Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[NH:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31]([OH:33])=O)(=[O:27])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:22]([CH3:23])[C:31](=[O:33])[C:30]1[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:26])=[O:27])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccc(F)cc1OCc1ccccc1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccc(F)cc1OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(2-(benzyloxy)-4-fluorophenyl)-N-methylpyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (637 mg, 69%). MS (ESI): m/z=559.131 [M+H]+.
Reaction SMILES: [NH:1]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:2]([C:18]([N:20]1[CH2:32][CH2:31][CH2:30][C@H:21]1[C:22]([NH:24][C@@H:25]([C:27]([NH2:29])=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.[H][H].CCOC(C)=O.[CH3:48][CH2:49][CH2:50]CCCC>CC(O)C.CC(C)=O.[Pd]>[NH:1]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C@H:2]([C:18]([N:20]1[CH2:32][CH2:31][CH2:30][C@H:21]1[C:22]([NH:24][C@@H:25]([C:27]([NH2:29])=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:49]([CH3:50])[CH3:48]
Reactant: CCCCCCC
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O

Procedure:
A solution of Boc-Lys(Cbz)-Pro-D-Ala-NH2 (80 gm) in 2-propanol (IPA, 800 mL) and acetone (108 mL) was hydrogenated over 4% Pd/C at 60 psi hydrogen. The catalyst was filtered off and rinsed with EtOAc, and the filtrate evaporated in vacuo to dryness. The residue was taken up in EtOAc (700 mL) and again evaporated in vacuo to dryness, and this procedure was repeated once. After dissolving the residue in EtOAc (250 mL) the solution was triturated with heptane (200 mL). The mixture was evaporated in vacuo to yield a solid which formed a suspension when treated with EtOAc (250 mL). The suspension was treated with heptane (100 mL), filtered and dried in vacuo to yield 64.2 gm Boc-Lys(iPr)-Pro-D-Ala-NH2. HPLC: 98.5 pa %, MS: (M+H)+ =456
Reaction SMILES: [C:1]1([CH:7]([C:9]2[O:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:19]1[CH2:20][O:21][CH2:22][CH:23]=1)(=O)=O>>[C:1]1([CH:7]([C:9]2[C:19]3[CH2:20][O:21][CH2:22][C:23]=3[C:11]([OH:10])=[C:12]([CH3:14])[N:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1coc(C(C)c2ccccc2)n1
Reactant: CS(=O)(=O)C1=CCOC1
Product: Cc1nc(C(C)c2ccccc2)c2c(c1O)COC2

Procedure:
4-α-Phenylethyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol is prepared, using the method described in Example 13, by reacting 2-α-phenylethyl-4-methyloxazole and 3-methylsulfonyl-2,5-dihydrofuran; melting point 163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[CH:7]=1.[N:19]1([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:18][C:5]1[CH:4]=[CH:3][C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[O:26])[CH2:24][CH2:23]2)=[CH:7][C:6]=1[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: Cn1c(-c2cc(Br)ccc2F)nc2ccccc21
Reactant: O=C(N1CCCC1)N1CCNCC1
Product: Cn1c(-c2cc(N3CCN(C(=O)N4CCCC4)CC3)ccc2F)nc2ccccc21
Yield: 44 %

Procedure:
The same procedure described in step c method J was followed but starting from 2-(5-bromo-2-fluoro-phenyl)-1-methyl-1H-benzoimidazole and piperazin-1-yl-pyrrolidin-1-yl-methanone. The crude reaction mixture was purified by preparative HPLC to afford 0.06 g of the title compound (44%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.ClC(OC(C)C)=O>C(Cl)Cl.CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 73, 0.132 g, 0.30 mmol) was dissolved in CH2Cl2 (9 mL). TFA (0.30 mL) was added to this solution and the mixture was stirred at ambient temperature overnight. The excess TFA and CH2Cl2 were removed under reduced pressure. The residue was redissolved in CH2Cl2 (9 mL). The solution was cooled to 0° C. in an ice bath, and diisopropylethylamine (1.5 mL) was added, followed by addition of isopropyl chloroformate (1.0M in toluene, 0.36 mL, 0.36 mmol). The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 h, then diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 9:4 EtOAc/hexane to give 0.12 g (93%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.7 Hz), 8.14 (d, 2H, J=8.3 Hz), 8.01 (d, 2H, J=8.6 Hz), 7.74 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.23 (bs, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (APCI), m/z 433 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)[CH:8]=2)[N:3]1[C:21](=[O:23])[CH3:22].C(N(CC)C(C)C)(C)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>O1CCOCC1>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38]([N:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([B:12]3[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]3)[CH:8]=2)[N:3]([C:21](=[O:23])[CH3:22])[C@@H:2]([CH3:1])[CH2:11]1)=[O:39]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2NC[C@@H]1C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 50 °C
Yield: 66.5 %

Procedure:
A 100 mL round bottom flask fitted with a nitrogen inlet, and stir bar was charged with (S)-1-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.8 g, 2.53 mmol), 1,4-dioxane (30 ml), N,N-diisopropylethylamine (2.65 mL, 15.18 mmol) and furan-2-carbonyl chloride (0.991 g, 7.59 mmol). The reaction mixture was purged with nitrogen and heated to 50° C. for 2 h. The mixture was cooled to rt and diluted with ethyl acetate (100 mL). The mixture was then washed with brine (50 mL), and the organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 9:1 hexanes-ethyl acetate) to afford (S)-1-(4-(furan-2-carbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.69 g, 66% yield) as a colorless foam. MS (ESI, pos. ion) m/z 411 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:5]=1.C1COCC1.O.[Li+].[OH-]>CC(O)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:30])=[O:2])=[C:12]([NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)O)c3)ccnc2n1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
The product from Example 208c (447 mg, 1.065 mmol) was dissolved in 5 ml of a 1:1 (THF:water) solution. To this was added LiOH (51 mg, 2.129 mmol) and the reaction mixture was heated to 60° C. for 2 h the reaction mixture was then allowed to cool to room temperature and brought to neutral with HOAc. The product was extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (180 mg, 42%).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:43]=[CH:44][CH:45]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([C:38]3[CH:42]=[CH:41][O:40][N:39]=3)[CH2:22]C(N3[C@@H](CC4C=CC=CC=4)COC3=O)=O)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH:48]O.[Li+].[OH-].Cl.C1[CH2:57][O:56]CC1>O>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:43]=[CH:44][CH:45]=2)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([C:38]3[CH:42]=[CH:41][O:40][N:39]=3)[CH2:22][C:57]([OH:56])=[O:48])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(C[C@@H](c1ccc(OCc2cccc(Sc3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCc2cccc(Sc3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1
Reaction time: 5 h

Procedure:
To a solution of the oxazolidinone (31.4) (73.0 mg, 0.111 mmol) dissolved in THF (11 mL), was added a 30% hydrogen peroxide solution (125 μL, 1.11 mmol) followed by a 2 M LiOH solution (277 μL, 0.555 mmol). The resulting slurry was stirred for five hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH of ˜3. The mixture was then extracted with EtOAc (3×30 mL), and the organic layer was washed with an acidic sodium sulfite solution (1×30 mL) and brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 31 (29.0 mg). MS ESI (pos.) m/e: 500.0 (M+H). 1H NMR (400 MHz, CD3CN) δ 8.32 (1H, d, J=1.6 Hz), 7.44-7.51 (3H, m), 7.33-7.41 (3H, m), 7.24 (2H, d, J=8.2 Hz), 7.12 (2H, d, J=8.6 Hz), 6.82 (2H, d, J=9.0 Hz), 6.15 (1H, d, J=1.6 Hz), 4.98 (2H, s), 4.44 (1H, t, J=7.8 Hz), 3.08 (1H, dd, J=16.4, 8.2 Hz), 2.83 (1H, dd, J=16.4, 7.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:6]([CH3:21])[C:7]=1[CH:8]1[C:12](=[O:13])[C:11](=[CH:14][CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][C:9]1=[O:20].[H][H]>CO.[Pd]>[CH3:21][C:6]1[CH:5]=[C:4]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[CH:8]1[C:12](=[O:13])[CH:11]([CH2:14][CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][C:9]1=[O:20]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(=CC2CCOC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(CC2CCOC2)C1=O
Yield: 41.4 %

Procedure:
To a solution of 2-(3,5-dimethylbiphenyl-4-yl)-4-[1-(tetrahydrofuran-3-yl)methylidene]-cyclopentane-1,3-dione (0.29 g, 0.8 mmol) in methanol (10 ml) is added 10% palladium on carbon (0.06 g), followed by stirring under a 1 bar hydrogen atmosphere for 8 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(3,5-dimethylbiphenyl-4-yl)-4-(tetrahydrofuran-3ylmethyl)-cyclopentane-1,3-dione (0.12 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.CC[N:15]=C=NCCCN(C)C.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[NH:3][C:4]3[CH:9]=[C:8]([C:10]([NH2:15])=[O:12])[CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc2nc(N3CCC(Cc4ccccc4)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.9 %

Procedure:
Benzimidazole-5-carboxylic acid (1.62 g, 10 mMol) was reacted with EDAC (1.92 g, 10 mMol) in 40 mL dry DMF at room temperature for 15 minutes. To the reaction mixture was added 4-benzylpiperidine (1.75 g, 10 mMol) and DMAP (˜20 mg, catalyst) and the mixture was stirred at room temperature for 20 h. It was poured into water and extracted with methylene chloride (3-100 mL). The combined extract was washed with water, brine and again with water. The extract was dried over MgSO4 and evaporated. The residue was chromatographed on a column of silica gel with chloroform-methanol (0 to 5% methanol). Evaporation of the desired fractions gave 1.5 g (47%) of the product after recrystallization from ethyl acetate-hexane. 1HNMR (CDCl3): δ=7.8 (s, 1H); 7.1-7.3 (m, 8H); 4.8-4.7 (broad m, 1H), 3.7-3.9 (broad m, 1H); 3.1-2.7 (broad m, 2H); 2.55 (d, 2H); 2.0-1.1 (m, 5H). MS (ESI) m/e 319 (M+), 318 (M+−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>O1CCCC1>[Br:12][C:13]([F:20])([F:19])[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9])=[O:15]
Reactant: Nc1ccc(F)cc1O
Reactant: CCOC(=O)C(F)(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1O)C(F)(F)Br
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
To 2-amino-5-fluorophenol (14 g, 110 mmol) in dry Tetrahydrofuran at 0° C. was added sodium hydride (55 wt % in mineral oil; 4.81 g, 110 mmol). The resulting mixture was stirred for 15 minutes at −15° C. Subsequently ethyl 2-bromo-2,2-difluoroacetate (24.59 g, 121 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for two hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with Na2SO4 and concentrated to yield 33 g of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24](=O)OC(C)(C)C)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>CCOCC>[NH3:1].[CH3:24][NH:23][CH2:22][C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Product: N
Temperature: 0 °C
Yield: 96.7 %

Procedure:
A solution of tert-butyl ({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl)-carbamate (600 mg, 1.44 mmol) in Et2O (5 mL) was added dropwise to a stirred solution of LiAlH4 (1.0M solution in Et2O, 4.32 mL, 4.32 mmol) at 0° C. THF (5 mL) was added and the reaction mixture heated at reflux overnight. Reaction mixture was cooled to 0° C. quenched with water (0.5 mL), aqueous NaOH (2.0M, 0.5 mL) and water (0.5 mL). Dichloromethane and ethyl acetate were added and the mixture filtered over a short pad of celite, and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 96:4:0.4 to 90:10:1 to give the title compound as a clear oil (230 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 2.64 (t, 2H) 2.54 (s, 2H), 2.50-2.58 (m, 4H), 2.26 (s, 3H), 2.14-2.08 (m, 2H), 1.98 (pentet, 2H), 1.84-1.76 (m, 4H), 1.68-1.56 (m, 2H), 1.52-1.32 (m, 6H); HRMS (ESI+) 331.2744 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:11](=[O:13])(=[O:12])[NH:14][CH2:15]1)([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)Nc1ccncc1S(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)N1CNS(=O)(=O)c2cnccc21

Procedure:
A mixture of 1 g of 4-isopropylaminopyridine-3- sulfonamide (Preparation 3) and 1 g of paraformaldehyde in 20 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 3 hours. After cooling, the crystalline precipitate is filtered and washed with isopropanol. The precipitate is dissolved in 150 cm3 of hot methanol. The possible insoluble material is filtered. The filtrate is concentrated to dryness and the residue is taken up in 30 cm3 of water. The aqueous suspension is adjusted to a pH of 7-7.5 (NaHCO3) and the precipitate corresponding to the title compound is filtered, washed with water and dried.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[O:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 88.3 %

Procedure:
A mixture of 29.4 g (0.200 mol) of 2-fluoro nitrobenzene, 41.0 g (0.200 mol) of 2-chloro-4-trifluoromethylphenol and 30.0 g (0.220 mol) of K2CO3 in 150 ml of DMSO was heated at 100° C. for six hours. The reaction mixture was poured over ice and extracted with ether. The organic phase was washed with water and saturated aqueous NaCl and dried (MgSO4). The solvent was removed by evaporation at reduced pressure to yield 56.1 g (88%) of the desired product as a yellow oil. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH:27]([Br:30])[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)Cc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 40.4 %

Procedure:
A mixture of 1.12 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.49 g of N-bromosuccinimide in 40 mL of CCl4 was irradiated (UV-lamp, pyrex filter) for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) afforded 0.54 g of 1-[(2'-carbomethoxybiphenyl-4-yl)-methyl]-2-(2-bromobutyl)-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ 9.87 (s, 1H); 7.86 (d, 1H); 7.54 (t, 1H); 7.46 (t, 1H); 7.30 (m, 3H); 7.11 (d, 2H); 6.16 (d, 1H); 5.32 (d, 1H); 4.79 (t, 1H); 3.65 (s, 3H); 2.32 (m, 2H); 1.34 (sext., 2H); 0.83 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-(6-bromonaphth-2-ylsulphonyl)piperazine-3-carboxylate to give 4-(6-bromonaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 42% yield, m.p. 117-121° C.;
Reaction SMILES: [C:1](O)(=O)C(O)=O.[NH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.C(OC(OCC)OCC)C.[CH3:23][C:24]1([CH3:32])[O:29][C:28](=[O:30])[CH2:27][C:26](=[O:31])[O:25]1>>[CH3:23][C:24]1([CH3:32])[O:29][C:28](=[O:30])[C:27](=[CH:1][NH:7][C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C:26](=[O:31])[O:25]1
Reactant: Nc1ccsc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)C(=O)O
Solvent: CCOC(OCC)OCC
Product: CC1(C)OC(=O)C(=CNc2ccsc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
A 200-mL, rb flask equipped with a magnetic stirbar and a reflux condenser was charged with 3-aminothiophene oxalate (6.9 g, 36 mmol) and triethoxymethane (61 ml, 365 mmol) under N2. After stirring for 15 min, 2,2-dimethyl-1,3-dioxane-4,6-dione (5.3 g, 36 mmol) was added in one portion to the light brown slurry, and the mixture was heated to 85 deg C. in an oil bath overnight. The next day, a dark precipitate had formed and the mixture was cooled to ambient temp. The mixture was then cooled in an ice bath and the mixture was vacuum filtered through paper. The brown-red solids were washed with MTBE, air dried, then dried under vacuum to yield 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (6.73 g, 73% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:12]=2[CH:13]=1.Cl.CS[C:22](SC)=[C:23]([C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])[C:24]#[N:25].[NH2:37][C@H:38]1[CH2:44][CH2:43][CH2:42][CH2:41][N:40]([CH2:45][C:46]([N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:47])[C:39]1=[O:53]>C(#N)C>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26](=[O:34])[C:23]([C:24]#[N:25])=[C:22]([NH:37][C@H:38]1[CH2:44][CH2:43][CH2:42][CH2:41][N:40]([CH2:45][C:46]([N:48]2[CH2:49][CH2:50][CH2:51][CH2:52]2)=[O:47])[C:39]1=[O:53])[NH:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([CH3:8])=[CH:13][C:12]=2[CH:14]=1
Reactant: Cc1cc2cc(N)ccc2o1
Reactant: CSC(SC)=C(C#N)C(=O)c1ccccc1Cl
Reactant: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2cc(NC(N[C@H]3CCCCN(CC(=O)N4CCCC4)C3=O)=C(C#N)C(=O)c3ccccc3Cl)ccc2o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 38.3 %

Procedure:
Triethylamine (0.04 mL, 0.29 mmol) was added to a suspension of 2-methyl-5-benzofuranamine·HCl (40 mg, 0.22 mmol) and acetonitrile (0.5 mL) at room temperature, which resulted in a clear solution. To the solution was added α-[bis(methylthio)methylene]-2-chloro-β-oxobenzenepropanenitrile(56 mg, 0.20 mmol) and the resulting solution was heated at 50° C. for 1 hour. To this mixture was added 1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (47 mg, 0.20 mmol) and the resulting mixture was heated at 70° C. After 4 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica, 0 to 2% methanol/dichloromethane) to give the title compound as a white solid (44 mg, 39%): MS (ESI, pos. ion spectrum) m/z 574/576 (M+H); HPLC (method A) tR 4.03 min.