Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: NCC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
To a suspension of Boc—(D)—Arg(Tos)—OH (1 g, 2.34 mmol) in CH2Cl2 (10 mL) was added DIEA (1 mL) at 0° C. To the clear solution was added Gly—OBn.HCl (0.52 g, 2.58 mmol) and BOP (1.2 g, 2.8 mmol). The solution was stirred for 4 h at 0° C. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1 N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound as a powder. ES—MS (M+H)+=576.3
Reaction SMILES: O(C)[Na].CO.Br.[C:7]([N:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]1=[O:17])(=[NH:9])[NH2:8].[CH3:18][N:19]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[C:20](=[O:28])[C:21]([C:26]#[N:27])=[CH:22]OCC>CO>[C:26]([C:21]([C:20](=[O:28])[N:19]([CH3:18])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[CH:22][NH:9][C:7](=[NH:8])[N:10]1[CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]1=[O:17])#[N:27]
Reactant: CCOC=C(C#N)C(=O)N(C)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Agent: Br
Agent: CO[Na]
Solvent: CO
Product: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
3.60 g (=3.67 ml, 20 mmol) of 30% strength NaOCH3 /CH3OH solution were added to a solution of 4.74 g (20 mmol) of 1-amidino-4,4-dimethyl-2-oxoimidazolidine hydrobromide in 47 ml of methanol at room temperature, and the mixture was stirred at 45° C. for 30 min. The solution was then cooled to 20° C. and, at 20° C., 5.97 g (20 mmol) of 2-cyano-3-ethoxyacrylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were added and the mixture was stirred at 20° C. for 20 min, at room temperature for 1.5 hours and while cooling in an icebath for 30 min. The solid which had separated out was filtered off with suction, washed with ether and worked up further as described in Example 1. Likewise, the residue from the filtrate (mother liquor) was further worked up as described in Example 1 and dried. 6.35 g (=77.7% yield) of, according to TLC (CH2Cl2 /C2H5 OH=10:1), virtually pure compound IV were obtained.
Reaction SMILES: CC([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1)[C:6]([O-:8])=[O:7])(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[F:17][C:15]([F:16])([F:18])[C:11]1[N:10]=[C:9]([CH2:5][C:6]([OH:8])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(C(=O)[O-])c1cccc(C(F)(F)F)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 1,1-dimethylethyl[6-(trifluoromethyl)-2-pyridinyl]acetate (698 mg, 2.67 mmol), triethylsilane (1.067 mL, 6.68 mmol) in Dichloromethane (DCM) (10 mL) was added TFA (2.68 mL, 34.7 mmol) dropwise via syringe. The reaction was stirred overnight at room temperature. LCMS analysis indicated good conversion, so the reaction was concentrated to a yellow oil. 5 mL of diethyl ether was added but no precipitation occurred, so the solution was concentrated to afford [6-(trifluoromethyl)-2-pyridinyl]acetic acid (535 mg, 2.61 mmol, 98% yield) as a yellow oil which solidified to a yellow solid. LC-MS (ES) m/z=206 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 2H), 7.70 (d, J=7.83 Hz, 1H), 7.81 (d, J=7.58 Hz, 1H), 7.97-8.16 (m, 1H), 12.26-12.88 (br. s., 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P([N:68]=[N+:69]=[N-:70])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:68]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:69]=[N-:70]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (2S,3R)-3-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol (1.0 equiv.), DIAD (2.0 equiv.), and PPh3 (2.0 equiv.) in THF (0.18 M) was added DPPA (1.0 equiv., 1M solution in THF). The reaction mixture was stirred at room temperature overnight. Upon removal of the volatiles under vacuo, the residue was purified by silica gel column chromatography (2-3-5% EtOAc/n-heptanes) yielding ((1R,2S)-3-azido-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)(tert-butyl)dimethylsilane (62%). 1H-NMR (400 MHz, CDCl3): δ 4.04-4.10 (m, 1H), 3.94 (dd, J=8.0, 6.4, 1H), 3.72 (d, J=7.2, 1H), 3.53 (t, J=8.0, 1H), 3.36 (dd, J=12, 8.0, 1H), 3.19 (dd, J=12.0, 6.7, 1H), 1.52-1.60 (m, 1H), 1.41 (s, 3H), 1.34 (s, 3H), 0.92 (d, J=7.2, 3H), 0.90 (s, 9 H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:19](=[O:21])[CH3:20].[Li]CCCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:19](=[O:21])[CH3:20])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(C)=O
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)cn1

Procedure:
A mixture of 5-benzyloxy-2-bromo-pyridine (1.0 g), N-methoxy-N-methyl-acetamide (780 mg) and THF (20 mL) under argon at −60° C. was added n-BuLi (2.6 M in toluene, 2.9 mL). After 1 hour the cooling bath was removed. After reaching room temperature the mixture was quenched by addition of saturated NH4Cl-solution. The mixture was distributed between EA and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica gel, heptane to EA/heptane 3:7) to provide the subtitle compound. MS ESI+: m/z=228 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl.[N:56]1[CH:61]=[CH:60][CH:59]=[C:58]([S:62](Cl)(=[O:64])=[O:63])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:58]2[CH:57]=[N:56][CH:61]=[CH:60][CH:59]=2)(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2cccnc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and pyridine-3-sulfonyl chloride hydrochloride as starting materials in 31% yield. LCMS for C29H30ClN8O3S (M+H)+: m/z=605.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:32]([O:31][C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1)=[CH2:30])[CH3:33]
Reactant: Fc1cc2ncccc2c(F)c1Cc1nnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 82.5 °C
Reaction time: 4 h

Procedure:
A solution of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (58 mg, 0.175 mmol) in dioxane (5 mL) was purged with argon for 1 min. Tributyl-(1-ethoxy-vinyl)stannane (0.2 mL, 0.53 mmol) was then added, followed by addition of PdCl2(PPh3)2 (14.4 mg, 0.021 mmol). The reaction mixture was purged with argon for another half min. The reaction mixture was stirred at 80-85° C. for 4 h; LC/MS showed the reaction was complete. The reaction mixture was diluted with EtOAc, and 15 mL of aqueous KF solution was added. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, concentrated to give the crude title compound, which was used without further purification. LCMS (method A): [MH]+=368, tR=5.39 min.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[N:7]=1
Reactant: COc1ccc(Br)c(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Br)c(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a solution of N-(2-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (4.0 g, 11 mmol) and 3-(3-aminophenyl)propan-1-ol (2.3 g, 15 mmol, prepared according to Example 12, Step B) in 1,4-dioxane (90 mL) was added p-toluenesulfonic acid monohydrate (0.31 g, 1.6 mmol). The mixture was heated at 80° C. over two days and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc to give the desired product as an off-white powder (4.35 g, 83%). LCMS for C21H22BrClN4O2 (M+H)+: m/z=477.0, 479.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C(O)C(=Cc1ccncc1)c1ccc(F)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-fluorophenylacetic acid (9 g, 58.4 mmol), 4-pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated at 150° C. for 1 h followed by evaporation and co-distillation with water. The resulting material crystallized on addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (30.0 g, 154 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butylester (52.5 g, 200 mmol) and cesium carbonate (80.1 g, 246 mmol) in anhydrous DMF (400 mL) was heated to 100° C. for 24 h. DMF was removed under high vacuum. The residue was then diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with water (3×50 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the orange-brown oily residue was added diisopropyl ether (300 mL), and the mixture was stirred at 0° C. for 2 h. Colorless crystals separated out that were filtered off and dried in vacuo to give a 1st crop of the title compound. The filtrate was then concentrated in vacuo, the residue was mixed with diisopropyl ether (100 mL), a small amount of the 1st crop was added as a seed, and the mixture was stirred overnight. The resulting white precipitate was filtered and dried in vacuo as 2nd crop of the title compound. 1H NMR (300 MHz, CDCl3): δ=1.33 (s, 12H), 1.48 (s, 9H), 1.85-1.93 (m, 2H), 2.15-2.18 (m, 2H), 2.83-2.92 (m, 2H), 4.23-4.39 (m, 3H), 7.76 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[C:29]([CH3:38])=[CH:28][C:27]2=[O:39])[CH2:20][CH2:19]1)[CH2:8][C:9](=[O:17])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:9](=[O:17])[CH2:8][NH:7][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[C:29]([CH3:38])=[CH:28][C:27]2=[O:39])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(CC(=O)Nc4ccccn4)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NCC(=O)Nc4ccccn4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To 5 mL of a dichloromethane solution containing 0.11 g of tert-butyl(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2-oxo-2-(pyridin-2-ylamino)ethyl)carbamate, 5 mL of trifluoroacetic acid was added and stirred at room temperature for 30 min. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 13 with 20% aqueous sodium hydroxide solution under ice-cooling. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 83 mg of N- (pyridin-2-yl)-N2-(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)glycinamide as a light brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:13]/[C:14]([C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1)=[O:15]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2,4-dimethoxybenzaldehyde (1 g, 6.00 mmol) and 3,4,5-trimethoxyacetophenone (1.27 g, 6.00 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with ethyl acetate (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated in vacuo. The product was purified by recrystallisation from ethanol to afford the title compound as a pale yellow solid, 1.67 g (78%). 1H-NMR (CDCl3) δ 8.0 (1H, d), 7.5 (1H, d), 7.4 (1H, d), 7.2 (2H, s), 6.6 (1H, dd), 6.5 (1H, d), 3.9 (9H, d), 3.85 (3H, s), 3.83 (3H, s). Mass Spectrum (FAB) m/e 359 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=[O:23].S(Cl)(Cl)=O.[CH3:29]O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([O:24][CH3:29])=[O:23]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)inden-3-ylacetic acid (51 g, 0.15 mol) in methanol (600 mL) at 0° C. there was slowly added thionyl chloride (26.8 g, 0.225 mol). The mixture was then stirred at room temperature for 2 hours and filtered to afford the title compound as a yellow solid, mp 73-75° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[CH2:22](Br)[CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>>[CH2:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1)[CH:23]=[CH2:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
In an analogous manner to the procedure described in Example 14, by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate with allyl bromide in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate as a colourless solid; m.p.: 113° C. (hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@@H:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]([C:34](N(C)OC)=[O:35])[N:31]([CH3:33])[CH:32]=3)=[CH:24][CH:23]=2)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:40][Mg]Br>C1COCC1>[C:34]([C:30]1[N:31]([CH3:33])[CH:32]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:15]([NH:14][C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=3)=[O:13])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)[N:29]=1)(=[O:35])[CH3:40]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Solvent: C1CCOC1
Product: CC(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude (4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoic acid (3.18 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. was added methylmagnesium bromide (10.6 mL, 10 equiv, 3.0 M in ether) dropwise by syringe. The reaction was stirred for 30 minutes at 0° C. and then carefully quenched with sat. aq. NH4Cl solution (10 mL), followed by 1N HCl solution (60 mL) such that the pH of the aqueous layer ˜5.5. The product was extracted with EtOAc (4×40 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound, which was used directly in the next reaction. ESMS [M+H]+=512.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13].[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1Br
Temperature: 70 °C

Procedure:
A solution of diethyl (2-bromo-4-nitrophenyl)propanedioate (5.6 g, 17 mmol) in 120 mL of methanol and 100 mL of water was added KOH (2.8 g, 50 mmol), and the mixture was heated to 70° C. for 3.5 hours. The reaction was cooled to ambient temperature, distilled off methanol under reduce pressure and adjusted pH to 2 with conc. HCl. Extracted with EtOAc and the organic layers were washed with water, brine and dried over anhydrous sodium sulfate, concentrated to get (2-bromo-4-nitrophenyl)acetic acid. 1H-NMR (300 MHz, CDCl3) δ ppm 8.39 (s, 1H), 8.07˜8.11 (m, 1H), 7.43 (d, J=8.3 Hz, 1H), 3.88 (s, 2H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].[OH-].[Na+].[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([CH2:19][CH2:20][NH:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1)(=[O:18])=[O:17]
Reactant: C=CS(C)(=O)=O
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-nitrobenzylamine hydrochloride (1.0 g, 5.3 mmol) in DCM was converted to the free base by treating with 2 N NaOH. The organic layer was separated and concentrated, and the residue was redissolved in MeOH. To this solution was added methylvinylsulfone (232 μL, 2.6 mmol), and the reaction was stirred at rt. After 5 h, the crude reaction mixture was adsorbed onto silica gel and purified by column chromatography to generate the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 3.93 (s, 2H), 3.16-3.24 (m, 4H), 3.01 (s, 3H). ES-LC/MS m/z=259 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[C:18]([N:17]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:16][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:15])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)NNC(=O)c1ccco1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)N(Cc1ccccc1)NC(=O)c1ccco1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.8 g), 1-furoyl-2-t-butyl hydrazine (2 g) and excess powdered potassium carbonate were stirred in dimethylformamide (50 ml) at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed several times with water. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The white solid product was chromatographed on silica gel (G:70-230 mesh) using methylene chloride as eluent to afford the product in good yield: m.p. 152-153.