Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[CH:6]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[C:4](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2][O:1]1
Reactant: CCOC(=O)C=Cc1ccccc1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CC1OCCc2ccccc21
Reaction time: 0.08 h

Procedure:
Ethyl 2-(2-hydroxyethyl)cinnamate (CXXX, EXAMPLE 112, theoretically 2.40 moles) is dissolved in THF (2.4 liters) and cooled to 0°. Potassium t-butoxide (5 mol %, 120 ml of a 1 molar THF solution) is added via syringe. After 5 min HPLC shows the cyclization is completed. Acetic acid (6 mol %, 8.2 ml, 144 mmol) is added. The slurry is filtered through approximately 300 g of 200 mesh silica gel. The solvent is removed under reduced pressure until approximately 0.5 liter of THF remained. Diatomaceous earth (100 g) is added followed by hexane (4.5 liters). This slurry is filtered through 200 mesh silica gel (400 g), washing with THF/hexane (1/9) until TLC shows no remaining product. Solvent removal gives the title compound. This material is filtered through silica gel more carefully, giving an analytical sample of the title compound, NMR (300 MHz, CDCl3) 7.1-7.2, 7.05, 5.26, 4.23, 4.12, 3.83, 3.0-2.7, 1.28; high resolution MS calculated for 220.1099, found 220.1105.
Reaction SMILES: O.[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5].Br[C:16]1[C:28]([O:29][CH2:30][CH3:31])=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][C:17]=1[O:32][CH2:33][CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([O:32][C:17]1[CH:18]=[C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:27]=[C:28]([O:29][CH2:30][CH3:31])[C:16]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:7][CH:8]=1)[CH3:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
H2O (261 mg, 14.48 mmol) was added to a stirred mixture of PdCl2(dppf) (106 mg, 0.145 mmol), [4-(methoxycarbonyl)phenyl]boronic acid (626 mg, 3.48 mmol), tert-butyl 4-bromo-3,5-diethoxybenzoate (1.00 g, 2.90 mmol) and K3PO4 (1.23 g, 5.79 mmol) in DME (8 ml) and the mixture was stirred at 100° C. overnight. The reaction mixture was filtered through celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by silicage column chromatography (hexane/EtOAc) to give intended compound as a colorless solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([Cl:20])[C:10]=2[N:9]=[C:8]1[CH3:21])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][OH:4])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(=O)OCCn1c(C)nc2c(Cl)nc3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc2c(Cl)nc3ccccc3c2n1CCO
Temperature: 26 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
A round bottom flask was charge with a stir bar, 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (9.2 g, 30.5 mmol), methanol (200 mL) and potassium carbonate (0.4 g, 3.0 mmol). The reaction was judged complete after stirring for 5 hours at 26° C. The solution was partitioned between chloroform and brine. The organic layer was removed and the aqueous fraction extracted with chloroform (6×). The organic fractions were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure to approximately 200 mL when crystallization was observed. The solution was stoppered and maintained at ambient temperature for 24 hours. The resulting fine white crystals were collected by filtration to provide 4.49 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][C:16]([N:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=5)[CH2:22][O:21][C:20]4=[O:31])=[N:15][C:14]=23)[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[K+].Cl.[NH:38]([C:40]([NH2:42])=[O:41])[NH2:39]>CCO.CO>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][C:16]([N:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=5)[CH2:22][O:21][C:20]4=[O:31])=[N:15][C:14]=23)[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:39]/[NH:38][C:40]([NH2:42])=[O:41]
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cn4)nc23)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: NC(=O)N/N=C/c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cn4)nc23)cc1F
Yield: 39 %

Procedure:
A solution of (S)-2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)b enzaldehyde (0.370 g, 0.878 mmol), potassium acetate (0.0948 g, 0.966 mmol) and hydrazinecarboxamide hydrochloride (0.108 g, 0.966 mmol) in 3:1 EtOH/MeOH (6 mL) was stirred at ambient temperature overnight. The solvents were evaporated under vacuum. The residue was purified by preparative TLC (10% MeOH in DCM) to give (S,E)-2-(2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzylidene)hydrazinecarboxamide (0.164 g, 39% yield) as a yellow powder.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N+:47]=3[O-:52])[CH:41]=[C:40]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:8][CH2:7][CH:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[Cl:35])=[CH:21][CH:22]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:37][C:38]1[CH:43]=[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N+:47]=2[O-:52])[CH:41]=[C:40]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH:39]=1)=[O:36]
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2cccc[n+]2[O-])c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2cccc[n+]2[O-])c1

Procedure:
To a CH2Cl2 solution (0.03 M) of tert-butyl (3-(cyclopropyl{3-(3-methoxypropyl)-5-[(1-oxidopyridin-2-yl)methoxy]benzyl}amino)-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 20 eq.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:24][CH:23]2[OH:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH3:37])(=[O:36])=[O:35])[CH2:24][C:23]2=[O:38])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-methylsulfonylphenyl)piperidin-3-ol (0.49 g, 0.91 mmol) obtained in Step 3 in 3 ml of dimethyl sulfoxide (DMSO), was added dropwise 0.5 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.5 g, 0.31 mmol) was added to the reaction mixture, which was then stirred for 2 hours, diluted with 20 ml of ethyl acetate, and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 210 mg of the titled compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:28].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:28])[C:16]=2[N:15]=[C:14]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
0.124 g (0.335 mmol) of 1-[4-(tert-Butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5-oxide was dissolved in 3 ml of methylene chloride. Two ml of concentrated aqueous ammonia (29%) and a solution of 70 mg (0.368 mg) of p-toluenesulfonyl chloride in 1 ml of methylene chloride were added thereto under ice-cooling and the mixture was stirred for 30 minutes, then stirred at room temperature for 3 hours. After brine was added, the reaction mixture was extracted with chloroform and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1 to 20:1 (v/v)) to obtain 0.114 g (0.309 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine shown below as a pale brown solid. ##STR60## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3460, 3370, 3100, 1710, 1640, 1540, 1380, 1260, 1170, 750.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C(Cl)Cl.C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: O=C1OCc2ccc(C(F)(F)F)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OC1OCc2ccc(C(F)(F)F)cc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
6-Trifluoromethyl-3H-isobenzofuran-1-one (1.77 g) is dissolved in methylene chloride (20 ml) and the mixture is cooled to −78° C., and thereto is added a 1.0M diisobutylaluminum hydride in toluene (19.5 ml) and the mixture is stirred for 1 hour and 20 minutes. The reaction solution is cooled to room temperature, and thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give 6-trifluoromethyl-1,3-dihydro-isobenzofuran-1-ol (1.36 g). MS (m/z): 187 [M+H—H2O]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1
Reactant: c1ccc(OC2CCNCC2)nc1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: Cl
Product: Brc1ccc2nccc(N3CCC(Oc4ccccn4)CC3)c2c1
Yield: 79.4 %

Procedure:
500 mg 6-bromo-4-chloroquinoline and 540 mg 2-(4-piperidyloxy) pyridine dihydrochloride were reacted by the same method as in Production Example 82, to give 629 mg of the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([O:17]C)=[O:16])=[CH:12][S:13][CH:14]=1.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([OH:17])=[O:16])=[CH:12][S:13][CH:14]=1
Reactant: COC(=O)c1cscc1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cscc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
Methyl 4-(2-Fluoro-4-iodo-phenylamino)-thiophene-3-carboxylate (270 mg, 0.72 mmol) was dissolved in a mixture of tetrahydrofuran:methanol (6:1, 3 mL) and a solution of lithium hydroxide (0.1 g, 4.2 mmol) in 1 mL of water was added. The solution was stirred at room temperature for 18 hours and the solvent was concentrated. The residue was dissolved in 5 mL of water and the solution was acidified to pH 1 with 1N HCl. The resulting solid was filtered and dried in vacuo to provide 210 mg (79% yield) of 4-(2-fluoro-4-iodo-phenylamino)-thiophene-3-carboxylic acid. MS (EI) for C11H7FINO2S: 364 (MH+).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:7]=1[O:8][CH2:15][CH2:16][O:17][CH3:18])[C:1]([O:12][CH3:13])=[O:11]
Reactant: COCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)OC)cc1OC
Yield: 99.8 %

Procedure:
A mixture of methyl vanillate (6.376 g, 35 mmol), 1-bromo-2-methoxyethane (5.56 g, 40 mmol), and K2CO3 (5.528 g, 40 mmol) in DMF (40 mL) were reacted according to the procedure described in Example 6A Step 1, to afford methyl 3-methoxy-4-(2-methoxyethoxy)benzoate as a solid (8.394 g, 99.8%). 1H NMR (300 MHz, CDCl3) δ 7.65 (dd, 1H), 7.54 (d, 1H), 6.92 (d, 1H), 4.23 (q, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.81 (t, 2H), 3.45 (s, 3H); LC-MS (ESI) m/z 241 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[C:22][Si](C(C)C)(C(C)C)C(C)C)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[F-].[Cs+]>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: COCCOCCOCCNC(=O)c1cc(N)cc(C#C[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product from step (iii) above (1200 g, 2.59 mol) in MeCN (8.8 L) was added CsF (433.6 g, 2.85 mol). The reaction was stirred at RT overnight, after which HPLC analysis showed 1.7% product, 97.4% starting material. Additional CsF (420 g, 2.76 mol) was charged and the reaction stirred at RT overnight, whereupon HPLC analysis revealed 91.0% product, 4.4% starting material. The mixture was filtered and the filtrate concentrated in vacuo to give material which was 92.5% product, 0.7% starting material by HPLC. The residue was dissolved in DCM (3 L) and EtOAc (3 L), before being split into two equal portions. Each portion was passed through a silica pad (1.6 kg), eluting with EtOAc (50 L). The filtrates were combined and concentrated in vacuo. The crude material was washed with heptane (2×4 L) to remove silyl impurities. A total of 719 g of sub-title compound was isolated (83% assay by 1H NMR, 75% active yield, 597 g active).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2]([CH:22]=[CH2:23])[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 60.4 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (1.03 g, 3.0 mmol), tributyl-(vinyl)-stannane (0.98 g, 3 mmol) and tetrakis-(triphenylphosphine)-palladium (0.07 g, 0.06 mmol) in toluene (30 ml) was heated under reflux conditions for 3 h, evaporated and purified by chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as colorless oil (526 mg, 60%). MS (ISP): m/e=291.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]2)=[CH:7][N:8]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>ClCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:4]2[C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[N:8][CH:7]=[C:6]([N:9]3[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]3)[N:5]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(C)n(-c2cnc(CN)c(Nc3ccc(Cl)cc3)n2)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ncc(-n2nc(C)cc2C)nc1Nc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 65.2 %

Procedure:
[3-Aminomethyl-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl ]-(4-chloro-phenyl)-amine (40 mg, 0.12 mmol), triethylamine (19 μL, 0.13 mmol) and dichloromethane (2 mL) was cooled on an ice bath. Acetic anhydride (12 μM, 0.12 mmol) was added and the mixture was stirred for 45 min. Aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give N-[3-(4-chloro-phenylamino)-5-(3,5-dimethyl -pyrazol-1-yl)-pyrazin-2-ylmethyl]-acetamide (29 mg, 64%) as a white solid. Mp. 228-230° C. LC-ESI-HRMS of [M+H]+ shows 371.1404 Da. Calc. 371.138712 Da, dev. 4.5 ppm
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([O:19][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:15]([F:18])([F:16])[F:17])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](O)C(F)(F)F)COC1(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](Oc2ccc([N+](=O)[O-])cc2)C(F)(F)F)COC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a cooled, stirred solution of (S)-2,2-dimethyl-4-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.99 g) and 1-fluoro-4-nitrobenzene (0.69 ml) in THF (20 ml) at 0° C. was added dropwise potassium bis(trimethylsilyl)amide solution (7.7 ml, 1 M solution in THF). The reaction mixture was stirred for 30 min at 0° C., then allowed to warm to room temperature and stirred for a further 1 h. The mixture was then diluted with dichloromethane and washed with sat. aq. ammonium chloride solution. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(R)-3,3,3-trifluoro-2-(4-nitro-phenoxy)-propyl]-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow viscous oil (2.7 g, 97%). MS (ISP): 435.3 ([M+H]+), 379.3 ([M+H—C4H8]+), 335.4 ([M+H—C4H8—CO2]+).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N1CCOCC1)C.ClCCl.[CH2:35]([NH:42][C:43](=[O:53])[C@H:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[NH2:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:17])[CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:42]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:43](=[O:53])[C@H:44]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH2:45])=[O:13])=[CH:5][CH:6]=1
Reactant: O=C(CN1CCC[C@H]1C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: N[C@@H](Cc1ccccc1)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 13.7 %

Procedure:
A solution of N-[2-(biphenyl-4-yl)-2-oxoethyl] L-proline (51 mg, 0.16 mmol, 1.0 eq), N-ethylmorpholine (125 uL, 0.98 mmol, 6 eq) in acetonitrile (0.5 mL) was cooled to 0° C. and treated with a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (170 uL, 0.27 mmol, 1.6 eq) followed by phenylalanine benzylamide (49 mg, 0.19 mmol, 3.1 eq). Purification by HPLC provided 12 mg (14%) of L-phenylalanine, N-[1-(2-(biphenyl-4-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]3[C:14]([CH:21]4[O:25][CH2:24][CH2:23][O:22]4)=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[C:39]([O:38][C:36](=[O:37])[CH2:13][N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]2[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[C:14]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[C:11]1=2)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(C)c2c1C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)OC(C)(C)C)c2c1C1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0.23 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-3-(1,3-dioxolan-2-yl)-4-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF at 0° C. was treated with NaH (2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min, then tert-butyl bromoacetate (4 eq.) was added. The reaction mixture was heated at 50° C. for 3.5 h then it was quenched by addition of aqueous NH4Cl (saturated solution) and diluted with Et2O. The aqueous phase was separated and extracted with Et2O. The combined organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and evaporated. The residue was purified by flash chromatography on silica gel (1:19 to 1:1 AcOEt/petroleum ether) to afford methyl 4-(2-tert-butoxy-2-oxoethyl)-5-(4-chlorophenyl)-6-cyclohexyl-3-(1,3-dioxolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate. This compound was dissolved in DCM and the resulting solution (0.1 M) was treated with TFA (16 eq.). The reaction was stirred at RT for 3 h then solvents were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:99 to 1:19 MeOH/DCM) to afford the title compound (55%).