Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1
Reactant: COc1cccc(C2CCCN2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C2CCCN2Cc2cccnc2)c1
Yield: 81.5 %

Procedure:
To a solution of 2-(3-methoxyphenyl)pyrrolidine (3.0 g) in dry acetonitrile (70 ml) was added milled potassium carbonate (6.1 g) followed by 3-picolyl chloride hydrochloride (3.1 g) at ambient temperature, under nitrogen, with stirring. The reaction mixture was stirred for 65 hrs, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated, and the residue was purified by flash column chromatography (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to give 3.7 g (83%) of 2-(3-methoxyphenyl)-1-(3-pyridinylmethyl)pyrrolidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1>>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[CH:26]([NH:25][C:10]([C:8]1[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=1)=[O:12])[CH2:27]2
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NC1CN2CCC1CC2)c1ccc2c(c1)OCO2

Procedure:
Following the procedure of Example 22, 1,3-benzodioxole-5-carboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]=[CH:3]1>CO.[Pd]>[O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A solution of tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (15.09 mmol, 1.0 eq.) in MeOH (40 ml) was degassed with argon for 15 min and then Pd—C (1.0 g) was added. The reaction mixture was stirred under H2 balloon pressure at 25° C. for 16 h. The mixture was filtered through celite and filtrate concentrated to give the desired product as a light yellow sticky solid. Yield: >99%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3Cl)[S:17][CH:18]=2)=[CH:10][CH:9]=1.[I-].[Na+]>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2csc(-c3cnccc3Cl)n2)cc1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Product: Clc1ccc(-c2csc(-c3cnccc3N3CCOCC3)n2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
Morpholine (5 ml) was added to compound (43) (120 mg, 0.40 mmol) and sodium iodide (156 mg, 0.40 mmol). The reaction mixture was heated to 80° C. and stirred for 6 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate. The extracts were combined, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and crystallized from ethyl acetate-n-hexane to give white crystals (100 mg, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[C:16]1([O:15][C:13](=[O:14])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(F)(F)F)cn1)Oc1ccccc1
Reaction time: 24 h

Procedure:
Dissolve 2-amino-5-trifluoromethylpyridine (162 mg, 1.0 mmole) in pyridine (2.0 mL) under nitrogen at room temperature. Add drop wise phenyl chloroformate (0.125 mL, 1.0 mmole) to the reaction mixture at room temperature. Stir the mixture for 24 hours and new spot is noticed in TLC (30% EtOAc/hexane). Evaporate the reaction mixture under vacuo and purify the crude by flash column chromatography on a silica gel using CHCl3 to afford (5-Trifluoromethyl-pyridin-2-yl)-carbamic acid phenyl ester as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=1)=[CH:9][C:8]2=[N:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.CC(C[AlH]CC(C)C)C.Cl>ClCCl.C1COCC1>[C:26]([O:25][N:24]=[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:3][OH:2])[CH:6]=2)[O:11][C:10]([C:15]2[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=2)=[CH:9]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CO)cc12

Procedure:
To a solution of 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid methyl ester (example 115B) (574 mg, 1.46 mmol) in dichloromethane (9 ml) at 0° C. was added a 1M solution of DIBAL-H in THF (12.8 ml). After 2 hours at 0° C. an additional amount of 1M solution of DIBAL-H in THF (6 ml) was added to complete the reaction. After hydrolysis with a 1M aqueous solution of hydrogen chloride, the reaction mixture was extracted with ethyl acetate. The organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[F:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:18][N:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:2]2[C:3]3[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:24]1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Reactant: CC(C)c1cc2c(Cl)ncnc2s1
Product: CC(C)c1cc2c(NC3CCN(Cc4cc(F)cc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (264 mg, 56%) from 4-chloro-6-isopropylthieno[2,3-d]pyrimidine (0.25 g, 1.18 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (0.4 g, 1.77 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated: 402.5; Observed: 403.1 (M++1).
Reaction SMILES: [CH3:1][C@H:2]([NH2:6])[C:3]([OH:5])=[O:4].C(OC([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C(N[C@H](C(OC(=O)[C@H](CCCCNC(OCC1C=CC=CC=1)=O)NC(O)=O)=O)CCCCNC(OCC1C=CC=CC=1)=O)(O)=O>>[CH3:1][C@H:2]([NH2:6])[C:3]([OH:5])=[O:4].[NH2:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18][NH2:17]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: O=C(O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](N)C(=O)O

Procedure:
To the poly-L-alanine/Nε-benzyloxycarbonyl-L-lysine copolymer (9/1) obtained in Production Example 16 were added 270 equivalents and 5 equivalents of trifluoroacetic acid (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) and thioanisole (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.), respectively, relative to the number of moles of N-carboxy-N′-benzyloxycarbonyl-L-lysine anhydride, and the mixture was reacted at room temperature to give a poly-L-alanine/L-lysine copolymer. This was dissolved in a dichloromethane-trifluoroacetic acid mixed solvent (50:70 (v/v)) to give a 4.4 wt % poly-L-alanine/L-lysine copolymer solution. A fiber structure made of a poly-L-alanine/L-lysine copolymer was obtained from this solution in the same manner as in Production Example 1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:9]1[C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C@H:41]([OH:45])C(O)=O)=[O:38])[CH2:33][C:34](=[O:36])[NH2:35])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C@H:41]([OH:45])[C:6]([N:8]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:9]1[C:10]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])=[O:38])[CH2:33][C:34](=[O:36])[NH2:35])=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1[C@@H](O)CCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 65.4 %

Procedure:
Following a procedure similar to that described in Example 11, 28 mg (0.10 mmol) of (3S)-1-t-butoxycarbonyl-N-t-butyl-3-hydroxy-L-prolinamide (prepared as described in Preparation 13) was deprotected to remove the t-butoxycarbonyl group. The resulting (3S)-N-t-butyl-3-hydroxy-L-prolinamide was then condensed with 52 mg (0.12 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1), to give 40 mg of the title compound as a white powder, melting at 111°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:7]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:7]1
Reactant: COc1ccc(CN2C(=O)c3cccc(OCCN(C)C)c3C2=O)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cccc(OCCN(C)C)c3C2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
2-(2,4-Dimethoxy-benzyl)-4-(2-dimethylamino-ethoxy)-isoindole-1,3-dione (201 mg, 0.52 mmol) was treated with a 1M solution of lithium aluminium hydride in THF (5 mL, 5 mmol). After 7.5 hours at r.t. a further portion of lithium aluminium hydride solution (5 mL, 5 mmol) was added and the mixture maintained for further 18 hours. The mixture was then cooled in ice and quenched by the dropwise addition of water (0.4 mL), 2N sodium hydroxide solution (0.8 mL) and water (0.8 mL). Magnesium sulfate was added, followed by ethyl acetate and then the mixture was stirred at r.t. for 1 hour. The solids were removed by filtration, being well washed with ethyl acetate. Concentration of the filtrate gave the title compound (192 mg, 103%) as a brown oil which was carried forward without further purification. 1H NMR (methanol-d4) 7.24 (1H, d), 7.16 (1H, d), 6.80 (2H, t), 6.55 (1H, d), 6.51 (1H, dd), 4.12 (2H, t), 3.92 (4H, s), 3.86 (2H, s), 3.82 (3H, s), 3.80 (3H, s), 2.76 (2H, t), 2.33 (6H, s). MS: [M+H]+ 357.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]([C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH2:22][CH2:23][NH2:24])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1>C1COCC1>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH:5]3[NH:12][C:13]([C:15]3[CH:26]=[CH:25][C:18]4[N:19]([CH2:22][CH2:23][NH:24][C:43]([N:40]5[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]5)=[O:44])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:11]1)[CH2:9]2
Reactant: O=C(Cl)N1CCC(O)CC1
Reactant: NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1ccc2c(c1)ncn2CCNC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (0.35 g, 0.988 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 4-hydroxypiperidine-1-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC cis and trans isomers of 1-{2-[(4-hydroxypiperidine-1-carbonyl)-amino]-ethyl}-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)amide.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8]Cl)[N:7]=1.[C:10]1([CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:21]2[CH2:22][CH2:23][CH:18]([O:17][CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:20]2)[N:7]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A stirred mixture of 2-amino-4-chloromethylthiazole hydrochloride (0.7 g), 4-(diphenylmethoxy)piperidine (0.78 g) and triethylamine (1.82 ml) in N,N-dimethylformamide (7.8 ml) was heated at 40° C. to 45° C. for 5 hours. After cooling to ambient temperature, the reaction mixture was filtered. The filtrate was poured into water (50 ml) and extracted with ethyl acetate (80 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (30 g) and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.78 g).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([NH2:18])([CH2:16][CH3:17])([CH3:15])[CH3:14]>>[C:13]([NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CCC(C)(C)N
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NC(C)(C)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and tert-amylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.Cl>ClCCl.O>[CH3:1][NH:2][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNCCc1ccc([N+](=O)[O-])cc1
Reaction time: 15 h

Procedure:
2.7 g (86 mmol) of methylamine are dissolved in 120 ml of dichloromethane while cooling with ice. 4.9 g (21 mmol) of 4-(2-bromoethyl)-nitrobenzene are added and the mixture is allowed to come up slowly to ambient temperature. After 15 hours stirring the solvent is eliminated in vacuo and the residue taken up in water. An acid pH is created using 2 N hydrochloric acid and the mixture is washed with dichloromethane. The aqueous phase is then adjusted to a basic pH using 4 N sodium hydroxide solution and the product is extracted with dichloromethane.
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH2:20][N:15]2[CH2:14][CH2:13][CH:12]([N:4]3[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:2][C:3]3=[O:18])[CH2:17][CH2:16]2)=[O:22])=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
In this example, 4.0 g of 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 3.5 g of α-bromo-p-chloroacetophenone, 4.2 ml of triethylamine and 60 ml of methanol are mixed and stirred at room temperature overnight. The white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 5.17 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 3.21 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:31])([CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C@@H:20]([OH:30])[CH2:21][CH2:22]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5].[CH2:32]([O:34]C(=O)C(CC(F)(F)C[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(C[C@@H](OC4CCCCO4)CC2)=CC3)CC1)C)C(OCC)=O)[CH3:33].CC1C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>CO.N1C=CC=CC=1>[C:32]([O:30][C@H:20]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18](=[CH:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][C:2]([F:31])([F:1])[CH2:3][C:4]([OH:7])([CH3:6])[CH3:5])[CH2:19]1)(=[O:34])[CH3:33]
Reactant: CCOC(=O)C(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Reactant: C[C@H](CC(F)(F)CC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC(F)(F)CC(C)(C)O)[C@@]4(C)CC[C@@H]32)C1
Yield: 96 %

Procedure:
The THP-ether (13) (26 mg, 0.0498 mmol) in methanol (4 ml) and THP (9) (4 ml) was treated with a catalytic amount of TsOH at room temperature for 1 hr. The usual work-up (ethyl acetate for extraction) gave the crude diol (21.4 mg). This diol was treated with acetic anhydride (1 ml) and pyridine (1 ml) at room temperature for 14 hr. The usual work-up (ethyl acetate for extraction) gave a crude product, which was applied to a column of silica gel (5 g). Elution with benzene-ethyl acetate (10:1) provided the acetate (14) (23.0 mg, 96%); mp 168°-170° C. (methanol). 1H-NMR δ: 0.82 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 1.07 (3H, d, J=6 Hz, 21-H3), 1.35 (6H, s, 26-H3 and 27-H 3), 2.03 (3H, s, acetyl), 4.55 (1H, m, 3-H), 5.36 (1H, m, 6-H). High resolution MS Calcd for C27H42F2O (M+ --CH3COOH): 420, 3202. Found: 420, 3206.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=3)[C:23]([O:25]C)=[O:24])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=3)[C:23]([OH:25])=[O:24])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 21.1 %

Procedure:
The title compound was prepared from methyl 2-(2-(7-phenylheptanoyl)oxazol-5-yl)isonicotinate (12 mg, 0.025 mmol) following General Procedure E. Preparative thin layer chromatography (2% AcOH/EtOAc) yielded the title compound as a white solid (2 mg, 17%): 1H NMR (CDCl3, 600 MHz) 8.85 (d, 1H, J=4.2 Hz), 8.42 (s, 1H), 7.93-7.90 (m, 2H), 7.26-7.30 (m, 2H), 7.17-7.16 (m, 3H), 3.12 (t, 2H, J=7.5 Hz), 2.61 (t, 2H, J=7.6 Hz), 1.79 (quint, 2H, J=7.4 Hz), 1.65 (quint, 2H, J=7.5 Hz), 1.44-1.40 (m, 4H); MALDI-FTMS m/z 377.1523 (M−H−, C22H21N2O4, requires 377.1507).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:29])[CH2:13][O:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[C:17]([C:26](O)=[O:27])[CH:16]=1)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]([C:74]([O:76][CH3:77])=[O:75])[CH2:65][CH2:66][C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70].Cl>CN(C=O)C>[CH3:77][O:76][C:74](=[O:75])[C@@H:64]([NH:63][C:26]([C:17]1[CH:16]=[C:15]([O:14][CH2:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:5](=[O:6])[NH:4][CH2:3][CH2:2][F:1])=[O:29])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=1)=[O:27])[CH2:65][CH2:66][C:67]([O:68][C:69]([CH3:71])([CH3:72])[CH3:70])=[O:73]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 950 mg 5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 15 ml DMF were added 0.39 ml DIPEA, 893 mg HATU and 596 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.3 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=1>>[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(OC(F)F)cc2)o1
Yield: 25 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4-difluoromethoxy-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 85 mg, 25%) which was obtained as a white solid. MS: m/e=369.9 [M+H]+.