5 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and butyric acid.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[OH:13][C:14]([CH3:18])([CH3:17])[C:15]#[N:16].O>C(Cl)Cl>[N:3]1([C:1]([O:13][C:14]([C:15]#[N:16])([CH3:18])[CH3:17])=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(C)(O)C#N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)OC(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A mixture of 1,1′-carbonyldiimidazole (5 g, 31 mmol) and 2-hydroxy-2-methylpropanenitrile (2.6 g, 31 mmol) in DCM was stirred at rt overnight. Water was added and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with ethyl acetate, to give 2.7 g (50%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([CH3:24])[C:9]2[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=2[N:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[CH:27]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([CH3:24])[C:9]3[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=3[N:3]=2)[CH2:29][CH2:28]1
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(Cl)nc2c(F)ccc(O)c12
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O)c12
Temperature: 90 °C
Yield: 23.1 %

Procedure:
A mixture of 2-chloro-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.26 g), cyclopropylboronic acid (0.12 g), caesium carbonate (0.92 g), dioxane (5.7 mL) and water (1.4 mL) was purged with argon, and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.058 g). The mixture was heated at 90° C. for 3 hours, cooled to room temperature, neutralised with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (5.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 3:2 by volume) gave title compound as a yellow oil (0.061 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27](O)=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:21][C:22]1[C:27]([O:19][C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In 300 ml of tetrahydrofuran were dissolved 40.0 g of N-t-butoxycarbonyl-leucyl-glycine and 38.8 g of pentachlorophenol, after which 30.0 g of dicyclohexylcarbodiimide (DCC) was added with ice-cooling, and the resulting mixture was subjected to reaction overnight. The insoluble material was collected by filtration and the solvent was removed by distillation to obtain a solid, which was recrystallized from ethyl acetate and petroleum ether to obtain N-t-butoxycarbonyl-leucyl-glycine-pentachlorophenyl ester. Yield: 65.9 g (88.5%). [α]D24 =-23.4° (C=1, dimethylformamide). Melting point (Mp): 155°-157° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Na+].[CH3:17]I>C(O)C>[CH3:13][C:4]1[S:3][C:2]([S:1][CH3:17])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1sc(S)nc1-c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(-c2ccccc2)c(C)s1
Reaction time: 2 h

Procedure:
To 14.9 g. of 2-mercapto-5-methyl-4-phenyl-thiazole is added 60 ml. of water and 19.5 ml. of a 15% aqueous solution of sodium hydroxide and the mixture is stirred until most of the material dissolves. The stirred mixture is then treated with methyl iodide (5 ml.) in ethanol (20 ml.). After two hours, the reaction is complete (tlc) and the reaction mixture is extracted with ether. The combined ether extracts are washed successively with a 10% solution of sodium carbonate and brine, dried and concentrated in vacuo to an oil, b.p. 138°-140° C. at 0.04 mm Hg.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[C:25]([NH:27][S:28]([CH:31]2[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[O:26])[C:5]1=[O:36])[CH:2]=[CH2:3].[C:38](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[C:25]([N:27]([S:28]([CH:31]2[CH2:33][CH2:32]2)(=[O:30])=[O:29])[CH3:38])=[O:26])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NS(=O)(=O)C2CC2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)N(C)S(=O)(=O)C2CC2)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide (8 mg, 0.014 mmol; Example 177, Step B) in DMF (1.0 mL) was added potassium carbonate (2.9 mg, 0.021 mmol) and iodomethane (1.1 μL, 0.017 mmol) at rt. The reaction was stirred for 1 hour. After this time more iodomethane (1.1 μL, 0.017 mmol) and potassium carbonate (2.9 mg, 0.021 mmol) was added and the reaction was stirred at rt for 60 hours. After this time the reaction was partitioned between EtOAc (20 mL) and 1.0 M LiCl (5 mL). The separated organic layer was washed with 1.0 M LiCl (5 mL), dried over MgSO4, filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1cccc(-c2ccc3oc(-c4cc(N)ccc4OC)nc3c2)c1
Product: COc1cccc(-c2ccc3oc(-c4cc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)ccc4OC)nc3c2)c1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole (50 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (28 mg, 0.14 mmol) the title compound was obtained (52 mg, 71%). 1H NMR (DMSO) δ 8.43(d, 1H), 8.33(s, 1H), 8.22(d, 1H), 8.10(m, 2H), 7.87(d, 1H), 7.74(m, 2H), 7.48(d, 1H), 7.41(t, 1H), 7.30(m, 2H), 6.96(dd, 1H), 4.04(s, 3H), 3.85(s, 3H). MS 521.3 m/z (M+H)+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:11][NH2:12].[BH4-].[Na+]>CO>[CH3:11][NH:12][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:3][CH:4]=1
Reactant: CN
Reactant: COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 138.6 %

Procedure:
To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) in methanol (1 L) was added a 40% aqueous solution of methylamine (113 ml, 1.31 mol) followed by 1 hour stirring at 0° C. Sodium borohydride (75 g, 1.98 mol) was added portionwise at 0° C. and the reaction mixture was stirred for 1 hour. The solution was concentrated to a smaller volume then, was diluted with water (200 mL) and the resulting solution was extracted with methylene chloride (3×500 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude N-methylbenzylamine (220 g, quantitative) as clear oil, which was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ.7.23 (t, J=8.0 Hz, 1H), 6.92-6.88 (m, 2H), 6.81-6.78 (m, 1H), 3.80 (s, 3H), 3.73 (s, 2H), 2.45 (s, 3H), 2.07 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCOCC2)c1C
Temperature: 80 °C
Yield: 65.2 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (700 mg, 2.473 mmol) in acetonitrile (10 mL), cesium carbonate (1.61 g, 4.946 mmol) and methyl iodide (1.82 g, 0.8 ml, 12.36 mmol) were added; resulting reaction mass was heated at 80° C. for 13 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (480 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18]([CH3:20])=O)[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH:13]([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(C(F)F)o2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(C(F)F)o1

Procedure:
From 2-amino-4-(5-difluoromethyl-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:23])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:27][C:28]#[N:29])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cc(F)cc(Cl)c2)C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 150.7 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (55 g, 0.156 mol) in acetonitrile (1.2 L) was cooled to 0° C., NaH (19.2 g, 0.48 mol, 60% in oil) was added in portions, then the mixture was stirred at rt for 1 hr. The mixture was cooled to −20° C. and bromoacetonitrile (57.7 g, 0.48 mol) was added dropwise. After 0.5 hr, additional NaH (19.2 g, 0.48 mol, 60% in oil) and bromoacetonitrile (57.7 g, 0.48 mol) was added. TLC showed 80% of the starting material was reacted. The reaction was quenched with saturated NH4Cl solution (200 mL), water (1 L) was added. Acetonitrile was removed by reduced pressure, CH2Cl2 (1 L) was added, the aqueous layer was back extracted with CH2Cl2 (3×500 mL), dried over Na2SO4 and concentrated in vacuo to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (90 g), which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[CH:10]2)=[CH:5][CH:4]=1.C[Sn](C)(C)[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]2[O:32][CH2:33][O:34][C:25]=2[CH:24]=1>C1COCC1.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>[CH2:33]1[O:34][C:25]2[C:26](=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[CH:7][CH:8]=3)[CH:24]=2)[O:32]1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)cc2c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (120 mg) and cuprous bromide (20 mg) were added to a solution of 7-Methoxy-2-trifluoromethanesulfonyloxynaphthalene 47 (336 mg, 1.1 mmol) and trimethylnitroarylstannane 62 (300 mg, 0.92 mmol) in THF (30 mL) at room temperature and stirred for 0.5 h. The mixture was then refluxed under N2 overnight. After cooling, THF was evaporated in vacuo and ethyl acetate (30 mL) was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4), and evaporated in vacuo. The residue was chromatographed using a 80:20 mixture of hexanes:ethyl acetate to give 48 (100 mg) in 34% yield; IR (KBr) 2915, 1627, 1509, 1481, 1425, 1333, 1262, 1218 cm−1; 1H NMR (CDCl3) δ3.92 (3H, s), 6.15 (2H, s), 6.88 (1H, s), 7.13-7.23 (3H, m), 7.48 (1H, s), 7.64 (1H, s), 7.74-7.81 (2H, m); 13C NMR δ55.81, 103.47, 105.90, 106.46, 111.60, 119.84, 124.13, 126.07, 128.50, 128.72, 129.75, 133.89, 134.97, 136.60, 143.42, 147.63, 151.45, 158.61; HRMS (EI) calcd for C18H13NO5 m/z: 323.0794; found: 323.0787.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.[OH2:23]>C(O)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[O:23])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(Cl)cc1
Reactant: O
Solvent: CC(=O)O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 5-(4-chlorobenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 20 ml of acetic acid at 10° C., was added 1.2 g of chromic anhydride. After stirring at room temperature overnight, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturatedaqueous sodium hydrogen carbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 1.7 g of 5-(4-chlorobenzoyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]1[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@@H:22]2[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN1C[C@@H](N)CCC1=O
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C[C@@H](Nc2nc(Cl)nc3c2SCC3)CCC1=O
Temperature: 130 °C

Procedure:
0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130° C. until there is no further reaction, then cooled and evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method B). 0.26 g (III-5) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.06 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.O.O.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1CC(N1CCCC1)CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Br)c2c1CC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-acetamido-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalene (0.36 g, 1.4 mmol) and sodium acetate trihydrate (0.38 g, 2.8 mmol) in acetic acid (15 mL) was treated with bromine (0.27 g, 1.7 mmol) and stirred at room temperature for 2 h. A precipitate was collected by filtration and the filtrate evaporated. The two solids were combined and dissolved in methylene chloride; water. The mixture was basified with 12.5% NaOH, and the organic phase separated. The aqueous layer was back extracted and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was heated in diethyl ether to form a solid, which was collected and dried (0.31 g).
Reaction SMILES: C1(C[O:8][C:9](=[O:43])[C@@H:10]([NH:19][C@@H:20]([CH3:42])[C:21](=[O:41])[O:22][C@@H:23]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24](=[O:33])[O:25]CC2C=CC=CC=2)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.[Pd]>[C:24]([C@@H:23]([O:22][C:21](=[O:41])[C@@H:20]([NH:19][C@@H:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:43])=[O:8])[CH3:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:33])=[O:25]
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The product of step b) (0.5 g) in ethyl acetate (30 ml) and trifluoroacetic acid (2 ml) was hydrogenated at 1 bar over 10% palladium on charcoal for 1 day. The catalyst was filtered off, the solvent evaporated and the residue purified by reverse phase HPLC with water/methanol mixtures as eluant, to give the title acid (0.14 g), mp 199°-200°.