Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:28](Cl)(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH3:41].Cl>N1C=CC=CC=1>[O:6]=[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCC/C=C\CCCCCCCC(=O)Nc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a cold (0° C.) solution of ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}-(oxo)acetate (140 mg, 0.37 mmol) in anhydrous pyridine (2 mL) was added (9Z)-tetradec-9-enoyl chloride (100 mg, 0.40 mmol) under inert atmosphere. The resulting reaction mixture was stirred for 1 h at 0° C. A 5 N aqueous solution of HCl (10 mL) was added and the mixture was extracted with Et2O (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a yellow oil. This crude product was purified by SPE (NH2 Isolute column) to give the title compound as a pale yellow oil (191 mg, 88%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.52 (m, 2H), 7.39 (d, 1H, J=8.0 Hz), 7.33 (d, 1H, J=7.9 Hz), 7.20 (m, 3H), 5.36 (m, 2H), 4.52 (s, 1H), 4.46 (s, 1H), 4.42-4.30 (m, 4H), 2.37 (t, 2H, J=7.5 Hz), 2.03 (m, 4H), 1.74 (m, 2H), 1.39-1.29 (m, 15H), 0.90 (t, 3H, 3=6.9 Hz). M−(LC/MS(ESI)): 587; M+(LC/MS(ESI)): 589. HPLC (Condition A), Rt: 7.24 min (HPLC purity: 97.3%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1cccc(C2OCCO2)n1
Yield: 99.2 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (3 g, 16.22 mmol) in toluene (60 mL) was added ethylene glycol (4.97 g, 80.2 mmol) and p-toluenesulphonic acid (0.152 g, 0.8 mmol). The reaction mixture was refluxed for 3 h. The solvent was removed under reduced pressure to afford the crude which was dissolved in ethyl acetate and washed with water. The organic layers were washed with a brine solution, and dried over sodium sulfate. The solvent was removed under reduced pressure to afford 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (3.7 g). The material was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:26][C:27]([C:29]2[C:30](=[O:42])[N:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:32]([CH3:35])[C:33]=2[CH3:34])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][C:22]3([OH:25])[CH2:24][CH2:23]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:43]([NH:50][CH2:51][C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:46]([O:45][C:43]([NH:50][CH2:51][C:52]([O:25][C:22]1([CH2:21][CH2:20][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:26][C:27]([C:29]5[C:30](=[O:42])[N:31]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:32]([CH3:35])[C:33]=5[CH3:34])=[O:28])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:23][CH2:24]1)=[O:53])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (218 mg, 0.384 mmol), N-Boc-glycine (133.4 mg, 0.768 mmol, Alfa), and DMAP (7.03 mg, 0.058 mmol, Aladdin) in 10 mL of dichloromethane was added DCC solid (323.4 mg, 1.54 mmol, Aldrich) slowly at 0° C. The reaction was then warmed up to rt and continued to stir at rt overnight. The reaction mixture was filtered and the solid was washed with dichloromethane (10 mL×2). The combined organic phases were washed with 20 mL of saturated NaNCO3 solution followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (PE: EA=1:6) to give the desired compound as a yellow solid (190 mg, 70%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[N:14]1([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21][CH:20]=2)=[O:19])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CCOC(=O)C(C)(C)CCCBr
Reactant: O=C(CCCCCn1ccnc1)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCOc1ccc(NC(=O)CCCCCn2ccnc2)cc1
Reaction time: 8 h

Procedure:
In 50 ml of ethanol was suspended 3 g of 4'-hydroxy-6-(1-imidazolyl)hexaneanilide hydrochloride. While stirring 2.8 g of anhydrous potassium carbonate and 2.4 g of ethyl 5-bromo-2,2-dimethylpentanoate were added to the suspension. The mixture was stirred for 8 hours under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure and the residue was dissolved in ethylene chloride. The solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from ethyl acetate to give the aimed product, ethyl 5-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylpentanoate.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(O)(C)(C)C.[K]>O1CCCC1.C(O)(C)(C)C.O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: C=CC(=O)OCC
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)CCN1C(=O)C(N=[N+]=[N-])CCc2ccccc21

Procedure:
A solution of 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepine-2-one [prepared as described by Watthey et al., J. Med. Chem., 28, p. 1511-15156 (1985)] in tetrahydrofuran/tert-butanol was cooled to 0° C. and treated with ethyl acrylate and 1N tert-butanol, potassium salt/tetrahydrofuran according to the procedure of Example 40 part (a) affording 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-propanoic acid, ethyl ester as a syrup. TLC (ethyl ether:hexane, 1:1) Rf =0.45.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:22][O:23][C:24](=[O:27])[CH2:25][CH:8]([C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(Br)ccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 6-bromo-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine (3.3 g, 9.0 mmol), bromo-acetic acid methyl ester (2.1 mL, 22.5 mmol) and K2CO3 (8.4 g, 60.8 mmol) were suspended in DMF (18.0 mL) and stirred at 40° C. for 1 hour before pouring into water (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 3-(6-bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester (3.9 g, quant.) as a light yellow solid. MS: 443.1 & 445.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (50 mg, 0.11 mmol) were added methanesulfonyl chloride (18 μL, 0.23 mmol) and DIPEA (59 μL, 0.34 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 15 min and diluted with CH2Cl2. The organic phase was then washed with 1M Na2CO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 28 mg (47%) of the title compound, m/z 517.7 [M−1]+
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[ClH:16]>[Pd].C(O)C>[ClH:16].[ClH:16].[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2ccnc2)cc1
Reaction time: 1.33 h
Yield: 96 %

Procedure:
A mixture of 4-(imidazol-1-yl)nitrobenzene (89.60 g, 0.474 mol) and 10% palladium on carbon (4.50 g) in ethanol (1200 ml) and 5N HCl (189 ml) was hydrogenated in two batches at 40 psi for 80 minutes. Water (450 ml) was then added to dissolve the product and the catalyst was removed by filtration, washing with more water, and the combined filtrates were evaporated in vacuo, using finally a freeze drier, to give 105.4 g (96%) of the title compound as a cream solid. δH (250 MHz, D2O) 7.22 (2H, d, J=8.8 Hz), 7.35 (1H, t, J=2.1 Hz), 7.44 (2H, d, J=9.0 Hz), 7.59 (1H, t, J=1.8 Hz), 8.89 (1H, t, J=1.5 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)N>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: COc1cc(N)ccc1OCc1ccccn1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Yield: 71.3 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (200 mg, 0.9 mmol) and 3-methoxy-4-(pyridin-2-ylmethoxy)aniline (249 mg, 1.08 mmol) to give the title compound as a white solid (262 mg, 72%); NMR Spectrum: 3.80 (s+t, 5H), 4.31 (t, 2H), 5.15 (s, 2H), 7.04 (d, 1H), 7.16 (dd, 1H), 7.35 (s+d, 2H), 7.54 (d, 1H), 7.85 (t, 1H), 8.23 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 409 (MH+).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[N:30][N:31]=3)[CH:20]=2)[O:7][C@H:6]1[CH2:37][O:38]C(=O)C)(=O)C.C[O-].[Na+].[H][H]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:37][OH:38])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[S:28][C:29]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[N:30][N:31]=1
Reactant: [H][H]
Reactant: CC(=O)OC[C@@H]1O[C@@H](c2ccc(Cl)c(Cc3nnc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3nnc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of (2S,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-((5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)phenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (187 mg, 0.31 mmol) from Step 3 in methanol (10 mL) was added sodium methoxide (25 wt % in methanol, 1.0 mL). The reaction mixture was stirred at ambient temperature for 2 h. Amberlite® IR120 hydrogen form was then added to neutralize the reaction mixture. The resin was filtered off and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (78 mg, 0.18 mmol, 58%) as a white solid.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>C(O)(=O)C>[C:21]([C:20]1[CH:19]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:26]=[CH:25][CH:24]=1)([OH:23])=[O:22]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-n2c(-c3ccccc3)cc3c2CCCC3)c1

Procedure:
A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 6.85 g. (0.05 mole) of m-aminobenzoic acid and 30 ml. of glacial acetic acid was heated under reflux for 6 hours, cooled and filtered. The filter cake was washed with water and recrystallized from ethanol to provide 5.7 g. (36%) of crystals, m.p. 191°-193°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]([NH:12][C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:32]=[C:13]([C@@H:15]4[CH2:19][CH2:18][CH2:17][N:16]4[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:7]=3[CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1COc2cc(Br)ccc2C1=O
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)COc1cc(Br)ccc1-2
Temperature: 130 °C
Yield: 57.3 %

Procedure:
A mixture of (2S)-tert-butyl 2-(7-bromo-4-oxochroman-3-ylcarbamoyl)pyrrolidine-1-carboxylate (3.23 g, 7.35 mmol) and ammonium acetate (5.6 g, 73.5 mmol) in xylenes (40 mL) was heated at 130° C. for 2 hours. The reaction was cooled to room temperature. The xylenes were removed under reduced pressure and the residue was diluted with dichloromethane (100 mL). Saturated sodium bicarbonate (200 mL) was added slowly with stirring until gas evolution had subsided. The phases were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluant of (10% methanol in ethylacetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (S)-tert-butyl 2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.77 g, 4.21 mmol, 57%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:16]([CH2:17][C:18]([O:20]C)=[O:19])[C:15](=[O:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13]3[CH2:33][CH2:34][C:35](=[O:36])[C:12]2=3)=[CH:7][CH:6]=1)#[N:4].O>O1CCCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[O:22])[N:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[C:13]3[CH2:33][CH2:34][C:35](=[O:36])[C:12]2=3)=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous sodium hydroxide solution (1 M, 15.0 mL, 15.0 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetate (example 3, 2.64 g, 5.62 mmol) in tetrahydrofuran (40 mL) and the mixture is stirred at room temperature for 4 h. Water is added and the mixture is extracted three times with ethyl acetate. The aqueous layer is acidified a) with hydrogen chloride and extracted twice with dichloromethane. These organic layers are combined and concentrated. Yield: 1.84 g; ESI mass spectrum [M+H]+=456; Retention time HPLC: 0.84 min (Z018_S04).
Reaction SMILES: [CH:1]1([N:7]([CH2:27][CH:28](OC)[O:29]C)[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH:1]1([N:7]([CH2:27][CH:28]=[O:29])[C:8](=[O:26])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CC=O)C3CCCCC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (50.3 g) in tetrahydrofuran (150.9 mL) was added to a solution of p-toluenesulfonic acid monohydrate (86.3 g) in tetrahydrofuran (100.1 mL) at 20° C. to give a solution. A line wash of tetrahydrofuran (50.3 mL) was then added and the solution stirred at ambient temperature for 1 h before being added to a solution of sodium hydroxide (19.6 g) and sodium chloride (100.6 g) in water (502.9 mL) at 5° C. A line wash of tetrahydrofuran (25.1 mL) was then added and the solution warmed to 20° C. 1-Butanol (100.6 mL) was added and the layers separated. The separated organic layer can be evaporated to dryness to afford the sub-titled compound as an orange/brown oil or the solution used directly in the next Step. MS [M+H]+=398.2 (MultiMode+)
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:13]=2[CH2:12][O:11]1)C1C=CC=CC=1>[Pd].CCO>[CH3:1][NH:8][CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=[CH:19][C:13]=2[CH2:12][O:11]1
Reactant: CN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 84.3 %

Procedure:
(−)-N-benzyl-N-methyl-1-[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, 1.06 mmol), palladium on carbon (10%, 45 mg) and EtOH (15 ml) was hydrogenated at 45 psi for 14 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness (0.25 g). Purification by flash chromatography (EtOAc/MeOH 2:1) afforded the pure title compound (0.23 g, 84%, >95% e.e.). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 225° C. [α]DMeOH=−81°. MS m/z (rel. intensity, 70 eV) 257 (M+, 2), 123 (bp), 106 (29), 77 (88), 51 (61).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[Cl:15]NC(=O)CCC(N)=O>C(#N)C>[Cl:15][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]([NH2:14])=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:10]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Solvent: CC#N
Product: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]

Procedure:
A solution of 2-(2chloro-ethoxy)-6nitro-phenylamine (1a, 30.0 g, 0.14 mol), N-chlorosuccinamide and acetonitrile (1.3 L) was refluxed for 4 hr. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL). The organic layer was washed with water (2×, 250 mL) and brine (250 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexane gave 33.5 g (95.3%) as orange solid, mp 109-110° C.; MS EI m/e 250/252/254 (M+).