Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCCCOC)c2c(c1)OCCO2
Temperature: 25 °C

Procedure:
The mixture of 8-hydroxy-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (1.65 g, 7.36 mmol), 1-bromo-3-methoxypropane (1.38 g, 8.83 mmol) and anhydrous K2CO3 (1.53 g, 11.0 mmol) in acetone (40 mL) is refluxed overnight. After cooling to room temperature, the mixture is poured into ice water and extracted with AcOEt. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 3:1) yields the title compound as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.32. MS: 297.0 [M+H]+. 1H-NMR (CDCl3): δ 1.41 (t, 3H), 2.16 (m, 2H), 3.40 (s, 3H), 3.61 (m, 2H), 4.20 (m, 2H), 4.31 (m, 2H), 4.35-4.45 (m, 4H), 7.27 (d, 1H), 7.31 (d, 1H) ppm.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:7]=[C:6]([S:20][CH3:21])[N:5]=1.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C1COCC1.C(OC)(C)(C)C>[CH3:21][S:20][C:6]1[N:5]=[C:4]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:7]=1
Reactant: OCCN1CCCCC1
Reactant: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(OCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 40 °C
Yield: 78 %

Procedure:
Sodium hydride (30 mg, 1.23 mmol) was added to a mixture of 4-chloro-2-methylthio-6-(3-trifluoromethyl-phenyl)-pyrimidine (187 mg, 0.62 mmol) and 1-(2-hydroxyethyl)piperidine (120 μl, 0.92 mmol) in dry THF (6 ml). The mixture was heated at 40° C. for 2 h. After cooling, water and tert-butyl-methyl ether were added. The aqueous layer was extracted twice with tBuOMe. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 95/5) to yield the above titled compound: 190 mg (yield: 78%).
Reaction SMILES: C(N=C=S)C.[N:6]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[N:9]([C:15]([C:17]1[O:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:20][CH:21]=1)=[O:16])[CH2:8][CH2:7]2.[Cl:29][CH2:30]Cl>>[Cl-:29].[Cl:29][CH2+:30].[N:6]12[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14]1)[N:9]([C:15]([C:17]1[O:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)=[CH:20][CH:21]=1)=[O:16])[CH2:8][CH2:7]2
Reactant: ClCCl
Agent: Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Solvent: CCN=C=S
Product: [CH2+]Cl
Product: [Cl-]
Temperature: 5 °C
Reaction time: 11 h

Procedure:
Ethylisothiocyanate (182 mg; 2.09 mmol) solved in dichloromethane (20 ml) was added dropwise to a mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone and dichloromethane (10 ml) at 5° C. The mixture was allowed to stir for 4 hours at 5° C. and 11 hours at room temperature. The solvent volume was reduced to a third and the solid product was isolated by filtration. Mp. >300° C.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C@H:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[ClH:27].[NH2:15][CH2:16][C@H:17]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 153.3 %

Procedure:
4M HCl/dioxane (5.49 ml, 22.0 mmol) was added to a solution of (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 1.10 mmol) in 2:1 dioxane:DCM (10 mL). The reaction mixture was stirred at room temperature overnight (16 hours), after which it was concentrated to ⅓ volume. The resulting cloudy mixture was diluted with ether, and the mixture was concentrated again to ⅓ volume. The mixture was diluted again with ether (20 mL), and the solids were isolated by filtration through a medium frit funnel with nitrogen pressure, rinsed with ether (5×10 mL), dried under nitrogen pressure, and dried in vacuo to give (S)-3-amino-2-(4-chlorophenyl)propanoic acid hydrochloride (0.199 g, 76.8% yield) as a white powder. HPLC >99 area % pure. LC/MS (APCI+) m/z 200.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[CH2:6][C:7]1[CH:41]=[CH:40][C:10]([C:11]([NH:13][C:14]2[C:15]3[CH:28]=[C:27]([C:29]([NH:31][N:32]([CH3:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[S:26][C:16]=3[N:17](C(OC(C)(C)C)=O)[N:18]=2)=[O:12])=[CH:9][CH:8]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[C:15]4[CH:28]=[C:27]([C:29]([NH:31][N:32]([CH3:39])[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[O:30])[S:26][C:16]=4[NH:17][N:18]=3)=[O:12])=[CH:40][CH:41]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and then 75 μL (1.11 mmol) of azetidine are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 3 mg of 4-azetidin-1-ylmethyl-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder melting from 155 to 160° C. LC-MS-DAD-ELSD: 461(+)=(M+H)(+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.CN1C(=O)CCC1.[CH2:21]([Mg]Cl)[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Reactant: CC(C)C[Mg]Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CC(C)C)nc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (1.66 g, 8.23 mmol) in dry THF (50 mL), Fe(acac)3 (320 mg, 0.901 mmol) followed by NMP (1.1 mL, 11.5 mmol) is added. The mixture is cooled to −74° C. before a 2 M solution of isobutylmagnesium chloride (7 mL, 14.0 mmol) in THF is added. Stirring is continued at −75° C. for 1 h, before the mixture is warmed to 0° C. The reaction is quenched by carefully adding water. The mixture is diluted with EA, washed with water followed by brine, dried over MgSO4, filtered and concentrated to give crude 2-isobutyl-6-methoxy-isonicotinic acid methyl ester (1.20 g) as an oil; LC-MS: tR=1.37 min; [M+1]+=224.12.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH2:9]([O:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.[OH-].[Na+]>[CH2:9]([O:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCCCCNOCc1ccccc1
Reactant: O=C(Cl)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 5-chlorovaleryl chloride (3.66 g, 23.6 mmol) in CH2Cl2 (50 mL) was slowly dripped into a mixture of amine 2 (n=4) (4.08 g, 20.0 mmol) in CH2Cl2 (100 mL) and 1N NaOH (200 mL) which had been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes and at room temperature overnight. The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×150 mL). The combined organic extracts were washed with saturated sodium chloride, and solvent was removed in vacuo. The crude oil was passed through a short silica gel column, eluting with EtOAc, to give 6.0 g (93%) of (3) as an oil; NMR δ 1.57-1.97 (m, 8 H), 2.35 (t, 2 H, J=6), 2.40 (t, 2 H, J= 6), 3.50 (t, 2 H, J=6), 3.67 (t, 2 H, J=6), 4.80 (s, 2 H), 7.37 (s, 5 H). Anal. (C17H23ClN2O2) C, H, N.
Reaction SMILES: C(=O)C1C=CC=CC=1.[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1>C(O)C>[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[C:31]4[S:27][C:28](=[O:33])[NH:29][C:30]4=[O:32])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O=C1CSC(=O)N1
Solvent: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1
Yield: 98.6 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (15 g, 60 mol), 2,4-thiazolidinedione (7.0 g, 60 mmol), and piperidine (8.0 mL, 81.2 mmol) in 450 mL of ethanol was refluxed for 6 hours. The solid which was formed on cooling the solution was collected to give the title compound as an orange solid (20.5 g, 99%); 1H NMR (300 MHz, DMSO-d6) δ 1.67 (t, J=5.6 Hz, 4 H), 3.47 (t, J=5.6 Hz, 4 H), 3.92 (s, 4 H), 7.07 (d, J=9.0 Hz, 2 H), 7.43 (d, J=9.0 Hz, 2 H), 7.67 (s, 1 H), 12.40 (brs, 1 H); MS (ES) m/z: 346.8 (MH+); HRMS Calcd. for C17H19N2O4S(MH+): 346.0987. Found: 346.0994. Anal. Calcd. for C17H18N2O4S: C, 58.94; H, 5.24; N, 8.09. Found: C, 58.92; H, 5.11; N, 7.96.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(N(CC)CC)C.O=C1N([ClH:59]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[ClH:59].[CH3:45][O:44][C:42](=[O:43])[CH2:41][NH:40][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:26])([F:27])[F:28])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH2:8])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24].[CH3:45][O:44][C:42](=[O:43])[CH2:41][NH:40][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:23]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Product: COC(=O)CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 107.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol) and methyl glycinate hydrochloride (512 mg, 0.408 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. After stirring for 5 minutes, bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) was added. The reaction mixture was reacted at room temperature for 20 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-({7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-amino)-acetic acid methyl ester 16a (90 mg, yield 53.6%) as a light yellow oil.
Reaction SMILES: C[N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=O.Br[C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[C:48](=[O:49])[C:47]3[CH:50]=[CH:51][C:52]([CH:54]4[CH2:56][CH2:55]4)=[CH:53][C:46]=3[NH:45][CH2:44][CH2:43]2)[C:35]=1[CH:36]=[O:37].[C:57](=[O:60])([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[CH:54]1([C:52]2[CH:51]=[CH:50][C:47]3[C:48](=[O:49])[N:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:34]([C:6]5[CH:5]=[C:4]([NH:17][C:18]6[CH:23]=[CH:22][C:21]([C:24]([N:26]7[CH2:27][CH2:28][O:29][CH2:30][CH2:31]7)=[O:25])=[CH:20][N:19]=6)[C:57](=[O:60])[N:2]([CH3:3])[CH:7]=5)[C:35]=4[CH:36]=[O:37])[CH2:43][CH2:44][NH:45][C:46]=3[CH:53]=2)[CH2:55][CH2:56]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(Br)cccc1N1CCNc2cc(C3CC3)ccc2C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(N3CCNc4cc(C5CC5)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 119 %

Procedure:
A mixture of 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (273 mg, 0.62 mmol, 1.2 eq), 2-Bromo-6-(8-cyclopropyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-benzaldehyde (200 mg, 0.52 mmol, 1 eq), X-Phos (6 mg, 0.012 mmol, 0.02 eq) Pd(dba)2 (11 mg, 0.019 mmol, 0.03 eq), Cesium carbonate (403 mg, 1.24 mmol, 2 eq) in 7 mL of a 6:1 mixture of dioxane:water was heated to 100 C for 14 hours under argon with stirring. The reaction was cooled, filtered through a sintered glass funnel, concentrated and directly loaded on a silica gel column, eluting with a gradient of 20 to 40% ethyl acetate in hexanes, followed by a gradient of 5 to 10% methanol in CH2Cl2 to give a solid, 383 mg of 2-(8-Cyclopropyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde, 87%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[N:34]=1.Cl[Si:38]([CH3:41])([CH3:40])[CH3:39]>C1COCC1.O>[F:21][C:22]1[C:27]([Si:38]([CH3:41])([CH3:40])[CH3:39])=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[N:34]=1
Reactant: CC1(C)COC(c2cc(F)c(F)cc2F)=N1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2cc(F)c(F)c([Si](C)(C)C)c2F)=N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of 8.7 ml (62.1 mmol) of diisopropylamine in 100 ml of dry THF under argon was cooled to -78° C. and treated with 28.3 ml (56.6 mmol) of 2.0M n-butyllithium. The LDA solution was stirred at -78° C. for 15 minutes. To this solution was added a solution of 11.8 g (51.5 mmol) of 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2-oxazoline in 50 ml of THF, and the reaction mixture was stirred for one hour at -78° C. To the reaction mixture was added 13 ml (102.5 mmol) of chlorotrimethylsilane, and the solution was warmed to room temperature. Water was added; the organic layer was dried over magnesium sulfate and concentrated. The crude product was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate to give 12.9 g of the title compound, mp 71°-72° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.CN(C)C=O.[NH2:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:41]>ClCCl>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:41])=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCCCC[C@@H](C)N
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC[C@@H](C)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg), 1-hydroxybenzotriazole (23.7 mg), JANDAJEL-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (289 mg) and N,N-dimethylformamide (1 mL) were mixed together and the mixture was stirred at room temperature for 3 hours. Subsequently, (2R)-2-aminoheptane (46.6 μL) was added and the mixture was stirred at room temperature for 17 hours and 40 minutes. This was followed by addition of dichloromethane (0.5 mL) and (2R)-2-aminoheptane (11.6 μL), stirring at room temperature for 4.5 hours, addition of JANDAJEL-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (96.6 mg) and additional stirring at room temperature for 17 hours. Subsequently, (isocyanatomethyl)polystyrene (232 mg) was added and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column (eluant:ethyl acetate:methanol=10:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[(2R)—N-(2-heptyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (9.0 mg).
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:14][C:15]1[CH:16]=[C:17]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:18]2[CH:19]([OH:28])[C:20]3[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3>CCN(CC)CC>[Br:14][C:15]1[CH:16]=[C:17]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:18]2[C:19](=[O:28])[C:20]3[C:25]([C:26]=2[CH:27]=1)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: CC(=O)OCc1cc(Br)cc2c1C(O)c1ccccc1-2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)OCc1cc(Br)cc2c1C(=O)c1ccccc1-2
Reaction time: 0.17 h

Procedure:
Dichloromethane (5 ml) was cooled to -60° under N2, oxalyl chloride (1.65 ml, 1M solution in CH2Cl2, 1.1 eq) was added followed by DMSO (234 ml in 1 ml of CH2Cl2). The resulting solution was stirred at -60° for 10 min. The 3-bromo-1-acetoxymethyl-9-fluorenol (0.480 g) in a suspension of CH2Cl2 (2 ml) was added dropwise and the solution stirred at -60° for 0.5 hour. Et3N (1.06 ml) was added dropwise and the solution stirred at -60° for 15 minutes. The cooling bath was removed and water (5 ml) was added and the reaction mixture stirred at room temperature for 20 minutes. The organic phase was separated and the aqueous phase was extracted with EtOAc; the combined extract was dried without further purification in the next step. ##STR411##
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the method of Example 56.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].[CH2:8]([O:15][C:16]1[C:23]([Br:24])=[CH:22][C:21]([Br:25])=[CH:20][C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H][H]>Cl>[Br:24][C:23]1[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:17]([CH:20]=[C:21]([Br:25])[CH:22]=1)[CH:18]=[N:2][NH:3][C:4]([NH:6][N:7]=[CH:18][C:17]1[CH:20]=[C:21]([Br:25])[CH:22]=[C:23]([Br:24])[C:16]=1[O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[NH:5]
Reactant: [H][H]
Reactant: O=Cc1cc(Br)cc(Br)c1OCc1ccccc1
Reactant: N=C(NN)NN
Agent: Cl
Product: N=C(NN=Cc1cc(Br)cc(Br)c1OCc1ccccc1)NN=Cc1cc(Br)cc(Br)c1OCc1ccccc1

Procedure:
To a mixture of 2.1 grams (0.015 mole) of N,N'-diaminoguanidine, hydrochloride in 50 milliliters of 2B-ethanol and 2.0 milliliters of concentrated hydrochloric acid was added 11.1 grams (0.03 mole) of 2-benzyloxy-3,5-dibromobenzaldehyde. The mixture was stirred and heated to reflux temperature and maintained at this temperature overnight. At the completion of the reaction, the insoluble crystals contained in the reaction mixture were removed by filtration and dried under reduced pressure. The solid crude 1,3-bis[((3,5-dibromo-2-benzyloxybenzylidene)-amino]guanidine, hydrochloride product was mixed with 250 milliliters of benzene refluxed, recovered by filtration and dried. The product was obtained in a yield of 11.3 grams and melted at 217°-218° C. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 41.83, 3.00 and 8.48 percent, respectively, as compared with the theoretical contents of 41.98, 2.92 and 8.44 percent, respectively, calculated for the abovenamed structure.