Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][CH2:15][C:16](Cl)=[O:17].OS(C(F)(F)F)(=O)=O>FC(F)(F)C(O)=O.CC(OC)(C)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:16](=[O:17])[CH2:15][CH2:14][O:10]2)=[CH:8][CH:9]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)CCCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCOc2cc(OC(F)(F)F)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A solution of 3-(trifluoromethoxy)phenol (7.13 mL, 55.0 mmol) and 3-chloropropanoyl chloride (5.5 mL, 57.6 mmol) in trifluoroacetic acid (25 mL) was stirred 15 minutes at ambient temperature, and then heated at 50° C. for 90 minutes. After stirring at ambient temperature overnight, the solution was added over 5 minutes to preheated triflic acid (20 mL) at 50° C. After 20 minutes, the mixture was removed from the oil bath, then cooled in an ice water bath. Crushed ice was added, slowly at first, keeping the temperature of the orange solution below 25° C. Eventually a solid precipitate formed, and the suspension was diluted with MTBE (200 mL). The mixture was cooled in an ice water bath. It was washed with brine and then four times with water, partially dried (Na2SO4), filtered, and concentrated. After standing overnight, the yellow mixture was dissolved in ethanol (180 mL) and added slowly over 22 minutes to 1.5 M aqueous Na2CO3 (180 mL) cooled with a water ice bath (internal temp did not exceed 15° C.). The suspension was permitted to come to ambient temperature overnight, and was then diluted with 2:1 EtOAc/hexanes (300 mL) and filtered. The solids were rinsed with more 2:1 solution (105 mL), and the aqueous phase of the filtrate was separated and extracted with 1:1 EtOAc/hexanes (3×100 mL). The combined organic phases were washed once with water (200 mL), and the aqueous phase was back-extracted once with 1:1 solution (40 mL). The organic phases were combined and washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated, chromatographed on silica (gradient elution, 5-20% Et2O/hexanes) to give the title compound (4.95 g, 21.3 mmol, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.85 (m, 1H), 7.08-7.01 (m, 2H), 4.61 (dd, 2H), 2.83 (dd, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[O:22][CH:23]([F:25])[F:24])[CH2:9]1)(OC(C)(C)C)=O.Cl.C(O)(=O)/C=C/C(O)=O>CC(O)C.C(OCC)C>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH:23]([F:25])[F:24])=[C:15]([CH:20]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(Br)ccc2OC(F)F)C1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CC(C)O
Product: FC(F)Oc1ccc(Br)cc1C[C@@H]1CNCCO1

Procedure:
N-Boc-(R)-2-(5-bromo-2-difluoromethoxy-benzyl)-morpholine, was deprotected using hydrogen chloride (4M, in methanol) and isolated using SCX-2 columns as described for example 4 followed by treatment with fumaric acid in IPA-diethyl ether afforded the morpholine example 61 as the fumarate salt as a white solid (108 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:16]1([OH:19])[CH2:17][CH2:18][C:13]2([O:20][CH2:10][CH2:11][O:12]2)[CH2:14][CH2:15]1
Reactant: Cc1ccccc1CCl
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: Cc1ccccc1CC1(O)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A solution of 2-methylbenzyl chloride (0.579 g, 4.12 mmol) in THF (20 mL) was treated with Mg (0.180 g, 7.50 mmol) and strirred at room temperature until all the Mg had dissolved. The mixture was cooled to 0° C., treated with a solution of 1,4-cyclohexanedione mono-ethylene ketal (0.579 g, 4.12 mmol) in THF (50 mL), warmed to room temperature, stirred overnight, quenched with saturated NH4Cl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide the desired product (0.48 g, 44%) MS (ESI) m/e 262 (M+H)+.
Reaction SMILES: C([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](C3C4C(=CC=C(OC(F)F)C=4)N(CC4OCCNC4)N=3)[N:15]=2)[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=1)=[O:7])(C)(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:42][Si:41]([CH3:44])([CH3:43])[CH2:40][CH2:39][O:38][CH2:37][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][N:15]=[C:16]2[C:8]([C:6]([NH2:5])=[O:7])=[CH:9]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CNCCO4)c4ccc(OC(F)F)cc34)nc12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C(N)=O)c2nccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 135.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(morpholin-2-ylmethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 159 μmol) in methanol (4 mL), cooled to 0° C. with ice bath, was added aqueous formaldehyde (1 mL, 13.4 mmol), followed by the addition of sodium triacetoxyborohydride (75.7 mg, 357 μmol). The reaction mixture was stirred at room temperature for 15 h then concentrated in vacuo. Purification by chromatography (silica, 4 g Analogix column, 0-10% methanol containing 10% ammonium hydroxide in dichloromethane) gave N-tert-butyl-2-(5-(difluoromethoxy)-1-(4-methylmorpholin-2-yl)methyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (63 mg, 62%). MS (M+H)+=644.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19](=[O:28])[CH:20]([CH2:23][CH2:24][CH:25](C)C)[NH:21]C.C(N(CC)CC)C.Cl.[Cl-].[Na+]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:28])[CH:20]([NH:21][S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3])[CH2:23][CH2:24][CH3:25]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCc1ccccc1
Reactant: CNC(CCC(C)C)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a stirred solution of 5.77 ml (66.78 mmol) of chlorosulfonyl isocyanate in methylene chloride was added, under nitrogen, phenylmethanol (6.89 ml, 66.57 mmol) at 0°-5° C. After stirring the above solution for 1 hour, a solution of 13.166 g (62.78 mmol) of 2-(3-methylbutyl)sarcosine methyl ester hydrochloride in methylene chloride containing triethylamine (27.33 ml, 194.62 mmol) was added at 0°-5° C., and the resulting mixture was stirred overnight allowing the mixture to warm to room temperature. The reaction mixture was poured into 600 ml of 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride and the combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 21.22 g (87.2%) of N-(carbobenzylxaminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester (Formula XII: R=CH3 ; R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3) which was purified by silica column chromatography (20% ethyl acetate in hexane) to afford an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:5][C:4]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[NH:52][C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44]2)=[CH:39][C:38]=1[O:54][CH3:55]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:55][O:54][C:38]1[CH:39]=[C:40]([CH:43]2[NH:52][C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44]2)[CH:41]=[CH:42][C:37]=1[O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:23][C:4]1[CH:5]=[C:6](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(/C=C\c2cc(OC)c(OC)c(OC)c2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 83.4 %

Procedure:
(Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (38a) (316.35 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (39d) (546 mg, 80% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10]([CH3:12])=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:7]=1[C:24](=[O:41])[NH:25][CH2:26][CH2:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[I-].[Na+].[N-:44]=[N+]=[N-].[Na+].CN(C=O)C>CC(O)C.C(OCC)(=O)C>[NH2:44][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10]([CH3:12])=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:7]=1[C:24](=[O:41])[NH:25][CH2:26][CH2:27][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1=C(C)NC(COCCCl)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(COCCN)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
0.12 g (0.20 mmol) of methyl 6-(2-chloroethoxy)methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylate and 0.030 g (0.20 mmol) of sodium iodide were dissolved in 2 ml of 2-propanol, and the obtained solution was stirred at 70° C. for 24 hours. The solvent was evaporated under reduced pressure. Dichloromethane was added to the residue, and sodium iodide thus precipitated was separated by the filtration. The filtrate was treated under reduced pressure, and 15 mg (0.23 mmol) of sodium azide and 2 ml of DMF were added thereto. The reaction mixture was stirred at 50° C. for 16 hours. Ethyl acetate was added thereto. After washing with water and saturated aqueous sodium chloride solution, the organic layer was concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=7/3) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2C[C@H](N3CCC[C@H]3C)C2)=[CH:21][CH:20]=1.[NH3:35]>>[CH3:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:35])=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Reactant: N
Reactant: CC1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Product: CC1CCCN1[C@H]1C[C@@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 2B except substituting the product from Example 3A for the product from Example 2A. 1H NMR (300 MHz, CD3OD) δ 1.22 (d, J=6 Hz, 3 H), 1.54 (m, 1 H), 1.84 (m, 2 H), 2.05 (m, 1 H), 2.19 (m, 2 H), 2.57 (m, 2 H), 2.71 (m, 2 H), 3.27 (m, 3 H), 7.39 (d, J=9 Hz, 2 H), 7.63 (d, J=9 Hz, 2 H), 7.79 (s, 4 H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([O:19][C@@H:20]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:29][C@@H:21]1OC(=O)C(F)(F)F)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH2:12]([O:19][C@@H:20]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:29][C@H:21]1[C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[O:8][CH3:9])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)C(F)(F)F
Reactant: COc1ccc(Br)c(OC)c1
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Br
Reaction time: 0.17 h

Procedure:
1-bromo-2,4-dimethoxybenzene (9.1 ml) was added to a solution of 2,3,4,6-tetra-O-benzyl-1-O-(trifluoroacetyl)-α-D-glucopyranose (20.0 g) in methylene chloride (100 ml) and the mixture was stirred for 10 minutes. Boron trifluoride-diethyl ether complex (3.9 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(5-bromo-2,4-dimethoxyphenyl)-D-glucitol (17.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1NCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 4-Fluoro-benzylamine (0.828 g, 6.62 mmol) in dry N,N′-dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (0.854 g, 6.62 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(4-Fluoro-benzylamino)-benzoic acid ethyl ester as a clear liquid (1.23 g, 75%, LCMS calc M+H 274, obs M+H 274).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[CH:23][C:22]=1[NH2:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH2:13]([NH:20][C:21]1[CH:26]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:24]=[CH:23][C:22]=1[NH:33][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: Nc1cnc(N2CCOCC2)cc1NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cnc(N3CCOCC3)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Propylphosphonic acid anhydride, cyclic trimer (0.356 ml; 0.610 mmol) is added to a mixture of 1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (85.000 mg; 0.508 mmol), N4-Benzyl-6-morpholin-4-yl-pyridine-3,4-diamine E-2.3 (133.000 mg; 0.468 mmol) and triethylamine (0.176 ml; 1.271 mmol) in THF (3.000 ml). The reaction mixture is stirred overnight (16 h) at RT. The reaction is quenched with 1M NaOH (2 ml) and diluted with water, then extracted twice with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: DCM/MeOH=100%/0% to 90%/10%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure.
Reaction SMILES: CCCCOC([NH:8][C:9]([C@@H:11]([NH:19][C:20]([C@@H:22]([NH:27][C:28]([C@@H:30]([NH:35][C:36]([C@@H:38]([NH2:49])[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:37])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.Cl>O1CCOCC1.CCOCC>[NH2:49][C@H:38]([C:36]([NH:35][C@H:30]([C:28]([NH:27][C@H:22]([C:20]([NH:19][C@H:11]([C:9]([NH2:8])=[O:10])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[CH2:23][C:24](=[O:25])[OH:26])=[O:29])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1
Reactant: CCCCOC(=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 0.05 h

Procedure:
7.1 g (10.5 mmoles) of BOC--Trp--Leu--Asp--Phe--NH2, prepared as described in Example 5, Step 2, are poured into 60 ml of hydrochloric acid in dioxane. The reaction mixture is initially turbid, but it gets clear within 3 minutes. After 10 minutes the solution is diluted with dry ether, the separated oily substance is solidified and filtered off. The resulting 6.96 g of hydrochloride are dissolved in 150 ml of warm water. Te pH of the solution is adjusted to 7 with solid sodium bicarbonate under cooling. The resulting suspension is filtered, and the precipitate is washed with a great proportion of water. 5.05 g (83.1 %) of H--Trp--Leu--Asp--Phe--NH2 are obtained; the chromatographically uniform substance melts at 228°-230° C. (decomposition). The product is identical with that obtained in Example 4, Step 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:19]S(C(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].Cl.O1CCOCC1>CO>[NH2:19][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-(2,6-dimethoxyphenyl)-5-(1,1-dimethylethylsulfinamido)pentanoate (5.560 g; 14.96 mmol) in MeOH (115 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (7.5 ml; 30.00 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The obtained yellow solution was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.73 min.; [M+H]+: 268.01 g/mol.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:33][C:34]([F:42])([F:41])[C:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC(C)=O)(C)C>CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:19][C:18]=3[C:29]([F:31])([F:32])[F:30])(=[O:16])=[O:15])[CH2:11][N:10]2[C:38]([C:35]2([C:34]([F:42])([F:41])[F:33])[CH2:37][CH2:36]2)=[O:39])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
(2S,4R)-4-[4-(2,2,2-Trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (20 mg, 41 umol; example 211a) was dissolved in DMF (0.4 ml) under a N2-atmosphere at ambient temperature. 1-Trifluoromethyl-cyclopropanecarboxylic acid (10 mg, 62 umol; CAS Reg. No. 277756-46-4), HATU (23 mg, 62 umol) and DIEA (10 ul, 62 umol) were added and the reaction mixture was stirred for 48 h at ambient temperature. Ice water/brine 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a yellow oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (13 mg, 21 umol; 51%) as colorless solid. MS (ESI): m/z=622.3 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)[CH3:10]>CN(C=O)C>[CH2:1]([N:15]1[CH2:14][CH2:13][NH:12][CH:11]([CH2:9][CH3:10])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCC1CNCCN1
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccccc2)CCN1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Benzyl bromide (38.7 g, 0.22 mol) was added in portions to a chilled (˜0° C.) solution of 2-ethylpiperazine (25 g, 0.22 mol) in DMF (150 mL) with such a rate that the temperature did not exceed 20° C. The mixture was stirred for 1 h, the solvent was evaporated and the residue was partitioned between CHCl3/0.5 M aqueous HCl. The aqueous phase was made alkaline (11 M NaOH) and extracted three times with CHCl3. The combined organic phases were dried (MgSO4) and concentrated. The resulting oil was purified by column chromatography on silica using CHCl3, followed by CHCl3/MeOH/NH4OH (95:5:0.3) as eluents to give 31.6 g (70%) of the title compound as a yellowish oil. Anal. (C13H20N2) H, N; C: calcd, 76.42; found, 75.85.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(=O)c3cc(C#N)c4ccc5ccccc5n34)cc2)CC1

Procedure:
The title compound was prepared as described for the Example 21, using 3-cyano (4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline (31 mg, 0.0986 mmol) and 4-methyl piperazine (212 mg, 0.212 mmol), and yielded 12.1 mg (68%). 1H NMR (CDCl3): 8.01 (m, 3H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.66 (s, 2H), 7.53 (m, 2H), 7.35 (s, 1H), 6.98 (m 2H), 3.70 (t, J=5.1 Hz, 4H), 3.00 (m, 4H), 2.66 (s, 3H).