Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[CH:20]([N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]=3[CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O1CCCC1>[CH:28]1([N:26]([CH3:27])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([OH:33])=[O:2])=[CH:11][CH:10]=4)[CH:23]=[C:22]([O:24][CH3:25])[C:21]2=3)[CH2:29][CH2:30]1
Reactant: COC(=O)/C=C/c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(/C=C/C(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of (E)-3-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acrylic acid methyl ester (Intermediate 86, 0.12 g, 0.27 mmol) in methanol (4 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as a white solid (0.041 g, 35%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22]([C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1.C([O-])(=O)C.[Na+:41]>CO>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22]([C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([O-:17])=[O:16])=[N:4][N:3]=1.[Na+:41].[Na+:41].[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22](=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([O-:17])=[O:16])=[N:4][N:3]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(SCC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.1 g of animal black was added at room temperature to a stirred solution of 1.1 g of the product of Example 7, 25 ml of methanol and 7.7 ml of a solution of sodium acetate in methanol and the mixture was vacuum filtered. The filter was rinsed with methanol and the filtrate was evaporated under reduced pressure at less than 30° C. to a volume of about 5 ml. 50 ml of pure ethanol were added thereto at room temperature and the mixture was stirred at 20°-25° C. for 15 minutes and was vacuum filtered. The product was rinsed 3 times with 5 ml of pure ethanol and 3 times with 10 ml of ether and was dried under reduced pressure to obtain 0.965 g of the syn isomer of disodium 3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(carboxymethyloxyimino)-acetamido]-ceph-3-eme-4-carboxylate with a specific rotation of [α] D20 =-55.5°±1.5° (c=1% in water).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:25]([O:24][C:22]([C:20]1[N:21]=[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[NH:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: [H][H]
Reactant: CCOC(=O)c1c[nH]c(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(C2CCNCC2)n1
Yield: 99.6 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(4-ethoxycarbonylimidazol-2-yl)piperidine (0.82 g) in ethanol (20 mL) was hydrogenated over 10% palladium on carbon (0.10 g) at a hydrogen pressure of 3.45 bar for 1 hour. The mixture was filtered through diatomaceous earth and the filter cake was washed with ethanol. The filtrate was evaporated to leave the piperidine derivative as a white foam (0.510 g); NMR: 7.65 (s, 1), 4.18 (q, 2, J=7.1), 2.99 (broad d, 2, J=12.2 H), 2.75 (m, 1), 2.55 (m, 2), 1.80 (broad d, 2, J=12.6), 1.57 (m, 2), 1.25 (t, 3, J=7.1); MS: m/z=252(M+1+28).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:8][CH:9]=1)=[O:3].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]([C:4]1[C:5]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:6][C:7]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)C1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cnc(Nc2ccc(N3CCC(C(=O)O)CC3)cc2)nc1NCc1ccccc1
Temperature: 60 °C
Yield: 51.2 %

Procedure:
A 15 ml THF-methanol (1:1) solution of 750 mg of ethyl 1-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxylate was mixed with 1 M sodium hydroxide aqueous solution, followed by stirring under heating at 60° C. for 1 hour. The reaction mixture was cooled down to room temperature and mixed with 1 M sodium hydroxide aqueous solution, and the precipitated solid was collected by filtration and washed with water and methanol. By recrystallizing the resulting solid from a THF-methanol mixed solvent, 361 mg of 1-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperidine-4-carboxylic acid was obtained as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(NCc2ccc(C(=O)O)cc2)cc1
Reactant: Nc1ccccc1N
Product: CS(=O)(=O)c1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1

Procedure:
The compound was obtained by reacting the acid 211a with 1,2-phenylenediamine following the procedure described in the scheme 1, step 5 (example 1). 1H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.35 (t, J=6.0 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.93 (dt, J=1.6, 8.0 Hz, 1H), 6.73 (dd, J=1.6, 8.0 Hz, 1H), 6.66 (d, J=8.8 Hz, 2H), 6.55 (dt, J=1.2, 7.6 Hz, 1H), 4.88 (bs, 2H), 4.43 (d, J=6.0 Hz, 2H). LRMS: (calc.) 395.5; (obt.) 396.4 (MH)+.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]([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)[CH3:16])[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)CO>O>[C:23]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([O:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)[CH3:16])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(OCCN1CCNCC1)(c1ccccc1)c1ccccc1
Yield: 71.1 %

Procedure:
A mixture of 2.6 g (6.8 mmole) of 4-ethoxycarbonyl-1-[2-(1,1-diphenylethoxy)ethyl]piperazine [prepared as described in step (a) above], 3.0 g (5.3 mmole) of potassium hydroxide, 9 ml of water and 30 ml of ethylene glycol was stirred at 160° C. for 2 hours while the water formed was removed by evaporation. The reaction mixture was then poured into ice water, and the mixture was extracted with chloroform, after which it was washed with water. The solvent was then removed by evaporation under reduced pressure, to obtain 1.5 g (yield 71%) of the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[CH3:26])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C)c(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(C)C)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2,5-dimethylphenylboronic acid in the presence of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′,5′-dimethyl-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 449.2 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[F:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(F)c2)C1

Procedure:
The title compound (D45) (244.9 mg) was prepared according to the experimental procedure described in Description 40 starting from tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (200 mg, 0.929 mmol, available at Aldrich#681318) and 3-Fluorophenol (0.083 ml, 0.929 mmol).
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCOC(=O)Cl
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCOC(=O)N1C[C@H](OCC)[C@H](Nc2nc(CC)c(-c3ccc(Cl)cc3Cl)nc2CC)C1

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting ethyl chloroformate and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][C:31](OC)=O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:30][C:31]1[NH:20][C:18](=[O:19])[C:3]2[C:4]([CH2:16][CH3:17])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(OC)c(Cl)c3)nc21
Yield: 27.7 %

Procedure:
18 mg (0.065 mmol) of 5-amino-3-ethyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 69 mg (0.323 mmol) of methyl 3-chloro-4-methoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 8 mg (28%) of a solid, Rf=0.75 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)[C@H:14]([CH3:25])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=4)[N:21]=[CH:20][N:19]=3)[C@H:14]([CH3:25])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(Cl)ncn3)[C@H](C)C2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)c(Cl)c4)ncn3)[C@H](C)C2)c(Cl)c1
Temperature: 80 °C

Procedure:
Bubble nitrogen through a mixture of 5-chloro-6-[4-(6-chloro-pyrimidin-4-yl)-3-(R)-methyl-piperazin-1-yl]-nicotinic acid ethyl ester (226 mg, 0.57 mmol), 3-chloro-4-fluorophenylboronic acid (99 mg, 0.57 mmol), K3PO4 (2M aqueous, 570 μL) and Pd(PPh3)4 (33 mg, 0.03 mmol) in dioxane for 10 min. Heat the mixture to 80° C. for 16 h under a nitrogen atmosphere. Cool the mixture and partition between EtOAc and water. Dry (Na2SO4) the organic layer and concentrate under reduced pressure to yield the crude product. Purify the residue with preparative plate chromatography (2×2 mm thick) using 40% EtOAc/hexanes as the eluent to afford the title compound as a foam. 1H NMR (400 MHz, CDCl3): δ1.38 (m, 6H, 2×CH3), 3.16 (m, 1H), 3.31 (dd, 1H, J=11 Hz), 3.51 (m, 1H), 4.12 (d, 1H, J=12.8 Hz), 4.21 (d, 1H, J=13 Hz), 4.39 (m, 3H), 4.77 (Br s, 1H), 6.82 (s, 1H), 7.25 (m, 1H), 7.89 (m, 1H), 8.07 (d, 1H, J=7 Hz), 8.18 (s, 1H), 8.71 (s, 1H), 8.79 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.5 g, 7.56 mol) in acetonitrile (25 mL) was Cs2CO3 (3.93 g, 12.06 mol) with stirring at RT. After 15 min, MeI (2.34 g, 16.48 mol) was added. The reaction mixture was stirred at rt for 14 h. The reaction was monitored by TLC. When SM was finished, reaction mixture was filtered through celite pad and filtrate was concentrated. Column chromatography of crude material afforded product 1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (29) as white solid (2.35 g, 90%).
Reaction SMILES: [C:1]([CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7])#[N:2].[NH2:38][OH:39]>CO>[NH2:2][C:1](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC#N)C1c1ccc(Cl)cc1Cl
Reactant: NO
Solvent: CO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 128 mg of (3RS,4RS)—N-(cyanomethoxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 1.92 ml of methanol was added 0.018 ml of a hydroxylamine solution at room temperature, followed by warming to 40° C. and stirring overnight. The reaction solution was cooled to room temperature and the precipitated crystal was then collected by filtration to obtain 26 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCSc1ccccc1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 92 from 6-hydroxy-carbostyril and 4-phenylmercapto-butyl bromide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([NH:10][C@H:11]([C:16]([O:18]C)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]([F:20])([F:21])[CH:3]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(c1ccccc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(c1ccccc1)C(F)(F)F)C(=O)O
Reaction time: 8 h

Procedure:
To a room temperature solution of methyl N-(2,2,2-trifluoro-1-phenylethyl)-L-leucinate (150 mg, 0.50 mmol) in 2:1 THF/MeOH was added 1M LiOH. The mixture was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and pH 3.5 phosphate buffer. The organic phase was washed with brine, dried over MgSO4 and concentrated to give N-(2,2,2-trifluoro-1-phenylethyl)-L-leucine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]1[NH:29][C:28](=[O:30])[C:27]2[C:22](=[C:23](Br)[CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH2:2][CH3:3].[CH2:32]=[CH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]1[NH:29][C:28](=[O:30])[C:27]2[C:22](=[C:23]([CH:32]=[CH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH2:2][CH3:3]
Reactant: C=CCCCCC
Reactant: CCCOc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1nc2c(Br)cccc2c(=O)[nH]1
Product: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCOCC4)ccc3OCCC)nc12
Yield: 53.2 %

Procedure:
The title compound is prepared analogously to the method of Example 1, starting with 2-(2-n-propoxy-5-morpholinosulfonylphenyl)-8-bromoquinazolin-4(3H)-one and 1-heptene.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC1CC=CCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimeehylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2Cl2 under N2 at 25° C. was added tert- butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: [ClH:1].[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].C[O:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][N:7]([CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][C:18]([OH:17])=[CH:19][CH:20]=2)[CH2:8][CH2:9]1)#[N:3]
Reactant: COc1ccc(OCCBr)cc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CC1(c2ccccc2)CCN(CCOc2ccc(O)cc2)CC1

Procedure:
The title compound was prepared from 4-cyano-4-phenylpiperidine hydrochloride (600 mg, 2.69 mmol), 2-(4-methoxyphenoxy)ethyl bromide (653 mg, 2.82 mmol) and K2CO3 (761 mg, 5.51 mmol) in two steps as a colorless solid (28 mg, 60%), mp 199-200° C.; 1H NMR (CD3OD) 2.48-2.64 (m, 4H), 3.48-3.64 (m, 2H), 3.73 (t, J=4.8 Hz, 2H), 3.95 (d, J=12 Hz, 2H), 4.36 (t, J=4.5 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 7.38-7.64 (m, 5H); HRMS calcd for C20H22N2O2 322.1681, found 322.1678.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][CH:7]=1.[ClH:14]>>[Br:13][C:9]1[C:10]([CH3:12])=[N:11][C:6]([Cl:14])=[CH:7][CH:8]=1
Reactant: Cl
Reactant: Cc1nc(N)ccc1Br
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1nc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (4.5 g, 66 mmol) was added slowly to a solution of 6-amino-3-bromo-2-methylpyridine (3.07 g, 16.4 mmol) in concentrated HCl (40 mL) at −20° C. After 1 h, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was carefully neutralized with ice-cold 5N NaOH until pH=11. The aqueous layer was extracted with Et2O (3×75 mL). The combined organic layers were washed with brine (1×75 mL), dried (Na2SO4) and concentrated in vacuo to afford 3-bromo-6-chloro-2-methylpyridine, as a white solid, which was used in the next step without further purification. LCMS calc.=205.9; found=206.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J=8.2 Hz, 1H); 7.07 (d, J=8.1 Hz, 1H); 2.66 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[S:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])=[S:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Fc1ccccc1N=C=S
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=S)Nc2ccccc2F)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-fluorophenyl isothiocyanate according to the procedure of Example 65. MS (ESI) m/z 546.