Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:24]=1[NH2:25].Cl.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([NH:25][C:24]1[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=1[O:22][CH3:21])=[O:7])#[N:2]
Reactant: N#CC(CC(=O)O)c1ccccc1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)CC(C#N)c2ccccc2)c(OC)c1
Temperature: 25 °C

Procedure:
To a dichloromethane (150 mL) solution of 3-cyano-3-phenylpropionic acid (5 g, 0.0286 mol) at 0° C. under a nitrogen atmosphere was added triethylamine (4 mL, 0.0286 mol) and 2,4,6-trimethoxyaniline.HCl (6.3 g, 0.0286 mol). To this solution was added DCC (6.2 g, 0.29 mol). The resulting mixture was allowed to warm to room temperature over 3 hours. This was then filtered and the filtrate partitioned between 1N HCl and dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid (5.1 g) was recrystallized from dichloromethane/hexanes, mpt 157°-160° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH2:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCN1CCc2ccccc21
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of indoline (17 parts), 1-bromoheptane (31 parts), potassium carbonate (24 parts) and N,N-dimethylformamide (30 parts) was stirred at 100° C. for 3 days. The cooled mixture was diluted with toluene, washed with water (×4), dried (MgSO4) and evaporated to leave 1-heptyl-2,3-dihydro-1H-indole (30 parts).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[O:43]1CC[C@H:45](O)[CH2:44]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([C@@H:14]3[CH2:45][CH2:44][O:43][CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O[C@H]1CCOC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn([C@@H]3CCOC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-tetrahydrofuran-3-ol and isolated as colorless gum. MS (m/e): 353.3 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:14])[CH2:11][CH2:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:17](O)[C:18]([F:21])([F:20])[F:19]>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:12][CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(O)C(F)(F)F
Reactant: CCC[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: c1ccccc1
Product: CCC[C@@H](CO[Si](C)(C)C(C)(C)C)N=CC(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of (S)-1-(tert-butyldimethylsilanyloxymethyl)-butylamine (27 g, 126 mmol) and trifluoroacetaldehyde methyl hemiacetal (17.2 g, 132 mmol) in benzene (250 mL) was heated at reflux, using a Dean-Stark trap to remove water. After 2 hours, no more water was collected. The reaction mixture was cooled and concentrated to give (S)-[1-(tert-butyldimethylsilanyloxymethyl)-butyl]-(2,2,2-trifluoroethylidene)-amine which was used in the next step without further purification or extended drying due to its volatility.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([SH:11])[CH:3]=1.CC(O[CH2:16][C:17]1[CH2:26][S:25][C@@H:20]2[C@H:21]([NH2:24])[C:22](=[O:23])[N:19]2[C:18]=1[C:27]([OH:29])=[O:28])=O>B(F)(F)F.C(#N)C>[NH2:24][C@@H:21]1[C:22](=[O:23])[N:19]2[C@@H:20]1[S:25][CH2:26][C:17]([CH2:16][S:11][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=1)=[C:18]2[C:27]([OH:29])=[O:28]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)nc2ccnn12
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2ccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.70 g of 7-methylpyrazolo[1,5-a]pyrimidine-5-thiol and 1.15 g of (7R)-7-amino-cephalosporanic acid were dissolved in 10 ml of a 20 percent solution of boron trifluoride in acetonitrile and stirred at room temperature for 1 hour. The reaction mixture was concentrated and taken up in 10 ml of water. The solid was filtered off under suction. There was obtained (6R,7R)-7-amino-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a reddish powder.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Ic1cccnc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1cccnc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 200 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 380 mg of 3-iodopyridine. After purification by silica chromatography (elution gradient of CH2Cl2 to CH2Cl2/MeOH 96/04), 48 mg of (S)-2-morpholin-4-yl-9-pyridin-3-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[C:14]2[CH:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([C:28]#[C:29][Si](C)(C)C)=[CH:22][CH:23]=5)[C:18]([CH3:35])([CH3:34])[C:17]=4[CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([NH:36][C:37](=[O:39])[CH3:38])=[CH:6][CH:7]=2.I[C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1>>[CH3:1][C:2]1([CH3:40])[C:14]2[CH:13]=[C:12]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([C:28]#[C:29][C:42]6[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=6)=[CH:22][CH:23]=5)[C:18]([CH3:35])([CH3:34])[C:17]=4[CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([NH:36][C:37](=[O:39])[CH3:38])=[CH:6][CH:7]=2
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CC(=O)Nc1ccc2c(c1)C(C)(C)c1cc(-c3ccc4c(c3)C(C)(C)c3cc(C#C[Si](C)(C)C)ccc3-4)ccc1-2
Product: CC(=O)Nc1ccc2c(c1)C(C)(C)c1cc(-c3ccc4c(c3)C(C)(C)c3cc(C#Cc5ccc([N+](=O)[O-])cc5)ccc3-4)ccc1-2

Procedure:
FIG. 3 shows a synthetic scheme (30) for the production of compound 20 (FIG. 2), where X is hydrogen. Compound 31, 7′-bromo-9,9,9′,9′-tetramethyl-9H,9′H-[2,2′]bifluoreny-7-ylamine, is acetylated and subsequently coupled with trimethylsilylacetylene to provide N-(9,9,9′,9′-tetramethyl-7′-trimethylsilanylethynyl-9H,9′H-[2,2′]bifluorenyl-7-yl)-acetamide 32. Trimethylsilyl derivative 32 is subjected to an organometallic cross-coupling reaction in the presence of 4-iodo-nitrobenzene to afford N-[9,9,9′,9′-tetramethyl-7′-(4-nitro-phenylethynyl)-9H,9′H-[2,2′]bifluoreny-7-yl]-acetamide 33. Acetylene 33 is converted to ketone 34—2-(7′-amino-9,9,9′,9′-tetramethyl)-9H,9′H-[[2,2′]bifluoreny-7-yl]-1-(4-nitro-phenyl)-ethanone—through the addition of H2O, which also effects the hydrolysis of the terminal acetamide. Alkylation of 34 provides the desired compound 35, 2-[7′-(2-mercapto-ethylamino)-9,9,9′,9′-tetramethyl-9H,9′H-[2,2′]bifluoreny-7-yl]-1-(4-nitro-phenyl)-ethanone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)CCC>>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[C:13]([C:11]([N:9]2[CH2:10][C:5]3[C:6](=[N:7][C:2]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=4)=[CH:3][CH:4]=3)[CH2:8]2)=[O:12])[CH:18]=1)(=[O:21])=[O:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C(F)(F)F)c1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3cccc(C(F)(F)F)c3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and tributyl-[3-(trifluoromethyl)phenyl]-stannane. White solid. MS (m/e): 559.2 [M+H]+, 100%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a mixture of 4-phenylbutan-1-ol (1.0 g, 6.6 mmol, 1.0 g) in DCM, cooled to 0° C. was added Dess Martin periodinane (8.4 g, 19.9 mmol, 3.0 eq). The reaction mixture was stirred at ambient temperature for 2 h, before being diluted with DCM and washed with 10% aq. NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the desired product (600 mg, 61%); 1H NMR (400 MHz, CDCl3) δ 9.77-9.76 (s, 1H), 7.32-7.27 (m, 2H), 7.23-7.18 (m, 3H), 2.69-2.65 (t, 2H), 2.45-2.49 (t, 2H), 1.94-2.00 (m, 3H). MS (ESI): 166.2 (M+H)+.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH3:20][NH:21]C.[BH4-].[Na+].Cl>CO>[CH3:20][NH:21][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: CNC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzaldehyde (76.2 mg, 0.3 mmol, 1.0 eq.) in MeOH (3.0 mL) was added dimethylamine (170 μL, 0.33 mmol, 1.1 eq.). The mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., NaBH4 (11.3 mg, 0.3 mmol, 1.0 eq.) was added in portions and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was carefully treated with dilute HCl (5 mL) and aqueous phase was extracted with EtOAc (3×10 mL). Combined organic extracts was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 5-(4-methylaminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a white solid. LCMS (m/z) 270 (M+H); 1H NMR (DMSO-d6) δ: 7.67-7.74 (m, 1H), 7.41-7.46 (m, J=8.5 Hz, 2H), 7.00-7.07 (m, 2H), 6.91-6.98 (m, 2H), 4.91 (s, 2H), 4.53 (s, 3H), 3.85 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Product: COc1ccccc1-c1cnn2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Yield: 68 %

Procedure:
The Suzuki coupling of (S)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (2-methoxyphenyl)boronic acid under the same conditions as described in example 5.6.5 to give 68% of the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 1.85-2.12 (m, 4 H) 3.40 (dd, J=7.58, 4.04 Hz, 2 H) 3.46-3.59 (m, 1 H) 3.59-3.67 (m, 1 H) 3.94 (s, 3 H) 4.19 (br. s., 1 H) 6.07 (d, J=7.07 Hz, 1 H) 6.99 (d, J=7.58 Hz, 1 H) 7.06 (td, J=7.45, 1.01 Hz, 1 H) 7.15-7.22 (m, 1 H) 8.14-8.28 (m, 1 H) 8.45 (d, J=6.82 Hz, 1 H) 8.51 (s, 1 H); LRMS (ESI) m/e 424.0 [(M+H)+, calcd for C23H29N5O3 423.0].
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:34]#[N:35].O>CN1CCCC1=O>[C:34]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(C#N)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 3 %

Procedure:
A mixture of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl ]1-[5-(4-fluorophenyl)2-methylthiazol-4-yl]methanone, E66 (216 mg, 0.42 mmol) and copper(I)cyanide (76 mg, 0.84 mmol) in N-methylpyrrolidinone (15 ml) was heated at reflux for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (2×). Solid sodium chloride was added to the aqueous layer which was further extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was Chromatograped (silica gel, 10-100% ethyl acetate-hexane then 1-20% methanol-ethyl acetate). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown amorphous solid (5.3 mg, 3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Sn](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=2)(=O)=O.[Cl-].[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:5][N:4]=1
Reactant: COc1ccc([Sn](C)(C)C)cn1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3cc(OC)c(OC)cc3c2)cn1

Procedure:
A mixture of 800 mg (2.94 mmol) of 2-methoxy-5-trimethylstannyl-pyridine, mg (2.94 mmol) of 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate, 374 mg (8.82 mmol) of anhydrous lithium chloride and 170 mg (0.147 mmol) of Pd(PPh3)hd in 15 mL of anhydrous dioxane is flushed thoroughly with nitrogen and refluxed for 6 hours. The mixture is diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (75 mL), dried (Na2SO4) and evaporated. The resulting residue is chromatographed on silica gel (eluting with chloroform) to give a solid material which is recrystallized from ethyl acetate to give 3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline m.p. 170.5°-171.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29]>C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Temperature: 45 °C
Reaction time: 25 h

Procedure:
4′-Bromomethyl-2-cyanobiphenyl (15 g, 0.0551 moles) was added to a mixture of potassium carbonate (19.05 g), DM water (45 ml), ethyl acetate (60 ml) and L-valine methyl ester hydrochloride (11.09 g, 0.066 moles) at 20-30° C. The reaction mixture was heated to 40-50° C. and stirred for 25 h. After completion of the reaction, the ethyl acetate layer was separated at 20-30° C., concentrated under reduced pressure and dissolved in o-xylene (90 ml)
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=2)[N:10]=1)([CH3:5])[CH3:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:25]([NH:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=2)[N:10]=1)([CH3:5])[CH3:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(CNCc1ccccc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A solution of Example 3 (103 mg, 0.3 mmol) and benzaldehyde (30.7 mg, 0.3 mmol) in methanol (1 ml) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (76.3 mg, 0.36 mmol) was then added and the mixture stirred at room temperature for 3 hours before being diluted with ethyl acetate and sodium hydrogen carbonate solution. The aqueous layer was separated and re-extracted with additional ethyl acetate. The combined organic layers was then washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/0.880 ammonia solution (20:1:0.1) to give the title compound (22 mg, 17%) as a pale yellow solid; MS(ES+) m/e 433/435 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC(O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
The racemic ethyl 3-hydroxyhexanoate 3.46 g (21.6 mmol) obtained in Reference example 1 was dissolved in methanol 24 ml, sodium hydroxide 0.95 g in water 24 ml was added dropwise with cooling, and the mixture was reacted with stirring in a stream of nitrogen at room temperature for two hours. Methanol was removed from the reactant under reduced pressure, and the residue was neutralized with 1N-HCl. After saturating the resultant by adding sodium chloride, the solution was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain racemic 3-hydroxyhexanoic acid 2.50 g (18.9 mmol, 87%). The resultant, benzyl bromide 6.47 g (37.8 mmol). sodium bicarbonate 3,81 g (45.4 mmol) and N,N-dimethylformamide 20 ml were reacted with stirring at room temperature for 27 hours in a stream of nitrogen. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was chromatographed with silica gel column to obtain racemic benzyl 3-hydroxyhexanoate 2.11 g (9.5 mmol, 50%).
Reaction SMILES: N=C=N.[NH:4](C(OCC1C=CC=CC=1)=O)[C@H:5]([C:10](O)=[O:11])[C@H:6]([CH2:8][CH3:9])[CH3:7].[NH2:23][C@H:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:4][C@H:5]([C:10]([NH:23][C@H:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:11])[C@H:6]([CH2:8][CH3:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N=C=N
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 90 %

Procedure:
In accordance with the carbodiimide method indicated Z-Ile-OH (4) was linked with H-Phe-OtBu (5). By means of subsequent catalytic diacylation of the intermediate benzyloxy-carbonyl-dipeptide ester (4-5a) it was possible to isolate H-Ile-Phe-OtBu (4-5b) with a yield of above 90 %.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[NH3:16]>CCO>[NH2:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1
Reactant: N
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2)cn1
Temperature: 145 °C

Procedure:
The 2-chloro-5-benzoylpyridine (100 g, 0.460 mol) was dissolved in 500 ml of 3A EtOH and 400 ml of anhydrous ammonia, placed in a bomb, then heated at 145° C. for 16 hours. The solvents were removed in vacuo and the remaining tan solid was recrystallized from EtOH/H2O yielding 77.4 g (85%) of product as a tan solid. EA, MS(FD).