Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:30]1[CH:35]=[CH:34][N+:33]([O-])=[CH:32][CH:31]=1)[O:4][C:5]1[C:14]([N:15](COCC[Si](C)(C)C)[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C([NH2:43])(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C(F)(F)F)C=CC=CC=1.O>[NH2:43][C:32]1[CH:31]=[C:30]([CH:3]([O:4][C:5]2[C:14]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:2]([F:38])([F:37])[F:1])[CH:35]=[CH:34][N:33]=1
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: FC(F)(F)c1ccccc1
Solvent: O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccnc(N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
Compound B4 (200 mg, 0.349 mmol) obtained in Step 1 of Example 42 was suspended in benzotrifluoride (10 mL). To the suspension were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture was further stirred at room temperature for 18 hours. Further, to the reaction mixture were added tert-butylamine (0.19 mL, 1.7 mmol) and p-toluenesulfonic anhydride (228 mg, 0.698 mmol) and the mixture was further stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was dissolved in benzotrifluoride (2.0 mL) and trifluoroacetic acid (2.0 mL) and the solution was stirred at 70° C. for 18 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and water were added to the residue. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/10) to give Compound 45 (83.2 mg, 54% yield).
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[C:1]([Si:5]([CH3:36])([CH3:37])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:20]([Cl:34])=[CH:21][C:22]([C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(-c4ccncc4)cc3Cl)C2=O)CC1

Procedure:
Using the method of Example 81 and trifluoro-methanesulfonic acid 4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-yl methyl}-3,5-dichloro-phenyl ester (Preparation 74) (0.398 g, 0.658 mmol), 4-pyridine boronic acid (0.242, 1.97 mmol) tetrakis(triphenylphosphine)palladium (0.076 g, 0.0658 mmol), dimethoxyethane (5 mL) and sodium carbonate (2M, 1.8 mL) gives the title compound. Purify the crude material over silica gel (3/1 hexane in ethyl acetate to ethyl acetate) to yield 0.189 g (54%) of the title compound: mass spectrum (m/z): 535(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH:29]([NH:32][CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30]>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:32]([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN(C(C)C)C(C)C
Temperature: 130 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and diisopropylamine (0.78 ml, 5.58 mmol) in DMF (10 ml) was stirred at 130° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (398 mg, 93%).
Reaction SMILES: [CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:4](=[O:6])[CH3:5])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:37][C:38]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]([O:49][CH3:50])[C:39]=1[C:40]([NH2:42])=[O:41]>CC(N(C)C)=O.O>[CH3:50][O:49][C:43]1[CH:44]=[C:45]([O:47][CH3:48])[CH:46]=[C:38]2[C:39]=1[C:40](=[O:41])[NH:42][C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])[CH2:12][CH2:11]3)=[CH:18][CH:17]=1)=[N:37]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CCN(C(C)=O)C1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(C(C)=O)C1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.385 g, 1.40 mmol), NaHSO3 (0.162 g, 1.50 mmol), and p-TsOH (0.024 g, 0.12 mmol) were added to a solution of 2-amino-4,6-dimethoxybenzamide (0.250 g, 1.20 mmol) in DMA (10 mL). The reaction was stirred at 150° C. for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.300 g, 55%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.76 (s, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.67 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.29-4.33 (m, 0.5H), 3.99-4.03 (m, 2H), 3.88 (s, 3H), 3.83 (5, 3H), 3.12-3.25 (m, 2H), 2.81-2.93 (m, 2H), 2.07 (s, 1.5H), 2.01 (s, 1.5H), 1.59-1.74 (m, 4.5H), 1.10 (t, J=6.7 Hz, 1.5H), 0.99 (t, J=6.7 Hz, 1.5H). ESI MS m/z 451 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1cc(Br)c(N)cc1[N+](=O)[O-]
Temperature: -7.5 °C
Yield: 77.4 %

Procedure:
2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to H2SO4 (410 mL) at room temperature to yield a clear solution. This clear solution was then cooled down to −5 to −10° C. A solution of KNO3 (83 g, 0.82 mol) in H2SO4 (410 mL) was added dropwise while the temperature was maintained between −5 to −10° C. Upon completion, the reaction mixture was poured into ice/water and extracted with EtOAc. The combined organic layers were washed with 5% Na2CO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by a column chromatography (ethyl acetate/petroleum ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (150 g, 78%).
Reaction SMILES: C(O[CH:5]1[O:14][C@@H:13]([CH3:15])[C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[F:23])(=O)C.C(O[C@@H]1O[C@@H](C)[C@@H](NC(=O)C(F)(F)F)[C@@H](OC(=O)C)[C@H]1F)(=O)C.O[C@H]1O[C@@H](CO)[C@@H](O)[C@@H](O)[C@H]1O.[BrH:59]>C(O)(=O)C>[C:9]([O:8][C@@H:7]1[C@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C@H:13]([CH3:15])[O:14][C@@H:5]([Br:59])[C@@H:6]1[F:23])(=[O:11])[CH3:10]
Reactant: Br
Reactant: CC(=O)OC1O[C@@H](C)[C@@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F
Agent: CC(=O)O[C@@H]1O[C@@H](C)[C@@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@H]1F
Agent: OC[C@@H]1O[C@H](O)[C@H](O)[C@H](O)[C@@H]1O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](F)[C@H](Br)O[C@@H](C)[C@H]1NC(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
1,3-Di-O-acetyl-2,4,6-trideoxy-2-fluoro-4-(trifluoroacetamido)-L-talopyranose [the mixture of Compounds (11) and (12)] (335 mg) obtained in Example 1-(8) above was dissolved in 3.4 ml of a solution of 30% hydrogen bromide in acetic acid. The resultant solution was allowed to stand at room temperature for 1 hour to effect the bromination reaction.
Reaction SMILES: [C:1]([CH2:5][C:6](OCC)=[O:7])(=O)[CH2:2][CH3:3].CS(O)(=O)=O.[CH2:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[NH:23])[CH2:17][CH3:18].[OH-].[Na+]>O.C(O)C>[CH2:2]([C:1]1[CH:5]=[C:6]([OH:7])[N:24]=[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])[N:23]=1)[CH3:3]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)CC(=O)CC
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc(O)cc(CC)n1

Procedure:
A solution of ethyl propionylacetate (0.79 g), 2-propoxybenzamidine methanesulphonate (1.45 g) and sodium hydroxide (0.60 g) in water (5 ml) and ethanol (5 ml) was stirred at ambient temperature for 22 hours. Most of the solvent was removed under reduced pressure and water (20 ml) was added. The mixture was acidified to pH 2 with concentrated hydrochloric acid and then extracted with chloroform (3×30 ml). the combined extracts were washed with dilute acetic acid, dried (magnesium sulphate) and evaporated under reduced pressure to yield a residue which was recrystallised twice from ether to yield the title compound, 373 mg, m.p. 97°-98.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1.[CH2:38](OC(OCC)OCC)C>>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]5[N:26]=[CH:38][NH:27][C:23]5=[CH:22][C:21]=4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1
Reactant: CCOC(OCC)OCC
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc4nc[nH]c4cc3-c3ccccc3)cc2)CC1
Reaction time: 1 h

Procedure:
6-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-2,3-diamine (4-4, 0.055 g, 0.11 mmol) was heated at reflux in triethylorthoformate. After 3 h the reaction was concentrated and stirred in 1M HCl for 1 h. The solution pH was adjusted to 7 with saturated aqueous Na2CO3. The mixture was extracted 3× with DCM. The residue was purified by flash column chromatography (elute with a gradient of 95:5 DCM/MeOH to 90:10). The resulting impure product was dissolved in 2 ml of formic acid and the resulting solution was heated to reflux for 2 h. The reaction was concentrated, diluted with saturated aqueous NaHCO3, and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (elute with a gradient of 95:5 DCM MeOH to 90:10) to afford 5-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (6-1). 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.93 (s, 1H), 7.42 (d, 2H, J=11.0 Hz), 7.37 (d, 2H, J=10.8 Hz), 7.37-7.21 (m, 6H), 4.20 (m, 1H), 3.65 (s, 2H), 3.14 (m, 2H), 2.65 (s overlapping with m, 5H), 2.23 (m, 2H), 1.80 (m, 2H). MS m/z (M+H)=499.16.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH2:8]([CH:7]1[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(O)CCS
Reactant: CC(C)CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)CC1OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 4.74 grams (0.055 moles) of isovaleraldehyde is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 8.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=3[O:19][CH3:20])=[CH:9][C:4]=2[N:3]=[CH:2]1.COC(OC)C1C=CC(OC2C=CC3NC=NC=3C=2)=C(OC)C=1.[NH2:44][CH:45]1[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH:44][CH:45]4[CH2:53][C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[CH2:46]4)=[CH:13][C:12]=3[O:19][CH3:20])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1cc(C=O)ccc1Oc1ccc2[nH]cnc2c1
Reactant: NC1Cc2ccccc2C1
Agent: COc1cc(C(OC)OC)ccc1Oc1ccc2[nH]cnc2c1
Product: COc1cc(CNC2Cc3ccccc3C2)ccc1Oc1ccc2[nH]cnc2c1

Procedure:
N-{[4-(1H-Benzimidazol-5-yloxy)-3-(methyloxy)phenyl]methyl}-2,3-dihydro-1H-inden-2-amine was prepared using a mixture of 4-(1H-benzimidazol-5-yloxy)-3-(methyloxy)benzaldehyde and 5-{[4-[bis(methyloxy)methyl]-2-(methyloxy)phenyl]oxy}-1H-benzimidazole and the procedure of General method 1, step 5 where 2-aminoindane is the amine.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1cccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: COc1cccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(3-methoxyphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.40 (t, J=7.8 Hz, 1H), 7.24-7.31 (m, 2H), 7.06-7.11 (m, 1H), 6.82 (d, J=13.5 Hz, 2H), 5.23 (s, 2H), 3.84 (s, 3H), 2.87 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H16F5NO4S, 474.1 (M+H). found 474.0.
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[OH:1][CH:2]1[CH2:23][N:22]([S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:37])[F:38])(=[O:35])=[O:34])[CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2O

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 2 step A) and 2-trifluoromethoxy-benzenesulfonyl chloride. Colourless solid. MS (ESI): 555.2 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7]
Reactant: COCCC1(C(=S)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COCCC1(C(=S)N[C@@H](Cc2ccc(N)cc2)C(=O)OC)CCCC1
Reaction time: 0.33 h
Yield: 106.4 %

Procedure:
To a suspension of N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (4.58 g, 11.6 mmol), zinc dust (7.50 g, 116 mmol) and ammonium chloride (9.20 g, 174 mmol) in methanol (200 mL) was added H2O (100 mL) slowly over 5 min. After stirring for 20 min, the reaction mixture was partitioned between ethyl acetate (400 mL) and sat. ammonium chloride solution (150 mL).The separated aqueous layer was back-extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residual oil was dried under high vacuum for 2 h to give crude 4-amino-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (4.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34](=O)[CH2:35][C:36](=[O:56])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[C:47]([CH2:48][O:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)=[CH:46][N:45]=[N:44]2)[CH:38]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:34](=[O:33])[CH2:35][C:36](=[O:56])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N:43]3[C:47]([CH2:48][O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][O:51]4)=[CH:46][N:45]=[N:44]3)[CH:38]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (220 mg, 0.55 mmol) according to the general procedure M. Obtained as a yellow oil(100 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Br)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. The piperidine (2.55 g, 0.03 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness, then placed under high vacuum for 3 hrs. The solid was treated with water, collected by filtration, washed with water, and dried at 50° C. under high vacuum over the weekend to give 3.93 g (66%) of title compound, mp 157°-58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:18][CH2:19][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])(=[O:17])[CH3:16].Cl>C(OCC)C.CCCCCC>[C:24]([O:23][CH2:22][C:20]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:21])[CH2:19][O:18][C:15](=[O:17])[CH3:16])(=[O:26])[CH3:25]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: -30 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Under an atmosphere of argon, 22.5 g of 2,4-difluorobromobenzene was dissolved in 200 ml of diethyl ether and to the resulting solution was added dropwise 73 ml of 1.63M n-hexane solution of n-butyllithium at -30° C. The resulting liquid was stirred for 1 hour and stored at -60° C. This liquid was carefully added dropwise using an injection cylinge to 150 ml of diethyl ether solution of 17.4 g of 1,3-diacetoxyacetone which was previously cooled to -30° C. After the resulting liquid was stirred at -60° C. for 2 hours, a temperature thereof was gradually raised to room temperature. Then, the reaction mixture was transferred to 100 ml of 1.2N aqueous solution of hydrochloric acid at 5° C. or below, and the organic layer was separated therefrom and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The organic layers were combined and washed with saturated aqueous solution with sodium chloride, dried over anhydrous magnesium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was purified by column chromatography on silica gel (hexane: ethyl acetate=1:1) to give 8 g of the desired compound.