Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[N:36]1[C:41]2[NH:42][C:43]3[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=3[NH:45][CH2:46][C:40]=2[CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([N:45]1[C:44]2[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=2[NH:42][C:41]2[N:36]=[CH:37][CH:38]=[CH:39][C:40]=2[CH2:46]1)=[O:6]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1

Procedure:
In the manner of Example 5, Step D, employing 2-chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid of Step B (0.971 g, 4.1 mmol), triethylamine (0.57 mL, 4.1 mmol), 2,4,6-trichlorobenzoylchloride (0.63 mL, 4.0 mmol), 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (0.67 g, 3.4 mmol) and 4-dimethylamino pyridine (0,42 g, 3.4 mmol) in dichloromethane (20 mL), was obtained a compound identical to that of Example 1, Step E.
Reaction SMILES: C([O-])C.[Na+].C(OCC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][N:18]=1>CCO>[NH2:18][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1nsc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2ccccc2c1N
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
A dry 2-neck 500 mL round-bottom flask (RBF) was charged with sodium ethanolate (46.2 mL, 124 mmol), diluted with 151 mL absolute EtOH, cooled in an ice bath and treated dropwise with diethyl malonate (17.98 mL, 118 mmol) under an atmosphere of nitrogen. After stirring for 20 minutes, the ice bath was removed and 3-chlorobenzo[d]isothiazole (20.0 g, 118 mmol) was added in one portion and stirred for 24 hours. The reaction solution was quenched with water, extracted with ether and treated with excess 4 M HCl/dioxane. A pinkish-white precipitate was filtered off, suspended in water, basified with Na2CO3, extracted with ether, washed with water and brine, dried over sodium sulfate, filtered and concentrated to yellow solids (˜20 g) which were recrystallized from ethanol/water and dried in a vacuum oven at 60° C. for 3 hrs to give ethyl 3-aminobenzo[b]thiophene-2-carboxylate (19.9 g, 76% yield).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.BrCCCCCC>>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: CCCCCCBr
Product: CCCCCCOc1ccc(C(=O)O)cc1

Procedure:
The same procedure as in the synthesis of 4-octyloxy benzoic acid of Example 26 was repeated except that bromohexane was used instead of bromooctane to obtain 4-hexyloxy benzoic acid. This 4-hexyloxy benzoic acid was condensed with (+)-4-(2-methyloctanoyl) phenol in the same manner as in the synthesis of 4-(2-methyloctanoyl) phenyl, 4-octyloxy benzoic acid ester of Example 26 to synthesize 4-(2-methyloctanoyl) phenyl, 4-hexyloxy benzoic acid ester having the aforementioned physical and chemical properties.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Yield: 99.5 %

Procedure:
Stir a mixture of 7-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (0.87 g, 2.40 mmol), 1-bromopinacolone (1.54 g, 8.68 mmol), and potassium carbonate (2.4 g, 17.4 mmol) in acetone (20 mL) for 4 h at RT. Concentrate the reaction mixture and then dilute the residue with EtOAc (100 mL) and water (50 mL). Adjust the pH of the mixture to 1 using 1 N HCl. Discard the aqueous layer. Wash the organic layer with brine, dry over Na2SO4 and filter. Concentrate the filtrate and purified by silica gel radial chromatography (5:95 EtOAc:hex to 15:85 EtoAc:hex) to give the title compound as a white solid (1.1 g, 82%). MS (ES) m/e 461 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH3:8])=[C:5]([C:9]([O:11]CC)=[O:10])[CH:4]=1)[CH3:2]>[OH-].[Na+]>[CH2:1]([C:3]1[O:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)oc1C
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C(=O)O)c(C)o1

Procedure:
Saponification of 0.5 g of the ester was carried out by refluxing 4 hours in 10 ml of 25% aqueous sodium hydroxide. Acidification precipitated the crude acid, which was recrystallized from water to obtain 5-ethyl-2-methyl-3-furoic acid as white needles, mp 97°-99° C.
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](=[O:26])[CH2:5][NH:6]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>CC(C)=O>[C:27]1([CH3:37])[CH:28]=[CH:29][C:30]([S:33]([OH:36])(=[O:34])=[O:35])=[CH:31][CH:32]=1.[Cl:1][CH2:2][O:3][C:4](=[O:26])[CH2:5][NH2:6]
Reactant: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: NCC(=O)OCCl

Procedure:
3.5 g of N-tritylglycine chloromethyl ester in acetone (25 ml) were treated with p-toluenesulphonic acid (1.9 g) in acetone (25 ml). After standing for one-half hour at room temperature, the resulting precipitate was collected on a filter. The product thus obtained had a melting point of 188°-190°C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12](O)=[O:13]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][OH:13]
Reactant: O=C(O)C1OCCc2c(Br)cccc21
Solvent: C1CCOC1
Product: OCC1OCCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid (0.500 g, 1.94 mmol) in 1 mL of THF was added BH3. THF (3.88 mL, 3.88 mmol) drop wise at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and aqueous sodium hydroxide (1 N, 2 mL). The contents were stirred for 3 h, and then extracted with EtOAc. The organic layer was dried and concentrated to give (5-bromo-3,4-dihydro-1H-isochromen-1-yl)methanol
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9](C4N(C5C=CC(F)=CC=5F)N=CN=4)[S:8][C:7]=3[C:6]=2[N:28]=1.C[C@H]1CNC[C@@H](C)N1.CC([O-])(C)C.[Na+].C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC>CC([O-])=O.CC([O-])=O.[Pd+2]>[S:8]1[C:7]2[C:6]3[N:28]=[CH:2][CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: c1cnc2c(c1)OCCc1ccsc1-2
Temperature: 120 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), (2S,6R)-2,6-dimethylpiperazine (164 mg, 1.44 mmol), tBuONa (47 mg, 0.48 mmol), Pd(OAc)2 (49 mg, 0.3 mmol) and 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered by celite. The filtrate was concentrated to dryness and purified by pre-TLC (EtOAc) to afford 220 mg of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene. (Yield: 62%) 1H NMR (DMSO, 400 MHz): δ8.28 (s, 1H), 8.22 (s, 1H), 7.94-7.88 (m, 1H), 7.72-7.67 (m, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.24 (t, J=2.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 4.20 (t, J=4.4 Hz, 2H), 3.99 (q, J=2.4, 12.8 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 2.87-2.82 (m, 2H), 1.10 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=495 [M+H]+
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:38][C@H:35]4[CH2:36][CH2:37][C@H:32]([OH:31])[CH2:33][CH2:34]4)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(N[C@H]4CC[C@H](O)CC4)nc3N(C3CCCC3)C2=O)c1

Procedure:
1-Cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(trans-4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.5 g (1.15 mmol) 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.389 g (3.45 mmol) trans-4-hydroxy-cyclohexylamine. The final product was purified by column chromatography (20:1 dichloromethane/ methanol). This gave 0.320 g (57%) of 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(trans-4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 108° C.–110° C.; MS (APCI) m/z 486.2, 487.2.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)(=O)C.C(O)C>[CH2:20]([O:19][C:15](=[O:18])[NH:16][N:17]=[CH:13][C:11]1[N:12]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:9][CH:10]=1)[CH3:21]
Reactant: CCOC(=O)NN
Reactant: O=Cc1c[nH]c(Cc2ccccc2)n1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)NN=Cc1c[nH]c(Cc2ccccc2)n1

Procedure:
To a 37.2 gm. portion of 2-benzyl-4-imidazolecarboxaldehyde in 200 ml. of ethanol is added 20.8 gm. of ethyl carbazate and a few drops of concentrated acetic acid. The mixture is reacted as described in Example 32 giving the desired product m.p. 184°-185° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][NH:20]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([F:38])=[C:34](F)[CH:35]=2)[C:30](=[O:39])[C:29]([C:40]([OH:42])=[O:41])=[CH:28]1)[CH3:26]>N1C=CC=CC=1>[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([F:38])=[C:34]([N:23]3[CH2:22][CH2:21][NH:20][CH:19]([C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:10]([S:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)(=[O:9])=[O:8])[CH:11]=4)[CH2:24]3)[CH:35]=2)[C:30](=[O:39])[C:29]([C:40]([OH:42])=[O:41])=[CH:28]1)[CH3:26]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: O=S(=O)(c1ccccc1)n1cc(C2CNCCN2)c2ccccc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cn(S(=O)(=O)c5ccccc5)c5ccccc45)C3)cc21
Temperature: 95 °C
Yield: 84.5 %

Procedure:
A mixture of 4.092 g of 1-(phenylsulfonyl)-3-(2-piperazinyl)-1H-indole and 1.012 g of 1-ethyl-6,7-difluoro1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 5 ml of pyridine was heated at 95° C. for 3 hours, then cooled and the solid collected, washed with methanol and ether, giving 1.94 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-indol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=2)=[N:2]1.O[CH2:21][CH2:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH2:32][C:33]([O-:35])=[O:34])=[CH:27][CH:26]=2>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:21][CH2:22][C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[CH:29][C:28]([CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=4)=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=2)=[N:2]1
Reactant: O=C([O-])Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1cc(-c2noc3ccccc23)ccc1O
Product: CCCc1cc(-c2noc3ccccc23)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
Using the procedures in Example 15, steps E and F, the title compound was prepared from 4-(1,2-benzisoxazol-3-yl)-2-propylphenol and 2-(2-hydroxyethyl)indole-5-acetate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:12](=[O:14])[C:11](=[N:10][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:8][CH:7]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)cc1
Yield: 73.3 %

Procedure:
2-(4-Trifluoromethylphenyl hydrazono) propionic acid (0.74 g, 3.0 mmol) was dissolved in dichloromethane (15 ml), and 4-chlorobenzyl amine (0.42 g, 3.0 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (0.58 g, 3.0 mmol) were added thereto. 20 hours later, the mixture was washed with 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, and dried on sodium sulfate and then filtrated. The residue obtained by concentrating the resulting filtrate was suspended in a mixed solvent of hexane and chloroform (1:1) and filtered to obtain N-(4-chlorobenzyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 62) (0.83 g, 2.2 mmol, 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:90])[C@@H:7]([CH2:81][CH2:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[NH:8][C:9](=[O:80])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:79])[CH:19]([NH:61]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:20][S:21][CH2:22][C@H:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>ClCCl>[C:1]([O:5][C:6](=[O:90])[C@@H:7]([CH2:81][CH2:82][C:83]([O:85][C:86]([CH3:87])([CH3:89])[CH3:88])=[O:84])[NH:8][C:9](=[O:80])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:79])[CH:19]([NH2:61])[CH2:20][S:21][CH2:22][C@H:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](CSCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccc(C(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](CSCC(N)C(=O)NCc1ccc(C(=O)N[C@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of (2R,6R) 4-[2-(9-fluorenylmethyloxycarbonylamino)-6,7-bis(palmitoyloxy)-4-thiaheptanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Reference Example 38 (243 mg) in dichloromethane (0.5 ml)-piperidine (2 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 to 1:3) to yield the title compound (195 mg, yield 97%) as a colorless wax-like substance.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4](O)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:8])=[CH:11][CH:12]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CCC(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCC(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 500 g of succinic acid anyhydride, 471 g of 4-amino-pyridine and 5,200 ml of xylene is heated to reflux while stirring and separating the water formed. After 30 minutes 15 ml of methane sulfonic acid are added and refluxing is continued until 5 moles of water are collected, requiring about 4 days. The mixture is cooled to room temperature, the supernatant is decanted off and the suspension combined with 1000 ml of isopropanol. It is stirred for 5 minutes, filtered, the residue washed with 250 ml of isopropanol and dried for 3 days under reduced pressure at room temperature and shortly at 50° , to yield the 1-(4-pyridyl)-pyrrolidin-2, 5-dione melting at 232°-235° .
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH2:11][N:12]2[C:16]([CH3:17])=[C:15]([Br:18])[CH:14]=[N:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=C.N1C(C)=CC=CC=1C.[OH2:27].ClCCl>O1CCOCC1.O.O=[Os](=O)(=O)=O>[Br:18][C:15]1[CH:14]=[N:13][N:12]([CH2:11][C:5]2([O:4][CH2:1][CH:2]=[O:27])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:16]=1[CH3:17]
Reactant: C=CCOC1(Cn2ncc(Br)c2C)CCCCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1c(Br)cnn1CC1(OCC=O)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 167B (3.13 g) in dioxane/water (3:1, 40 mL) was added 2,6-lutidine (2.5 mL), OsO4 (2.5% in tert-butanol, 2.75 mL), and NaIO4 (8.55 g) under argon. The reaction mixture was stirred at room temperature for 4 hours, then water (50 mL) and dichloromethane (200 mL) were added. The organic layer was separated, and the water phase was extracted by dichloromethane (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. After filtration, the solvent was removed to give the crude product which was used in the next step without further purification.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)=[O:6].[NH2:13][C:14]([NH2:16])=[S:15].[Na+].[Cl-]>CN(C=O)C.CC#N>[CH3:3][O:4][C:5]([N:7]1[CH2:8][CH:9]=[CH:10][C@H:11]2[S:15][C:14]([NH2:16])=[N:13][C@@H:12]12)=[O:6]
Reactant: COC(=O)N1C=CC=CC1
Reactant: NC(N)=S
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)N1CC=C[C@H]2SC(N)=N[C@H]21

Procedure:
A solution of Br2 (0.71 ml, 13.9 mmol, 1 equiv.) in DMF (5 ml) is added over 10 min to a solution of N-methoxycarbonyl-1,2-dihydropyridine 1 (1.92 g, 13 mmol, 1 equiv.) and of thiourea (3.95 g, 52 mmol, 4 equiv.) in DMF (15 ml)/CH3CN (5 ml) at ambient temperature and under argon. The reaction being complete from the end of the addition of the bromine, the reaction mixture is concentrated approximately twofold, poured onto ice-cold water (200 ml) and then filtered through a Buchner funnel. The filtrate is basified (5% Na2CO3) until a pH of greater than 10 is obtained and is then saturated with NaCl. After extracting with DCM, drying over MgSO4 and evaporating the solvent, the liquid obtained (10.8 g) is chromatographed on silica gel using DCM (sat. NH3) and then DCM (sat. NH3)/MeOH, 2%. The product 6 (Rf=0.39, DCM/MeOH(NH3), 98:2) is obtained in the form of a white solid (0.32 g, 11%).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][C:15](=O)[CH:14]([O:19][CH3:20])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CO>[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][C@H:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:14]([O:19][CH3:20])[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.7 %

Procedure:
Sodium cyanoborohydride (0.17g, 27 mmol) and 5.2g of 3A molecular sieves were slowly added at room temperature to a stirred solution of 1-phenylmethyl-3-methoxy-4-piperidone (5b, Ig, 4.56 mmol) from Example 3 in 40ml of methanol, 2.55g (27 mmol) of aniline and 3.57ml of 2.55N hydrochloric acid in methanol. The reaction mixture was stirred at room temperature for 3 days, after which time the molecular sieves were filtered off and the solution was made acidic with 10ml of 10% hydrochloric acid. The methanol was evaporated under vacuum and the residue was diluted with 20ml of water, then extracted with ether (50ml). The aqueous layer was then made alkaline with 10% sodium hydroxide solution and extracted with 3×100ml of ether. The combined organic layers were dried, then concentrated under vacuum and purified by column chromatography (silica gel; ethyl acetate/hexane; 1:1) to yield the intermediates cis-1-phenylmethyl-3-methoxy-4phenylaminopiperidine (7b, 0.52g, 38.23%) and trans-1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b, 0.05g, 3.7%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[C:29]([NH2:34])[N:28]=1>C(O)C>[Cl:26][C:27]1[CH:32]=[C:31]([N:11]2[CH2:12][CH2:13][O:14][CH:9]([C:7]3[NH:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[N:8]=3)[CH2:10]2)[N:30]=[C:29]([NH2:34])[N:28]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Fc1ccc2[nH]c(C3CNCCO3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(F)ccc4[nH]3)C2)n1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a suspension of 5-fluoro-2-(2-morpholinyl)-1H-benzimidazole (200 mg, 0.904 mmol) and Hunig's base (409 mg, 3.16 mmol) in ethanol (10 mL) stirred at room temperature was added 4,6-dichloro-2-pyrimidinamine (148 mg, 0.904 mmol), and the reaction mixture was stirred overnight at 85° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The organic solvent was evaporated in vacuo to give the crude product. The residue was triturated with EtOAc (1×5 mL). The resulting solid was filtered and collected to afford the title compound (250 mg). LC-MS (ES) m/z=349 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([N:10]1[CH2:34][CH2:33][CH2:32][C@H:11]1[C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[OH:19])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[C:35](Cl)(=[O:37])[CH3:36].N1C=CC=CC=1>O1CCCC1>[NH:1]([C:35]([CH3:36])=[O:37])[C@H:2]([C:8]([N:10]1[CH2:34][CH2:33][CH2:32][C@H:11]1[C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:16][CH2:17][C:18](=[O:19])[OH:20])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(=O)Cl
Reactant: NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 12 h

Procedure:
A mixture of 500 mg of Gln-Pro-Glu-Asn, 0.7 ml of acetyl choride, 0.5 ml of pyridine and 10 ml of tetrahydrofuran is kept at 20° for 12 hours. The mixture is evaporated, the residue is purified by means of TLC to yield Ac-Gln-Pro-Glu-Asn.