Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:9][NH2:10])[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[NH4+:17].C(Cl)C(O)C>CO>[NH2:17][CH2:11][CH:13]([OH:15])[CH2:14][NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][CH:1]([CH2:9][NH2:10])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: NCC1CCC(CN)CC1
Reactant: ClCC1CO1
Agent: CC(O)CCl
Agent: [OH-]
Solvent: CO
Product: NCC(O)CNCC1CCC(CN)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
1,4-Cyclohexanebis(methylamine) (14.2 g., 0.1 mole) is dissolved in 50 ml. of anhydrous methyl alcohol and the solution cooled to +5° C. in an ice bath. Epichlorohydrin (9.3 g., 0.1 mole) is added in a 2-minute period and the temperature maintained at +5° C. for 2 hours; reaction is allowed to continue at 10° C-15° C. until thin layer chromatography of an aliquot (silica gel plate with development using a solution of 1 volume concentrated aqueous ammonium hydroxide in 4 volumes of methyl alcohol) indicated nearly complete conversion of the starting diamine to the propylene chlorohydrin. The solution is then added to 100 ml. of dry with methyl alcohol previously saturated at 0° C. with dry ammonia gas by continuous dropwise flow at +5° C. with good agitation and external cooling. After stirring 2 hours at °5° C., it is allowed to warm to 20° C. and mixed overnight. The reaction is competed by heating at 45° C.-55° C. for 6 hours. The solvent and ammonia was removed by stripping and the product purified using fractional distillation under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([C:19]([OH:21])=[O:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.O.NN.[OH-].[K+].C(O)COCCOCCO>>[CH3:1][C:2]1([C:19]([OH:21])=[O:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCC(=O)c2cc(C3CCCCC3)ccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CC1(C(=O)O)CCCc2cc(C3CCCCC3)ccc21
Temperature: 195 °C

Procedure:
A mixture of 12 g of l-methyl-4-oxo-6-cyclohexyl-1,2,3,4-tetrahydronaphthalene-1 -carboxylic acid, 10 g of hydrazine hydrate, 13.7 g of potassium hydroxide, and 85 ml of triethylene glycol is heated at 130°-140°C for 2 hours. After that, while distilling off a mixture of hydrazine and water, the temperature is raised up to 195°C, and the batch is stirred until the evolution of nitrogen ceases. The mixture is then diluted with 50 ml of water, acidified with concentrated hydrochloric acid, then extracted with ethyl acetate. The resin-like crude product remaining after evaporation of the ethyl acetate is crystallized from toluene and yields 1-methyl-6-cyclohexyl-1,2,3,4-tetrahydronaphthalene-1carboxylic acid of the formula ##SPC12##
Reaction SMILES: [CH2:1]([C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:39]([NH:41][CH2:42][CH2:43][OH:44])[CH3:40].Cl[CH2:46][CH2:47]Cl>>[CH2:1]([C:8]1[N:16]([CH2:40][CH2:39][N:41]([CH2:46][CH3:47])[CH2:42][CH2:43][OH:44])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: ClCCCl
Reactant: CCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCn1c(=O)c2c(nc(Cc3ccccc3)n2CCN(CC)CCO)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 120 °C

Procedure:
A mixture of 2.1 gm of 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9), 1.02 gm of sodium carbonate, 3.82 ml of 1,2-dichloroethane and 0.59 ml of 2-(ethylamino)ethanol was heated in a steel pressure vessel under argon at 120 degrees C. for 3–5 hours*. The mixture was then cooled and vented to the atmosphere. The semisolid reaction mixture was triturated several times with 5–10 ml portions of methanol followed by methylene chloride and the combined solutions were evaporated to dryness. The residue was purified by column chromatography on silica gel using a gradient of 1:1 ethyl acetate-hexanes, ethyl acetate and 5% methanol in ethyl acetate. The appropriate fractions were collected and evaporated to dryness to yield a light orange solid of 8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[N:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNCc2ccccc2OCCCN2CCCCC2)cc1
Yield: 80.2 %

Procedure:
N-[[2-[3-(1-Piperidinyl)propoxy]phenyl]methylene]benzeneethanamine (61.5 g) is reduced with 20 g of sodium borohydride in 320 ml of methanol following the procedure described in Example 1B to yield 49.6 g of product as an oil, boiling point 216°-221° C. at 0.3-0.4 mm of Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=3)=[CH:18][CH:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(O)cc2)C1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A solution of 62 mg (0.21 mmol) of the crude (RS)-[1-(4-hydroxy-phenyl)-5-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester in 3 ml of 2-butanone is treated with 0.031 ml (0.23 mmol) of 3-fluorobenzyl-bromide and 59 mg (0.42 mmol) of potassium carbonate and the mixture is stirred at 50° C. for 18 h. For the working-up, the reaction mixture is diluted with ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 2:1 mixture of n-hexane and ethyl acetate as the eluent. There are obtained 61 mg (72% of theory) of (RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester as a white solid. MS: m/e=401 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11](Cl)(Cl)=[O:12].Cl.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:38]=[C:37]4[C:32]([CH2:33][CH2:34][NH:35][CH2:36]4)=[CH:31][CH:30]=3)[N:26]=[C:25]([NH2:39])[N:24]=2)[CH2:19][CH2:18]1>>[NH2:39][C:25]1[N:26]=[C:27]([C:29]2[CH:38]=[C:37]3[C:32]([CH2:33][CH2:34][N:35]([C:11]([NH:10][CH:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)=[O:12])[CH2:36]3)=[CH:31][CH:30]=2)[CH:28]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]2)[N:24]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCc5ccccc53)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 2,3-dihydro-1H-inden-1-amine (Aldrich, Cat. #A59506), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=484.2.
Reaction SMILES: C(N[CH2:6][C:7]1[C:8]([OH:35])=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([Cl:34])[CH:25]=2)[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=2)[CH:12]=1)(C)(C)C.BrC1C=C(Br)C=C(C=[O:41])C=1O.ClC1C=C(B(O)O)C=CC=1C(F)(F)F>>[Cl:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:12]=[C:7]([CH:6]=[O:41])[C:8]([OH:35])=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[C:26]([Cl:34])[CH:25]=3)[CH:10]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: CC(C)(C)NCc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)cc(-c2ccc(C(F)(F)F)c(Cl)c2)c1O
Agent: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Product: O=Cc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)cc(-c2ccc(C(F)(F)F)c(Cl)c2)c1O

Procedure:
3,3″-Dichloro-4′-hydroxy-4,4″-bis(trifluoromethyl)-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde was prepared using the procedure described in Intermediate 5 from 3,5-dibromosalicylaldehyde and 3-chloro-4-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.C1(C)C(C)=CC=CC=1.N([C:24]1[NH:25][CH2:26][CH2:27][N:28]=1)[N+]([O-])=O.C1C=CC=CC=1>CC(C)=O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([OH:11])[CH2:2][NH:1][C:24]2[NH:28][CH2:27][CH2:26][N:25]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1ccc(F)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: OC(CNC1=NCCN1)c1ccc(F)cc1
Temperature: 160 °C

Procedure:
To a solution of 6.5 parts of α-(aminomethyl)-p-fluorobenzyl alcohol in 8 parts of xylene are added 5.2 parts of 2-(nitramino)-2-imidazoline. The mixture is heated in an oil-bath to about 160°C. till gas-evolution is ceased (about 15 minutes). The reaction mixture is cooled and treated with benzene and acetone. The product is sucked off and crystallized from 4-methyl-2-pentanone, yielding p-fluoro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 153.4°C.
Reaction SMILES: CC([O-])(C)C.[K+].[Br-].[C:8]([O:12][C:13](=[O:20])[CH2:14][S+]1CCCC1)([CH3:11])([CH3:10])[CH3:9].C(O)C(F)(F)F.[C:27]([O:31][C:32]([NH:34][C@:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:39]=[CH:38][C:37](=[O:40])[CH2:36]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C.CC(OC)(C)C>[C:44]([O:43][C:41]([C@:35]1([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:36][C:37](=[O:40])[C@@H:38]2[C@H:39]1[C@H:14]2[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:20])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C=CC(=O)C1
Reactant: CC(C)(C)OC(=O)C[S+]1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: OCC(F)(F)F
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
Add KOtBu (42 mL, 42 mmol, 1 M solution in THF, 2.5 equiv) to a 0° C. solution of 1-(2-tert-butoxy-2-oxoethyl)tetrahydrothiophenium bromide (11.9 g, 42 mmol, 2.5 equiv., Preparation 48) in acetonitrile (30 mL) under N2 over 10 minutes keeping the temperature below 5° C. Stir the milky solution cold for 1.5 hours. Add trifluoroethanol (6.9 g, 69 mmol, 4.1 equiv) dropwise. Add a solution of (1S)-1-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonyl)-cyclopent-4-en-3-one (5 g, 16.8 mmol, Preparation 47) and trifluoroethanol (13.3 g, 132 mmol, 7.9 equiv) in acetonitrile (20 mL), over 5 minutes, maintaining the temperature at 3-5° C. Stir the solution for 4.5 hours at 0-5° C. Add MTBE (155 mL) and 120 (80 mL) to the cold reaction mixture. Separate the layers and wash the organic layer with H2O (50 mL), then 20% brine (50 mL). Concentrate the organic layer via atmospheric pressure distillation to approximately 30 mL. Add heptane (100 mL) and concentrate the solution. Add additional heptane as needed until the vapor temperature of the distillate reaches 93° C. Add THF (65 mL) to yield a solution of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[CH2:24](I)C>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][CH3:24])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Cl)c1
Reactant: CCI
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: CCSc1ccc(N)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-4-thiocyanoaniline (40 g., 0.22 mole) in ethanol (250 ml.) is added to a stirred solution of sodium sulfide nonahydrate (58.5 g., 0.22 mole) in water (110 ml.) and the mixture is warmed (50° C.) for 45 minutes. Ethyl iodide (36.6 g., 0.22 mole) is added and stirring is continued for 2 hours at 50° C. and then at room temperature overnight. The reaction is poured into water (3 liters) and the product extracted with either. The combined extracts are washed with water and dried (CaSO4). Removal of the drying agent and solvent gives 2-chloro-4-ethylthioaniline, an oil.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][CH2:38][CH3:39])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][CH2:38][CH3:39])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.3 Hz, 2H), 7.68-7.62 (m, 4H), 7.46 (t, J=6.6 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 6.74 (s, 3H), 4.21 (t, J=6.1 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.52-1.43 (m, 8H), 1.32-1.24 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ES) m/e 514 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C@H:17]2[CH2:21][O:20][C:19](=[O:22])[N:18]2[C:23](=[O:33])[CH2:24][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:52]=[N+:53]=[N-:54])(=O)=O)(C)C.C(O)(=O)C>O1CCCC1.O>[N:52]([C@@H:24]([C@@H:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:26])[C:23]([N:18]1[C@@H:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][O:20][C:19]1=[O:22])=[O:33])=[N+:53]=[N-:54]
Reactant: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](c1ccccc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Potassium bis(trimethylsilyl)amide (2.0 mL, 1.8 mmol, 0.91 M in tetrahydrofuran) was added to (S)-4-phenyl-3-((S)-3-phenyl-butyryl)-oxazolidin-2-one (500 mg, 1.6 mmol) in anhydrous tetrahydrofuran (8 mL) at −78° C. and stirred for 1 hour. In a separate flask, a solution of 2,4,6-triisopropylbenzenesulphonyl azide (625 mg, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. was added via cannula to the anion at −78° C. and stirring continued for 2 hours. Acetic acid (0.45 mL, 7.8 mmol) was added to the reaction at −78° C., the mixture warmed to room temperature and stirred overnight. The mixture was poured into water (30 mL) and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The crude product was purified on silica gel with 2:1 dichloromethane/hexane to give (S)-3-((2S,3R)-2-azido-3-phenyl-butyryl)-4-phenyl-oxazolidin-2-one (230 mg, 41%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:30])[NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28]O)[CH2:23][CH2:22]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:1][CH2:28][CH2:27][C@H:24]3[CH2:23][CH2:22][C@H:21]([NH:20][C:19]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:30])[CH2:26][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a white amorphous lyophilizated solid following Scheme 1 and in analogy to Example 2 using 2-hydroxy-7-methoxy-quinoxaline, [trans-4-(2-hydroxy-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[NH:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[N:24]1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:28][C:25]4[CH:26]=[CH:27][NH:23][N:24]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1cc[nH]n1
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(NCc4cc[nH]n4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=334.3 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and pyrazol-3-carbaldehyde as described in example 26.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([CH:13]=O)=[CH:5][CH:4]=1.[Br-:15].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C>C(#N)C.ClCCl.CN(C=O)C>[Br:15][CH2:13][C:6]1[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: [Br-]
Reactant: COc1ccc(C=O)c2c1OCCO2
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CBr)c2c1OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8-methoxy-1,4-benzodioxane-5-carbaldehyde (12 g, 62 mmol) in acetonitrile (140 mL) was added lithium bromide (12 g, 110 mmol), and then trimethylsilyl chloride (12 mL, 95 mmol) was added dropwise. After 15 minutes, the mixture was ice-cooled, and 1,1,3,3-tetramethyldisiloxane (19 mL, 110 mmol) was added dropwise, followed by stirring at room temperature for 2 hours. The mixture was diluted with dichloromethane, and then was filtered through Celite. The solvent was evaporated in vacuo to give a pale yellow oil. To a solution of the obtained crude 5-bromomethyl-8-methoxy-1,4-benzodioxane in DMF(180 mL) was added sodium cyanide (9.2 g, 190 mmol), followed by stirring at room temperature for 60 hours. To the mixture was added water under ice-cooling, and the precipitated solid was collected by filtration to give Compound 1a (6.8 g, 53%) as an ash-colored solid.
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:1]/[C:2](/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:16]\[O:17][C:30](=[O:31])[C@@H:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:28][C:26](=[O:27])[O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/OC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate [see Preparation 4] and (2R)-2-{[(benzyloxy)carbonyl]amino}-2-phenylethanoic acid to afford tert-butyl (2S)-2-[(Z,5R)-1-amino-4,7-dioxo-5,9-diphenyl-3,8-dioxa-2,6-diaza-1-nonen-1-yl]-1-piperidinecarboxylate as an oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][C:21]1([CH2:24][O:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][C:21]1([CH2:24][O:25][C@H:26]2[CH2:27][CH2:28][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:52]5[NH:53][C:4](=[O:7])[O:5][N:3]=5)=[CH:44][CH:45]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:30][CH2:31]2)[CH2:22][CH2:23]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O[Si](C)(C)C(C)(C)C)CC3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogen carbonate (0.63 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 40 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.073 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). Tetrabutylammonium fluoride (0.94 mL, 1.0 M tetrahydrofuran solution) was added and the mixture was stirred at 70° C. for 3.5 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.076 g, 34%).