Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:5][C:4]([F:7])([F:6])[C:3]([CH2:2][NH:1][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)([OH:21])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Reactant: COc1cccc(-n2ncc3c(Br)cc(C)cc32)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Yield: 85.9 %

Procedure:
A mixture of 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18, 743 mg, 2.4 mmol), 4-bromo-6-methyl-1-[3-(methyloxy)phenyl]-1H-indazole (Intermediate 16, 657 mg, 2.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.13 mmol), racemic-BINAP (141 mg, 0.23 mmol) and sodium tert-butoxide (429 mg, 4.46 mmol) in toluene (30 mL) was heated under reflux in an atmosphere of nitrogen for 2 hours. The mixture was cooled, combined with crude product from a similar smaller scale preparation (260 mg input of Intermediate 18), and diluted with toluene (100 mL) and ethyl acetate (50 mL). The resulting solution was washed successively with 1M hydrochloric acid (75 mL), 8% aqueous sodium bicarbonate (75 mL) and brine (75 mL), passed through a hydrophobic rit and evaporated under reduced pressure. The residue was purified by silica gel chromatography using the Flashmaster II (70 g cartridge) eluting with a 0:100 to 50:50 cyclohexane:ethyl acetate gradient over 60 minutes to give impure product (970 mg). Further purification using the Flashmaster II (100 g cartridge) eluting with a 100:0 to 75:25 dichloromethane:tert-butyl methyl ether gradient over 50 minutes gave the title compound (72 mg). A quantity of less pure material (137 mg) was also obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C:5]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(C(C1C=CC=CC=1)(CC=C)C(OC)=O)C=C>>[CH2:4]([C:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH:2]([CH3:21])[CH3:1]
Reactant: COC(=O)C(CC=C(C)C)(CC=C(C)C)c1ccccc1
Agent: C=CCC(CC=C)(C(=O)OC)c1ccccc1
Product: COC(=O)C(CCC(C)C)(CCC(C)C)c1ccccc1

Procedure:
The title compound was prepared following the procedure of Example 4B, substituting the product of Example 6A for the product of Example 1A. 1H NMR (300 MHz, CDCl3): δ 7.26 (m, 5 H), 3.64 (s, 3 H), 1.99 (m, 6 H), 1.48 (m, 2 H), 0.92 (m, 14 H).
Reaction SMILES: NN.[CH:3]([N:16]1[CH2:21][C@@H:20]([CH3:22])[N:19]([CH2:23][CH2:24][CH2:25][N:26]2C(=O)C3C(=CC=CC=3)C2=O)[C@@H:18]([CH3:37])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH:3]([N:16]1[CH2:17][C@@H:18]([CH3:37])[N:19]([CH2:23][CH2:24][CH2:25][NH2:26])[C@@H:20]([CH3:22])[CH2:21]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1CCCN
Temperature: 70 °C
Yield: 70.6 %

Procedure:
Hydrazine (1.10 g, 34.2 mmol) is added to a stirred solution of 2-[3-(4-benzhydryl-2,6-cis-dimethylpiperazin-1-yl)-propyl]-isoindole-1,3-dione (1.98 g, 4.28 mmol) in ethanol (70 mL). The mixture is heated at 70° C. for 12 hours to form a suspension. At room temperature the mixture is filtered and the filtrate is concentrated to give 3-(4-benzhydryl-2,6-cis-dimethyl-piperazin-1-yl)-propylamine (1.02 g, 71% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[N:6][C:7]=1[C:8](=[O:16])[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.[OH-].[Na+].CC1CCCO1>O>[NH2:1][C:2]1[C:7]([C:8]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])=[N:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][NH:26][CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: COCCCN(CCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: COCCCNCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 70 °C

Procedure:
Tert-butyl (3-{4-[5-amino-6-(pyridin-3-ylcarbamoyl)pyrazin-2-yl]phenyl}propyl)(3-methoxypropyl)carbamate (1 kg) and water (8 L) were added to the reactor, stirred and heated up to 70° C. 36% Hydrochloric acid (606 ml) was added slowly controlling rate of gas evolution. The contents were stirred for 45 minutes at 70° C. The pH was adjusted to 3-4 by addition of sodium hydroxide (325 ml). The contents were cooled to 50° C. and 2-methyltetrahydrofuran (5 L) was added. The pH was then adjusted to pH 11-12 by the addition of 48% sodium hydroxide liquor (170 ml). The contents were then cooled to 40° C. The batch allowed to settle and the two layers separated. The aqueous layer was washed with 2-methyltetrahydrofuran (2.5 L). The combined organic layers were washed with a solution of 10% w/v aqueous sodium chloride solution. The organic layer was distilled to remove 3.75 L of distillate. The remaining liquors were heated to 50° C. and methyl-t-butyl ether (4 L) added. The liquors were cooled to 10° C. over 4 hours then isolated by filtration. The solid was washed with methyl-t-butyl ether (2 L×2) and dried in a vacuum oven at 50° C. 3-amino-6-(4-{3-[(3-methoxypropyl)amino]propyl}phenyl)-N-pyridin-3-ylpyrazine-2-carboxamide (721 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[H][H]>CO.C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: C=C(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F

Procedure:
760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C1COCC1.CO.O>[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(=O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (5.67 g, 135 mmol) was added to a solution of 5A (11.4 g, 45.0 mmol) in THF (120 mL), MeOH (120 mL) and H2O (40.0 mL). The above mixture was then heated to 50° C. for 1 h. After 1 h, the heating was reduced to rt and stirring was continued for overnight. To the reaction mixture was then added H2O (50 mL) and the organics were concentrated. The remaining aqueous layer was made acidic with 1.0 N HCl solution to precipitate out the solids. The solids were collected by filtration, washed with H2O and dried under vacuum overnight to give 5B. 1H NMR (400 MHz, DMSO-d6) δ 13.68 (br. s., 1H), 8.36 (d, J=1.5 Hz, 1H), 8.25 (dd, J=8.1, 1.3 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 6.38 (s, 1H), 4.05-3.89 (m, 4H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]4[C@@H:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][N:18]([C@H:27]([CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)[C:28]([O:30]CC5C=CC(OC)=CC=5)=[O:29])[CH2:17]4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[F:1][C:2]1[CH:47]=[CH:46][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]4[C@@H:20]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:19][N:18]([C@H:27]([CH:40]5[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]5)[C:28]([OH:30])=[O:29])[CH2:17]4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5cc(F)ccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3cnc4cc(F)ccc43)CC2)[C@@H](c2ccccc2)C1
Yield: 90.1 %

Procedure:
The title compound was prepared from 41 mg of α-(R)-(3-(S)-((4-(5-fluoro-benzoimidazol-1-yl)-piperidin-1-ylmethyl))-4-(S)-phenyl-pyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (from Step D) and 4 mL of TFA, 0.3 mL of anisole, using a procedure analogous to that described in Example 95, Step E to provide 30 mg of the title compound as a solid. ESI-MS 519 (M+H); TPLC A: 1.65 min.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][PH:8](=[O:10])[CH3:9].C[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:7][P:8]([CH3:9])([CH:2]([OH:3])[C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: C[PH](C)=O
Reactant: COC(=O)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(O)P(C)(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 17.6 g (0.2 mol) of methyl glyoxylate in 30 ml of dioxane is added dropwise to a solution of 15.6 g (0.2 mol) of dimethylphosphine oxide in 50 ml of dioxane. A spatula-tip of sodium methylate is added, the mixture is stirred at 25° C. for 24 hours and the evaporated residue is freed from adhering dioxane under a high vacuum and taken up in ethyl acetate to give, after trituration, 16.4 g (49.4%) of colorless product of melting point 84°-86°.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]([F:26])([F:25])[S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O)(=[O:15])=[O:14].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([S:13]([C:12]([F:26])([F:11])[F:25])(=[O:14])=[O:15])[CH:17]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: O=S(=O)(c1cccc(-c2nc(-c3cccnc3)no2)c1)C(F)(F)F

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and the compound of Example 6B. 1H NMR (300 MHz, DMSO-d6) δ 7.73 (dd, J=4, 5.0 Hz, 1H), 7.85 (t, J=8 Hz, 1H), 8.13 (m, 1H), 8.43 (m, 1H) 8.5 (m, 1H), 8.6 (m, 1H), 8.92 (m, 1H), 9.37 (m, 1H) ppm; MS (DCI/NH3) m/z 356 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[S:10]1[CH:14]=[CH:13][N:12]2[CH:15]=[N:16][CH:17]=[C:11]12.O>ClCCCl>[Cl:1][CH2:2][C:3]([C:17]1[N:16]=[CH:15][N:12]2[CH:13]=[CH:14][S:10][C:11]=12)=[O:4]
Reactant: c1cn2cncc2s1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: O=C(CCl)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Chloroacetyl chloride (5.97 ml) was added to a solution of 12.5 g of aluminum chloride in 40 ml of 1,2-dichloroethane. The mixture was stirred at room temperature for 20 min. A solution of 1.93 g of imidazo[5,1-b]thiazole in 20 ml of 1,2-dichloroethane was added thereto. The mixture was heated under reflux for 2 hr. Water was added thereto, followed by extraction with dichloromethane. The organic layers were combined together. The combined organic layers were washed with a dilute aqueous sodium hydroxide solution and saturated brine in that order. The solvent was removed by distillation. Isopropyl ether was added to the residue. The resultant powder was collected by filtration to obtain the title compound.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:39])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:39])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2ncccc2C)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1cccnc1CSc1c[nH]c(=O)c(O)c1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-{[(3-methylpyridin-2-yl)methyl]sulfanyl}pyridin-2(1H)-one (Intermediate 19).
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Si:15]([CH3:45])([CH3:44])[O:16][Si:17]([CH3:43])([CH3:42])[O:18][Si:19]([CH3:41])([CH3:40])[O:20][Si:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)([CH3:23])[CH3:22])=[CH:6][CH:5]=1)([O-])=O.[H][H]>>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Si:15]([CH3:44])([CH3:45])[O:16][Si:17]([CH3:43])([CH3:42])[O:18][Si:19]([CH3:40])([CH3:41])[O:20][Si:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)([CH3:22])[CH3:23])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: C[Si](C)(CCCCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCCCOc1ccc([N+](=O)[O-])cc1
Product: C[Si](C)(CCCCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCCCOc1ccc(N)cc1
Yield: 99.6 %

Procedure:
2.71 g of the above (2d) (3.73 mmol) and 15 mL of a 10 wt % Pd/C ethyl acetate solution (0.0150 g) were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite, and then concentrated to obtain a colorless oily material of 1,7-bis(4-aminophenoxyhexyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3d) (2.47 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3d), and results are shown below.
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[Cl-:33].[NH4+].O>C(O)(C)C>[ClH:33].[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: [Cl-]
Agent: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: Cl
Reaction time: 20 h

Procedure:
In a 200 mL roundbottom flask, compound 1 (200 mg, 0.46 mmol) was dissolved in 40 mL isopropyl alcohol. The solution was stirred and vortexed at room temperature until it became homogeneous. A 7% (w/w) solution of ammonium chloride in water (20 mL, 26 mmol)) was then added dropwise to the stirring solution. The stirring was stopped and the solution was permitted to stand at room temperature for 20 h. White crystals formed. The crystals were collected on a Büchner funnel, washed with 1:1 isopropanol:water (3 mL), and dried for 30 minutes. The crystals were collected to yield the monohydrochloride salt of compound 1 (27 mg, 12% yield).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:6]([CH2:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]3=[O:3])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CCCCC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
An oily suspension (50% by weight; 3.1 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (195 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. A solution of 2-hexanone (6.5 g) in anhydrous dimethylformamide (5 cc) is then added and stirring is continued for 8 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into water (1.5 litres). The solid obtained is separated by filtration, washed with water and dried in the air. After recrystallization in ethanol, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(2-oxohexyl)-1-isoindolinone (3.6 g), m.p. 161° C., is obtained.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][C:14](=[O:15])[C:10]=2[CH:9]=1)=[O:5])C.O.OS(O)(=O)=O.[Na+].[Cl-]>O1CCCC1.C(O)C.C(O)(=O)C.C(OCC)(=O)C.CCCCCC>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][C:14](=[O:15])[C:10]=2[CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(c1)C(=O)CO2
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: O=C(O)COc1ccc2c(c1)C(=O)CO2
Yield: 65 %

Procedure:
4.72 g (20 mmol) XIX were heated under reflux for 15 h in a mixture of 200 ml tetrahydrofuran, 100 ml water and 10 ml concentrated H2SO4. Ethyl acetate and saturated NaCl solution were added to the reaction solution. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4 and freed from the solvent. Flash chromatography (200 g SiO2, n-hexane:ethyl acetate=1:2+1% acetic acid, applied with ethanol) produced 2.78 g (13 mmol, 67%) XX.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Br:5][C:6]1[N:11]=[C:10]([CH:12](O)[CH3:13])[CH:9]=[CH:8][CH:7]=1>>[N:1]1([CH:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([Br:5])[N:11]=2)[CH3:13])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: CC(O)c1cccc(Br)n1
Product: CC(c1cccc(Br)n1)N1CCC1

Procedure:
The title compound was prepared according to the procedure in Example 139 Step 1 using azetidine (0.141 g, 2.48 mmol) and 1-(6-bromopyridin-2-yl)ethanol (0.500 g, 2.48 mmol) as the starting materials.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:32][CH3:33])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC=CC=4)=[CH:16][CH:15]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:12]3[CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=[C:11]3[CH2:32][CH3:33])=[CH:19][CH:18]=2)=[O:24])(=[O:42])=[O:43])=[CH:39][CH:40]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-(4-cyanophenyl)-2-ethyl-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 534 [M+H]+, 532 [M−H]−, 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.7 Hz), 2.92 (2H, t, J=7.1 Hz), 3.47-3.55 (2H, m), 6.61 (1H, br), 7.27-7.37 (4H, m), 7.50 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.6 Hz), 7.77 (2H, d, J=8.6 Hz), 7.89 (2H, d, J=8.6 Hz).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)CCOC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)CCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 78.3 %

Procedure:
In the same manner as in Example 81, 153 mg of the title compound was prepared from 150 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 120 mg of isopentyloxycarbonyloxymethyl iodide.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:29])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=405.20.