Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:35])[CH2:21][CH2:22][C:23]([F:34])([F:33])[C:24]([O:27]C(OCC)C)([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43]C2CCCCO2)[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:33][C:23]([F:34])([CH2:22][CH2:21][C@H:20]([C@@H:19]1[C@:36]2([CH3:42])[C@H:16]([C@H:15]3[C@H:39]([CH2:38][CH2:37]2)[C@:40]2([CH3:41])[C:12]([CH2:11][C@@H:10]([OH:43])[CH2:9][C@@H:8]2[OH:7])=[CH:13][CH2:14]3)[CH2:17][CH2:18]1)[CH3:35])[C:24]([OH:27])([CH3:25])[CH3:26]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1.87 g (0.0027 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, 70 mL of methanol and 0.30 g of p-toluenesulfonic acid monohydrate was stirred at 25° C. for 4 hr. The mixture was quenched by adding 1.0 g of sodium bicarbonate and stirring for 0.5 hr. The mixture was then evaporated to dryness. The residue was triturated with ethyl acetate, filtered, and evaporated to dryness. The crude solid was recrystallized from ethyl acetate to yield [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol, mp 177°-179°, [α]D21 -15° (c 0.6, MeOH).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([O:23]CC4C=CC(OC)=CC=4)=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]/[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 10.1 %

Procedure:
A stirred solution of 4-methoxybenzyl (6-R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylate (0.509 g, purity 9% E-isomer, 84% Z-isomer, 0.99 mmol) in dichloromethane (15 ml) was cooled to 2° C. Titanium tetrachloride (0.5 ml, 4.5 mmol) was added in 1 min. After 30 min the brown suspension was mixed with a chilled mixture of dichloromethane (50 ml) and a 2 M solution of hydrochloric acid in water (50 ml). The organic phase was separated and extracted with a 2 M solution of hydrochloric acid in water (3×50 ml) The aqueous phases were extracted with dichloromethane (25 ml). The combined organic phases were analyzed using HPLC: 0.036 g (6R,7R)-7-phenylacetamido-3-[(E)-1-propenyl]-ceph-3-em-4-carboxylic acid (0.10 mmol, yield 10.2%); 0.301 g (6R,7R)-7-phenylacetamido-3-[(Z)-1-propenyl]-ceph-3-em-4-carboxylic acid (0.84 mmol, yield 84.8%). The overall yield is therefore 95.0%.
Reaction SMILES: [O-]CC.[Na+].[H-].[Na+].[CH3:7][N:8]([CH3:20])[CH:9]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](=[O:13])[CH3:12].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOCC.C(OCC)(=O)C.O.C(O)(=O)C.C(O)C>[CH3:20][N:8]([CH3:7])[CH:9]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](=[O:13])[CH2:12][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC(=O)C(=CN(C)C)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)C(=CN(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of sodium ethoxide was prepared by addition of ethanol (1.6 ml) to a stirred suspension of sodium hydride (1.3 g 50% dispersion, washed with petroleum spirit 40°-60° C.) in ether (50 ml) under nitrogen. A solution of 4-dimethylamino-3-phenyl-3-buten-2-one (4.8 g) and diethyl oxalate (5.2 ml) in ether (50 ml) was added to the stirred sodium ethoxide suspension at 5° to 10° C. and the resulting clear solution was stirred for 2 hours at room temperature, then cooled and treated with glacial acetic acid (2.5 ml) and water (50 ml). Ethyl acetate was added to dissolve the solid which formed and the solvent layer was washed with water, dried, and evaporated. The solid residue was recrystallised from ethyl acetate-petroleum spirit (60°-80° C.) to give ethyl 6-dimethylamino-2,4-dioxo-5-phenyl-5-hexenoate (mp 110° C.).
Reaction SMILES: CO.Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH:21](OC)[O:22]C)=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:7][CH:6]=1>O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])/[CH:21]=[O:22])=[CH:7][CH:6]=1
Reactant: COC(OC)/C(=C/c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C/C(=C/c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Thereafter, a mixture of 1,000 ml of distilled water, 500 ml of methanol, 50 ml (59.7 g; 0.62 mole) of concentrated hydrochloric acid and 350 g (0.98 mole) of (E)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3,3-dimethoxyprop-1-ene (I) is refluxed for 4 hours, while stirring. The mixture is cooled to room temperature and 1,000 ml of water are then added, while stirring. 300 g (0.96 mole; 98% of theory) of (E)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-acrolein are isolated in the form of pale yellowish crystals of melting point 106°-109° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31]>>[OH:32][CH:29]([CH2:30][OH:31])[CH2:28][NH:27][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:22]
Reactant: NCC(O)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NCC(O)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 89 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and 3-amino-1,2-propanediol (36 mg, 0.393 mmol), was prepared N-(2,3-dihydroxypropyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 91% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.49 (br s, 1 H), 8.56 (s, 1 H), 7.39 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.13 (s, 2 H), 3.92 (m, 1 H), 3.67-3.54 (m, 4 H), 3.57 (s, 3 H).
Reaction SMILES: [C:1]([C:4]1[C:11]([OH:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH3:13])[C:7]([C:8]#[N:9])=[C:10]([I:14])[C:11]=1[OH:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C#N)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C)c(C#N)c(I)c1O
Temperature: 80 °C
Yield: 62.9 %

Procedure:
The 4-acetyl-5-hydroxy-2-methylbenzonitrile (6.7 g, 38 mmol) was dissolved in acetic acid (80 mL) and the N-iodosuccinimide (10.0 g, 46 mmol) was added. The reaction was heated to 80° C. in an oil bath and monitored by LC/MS. After heating for 4 hrs the reaction was complete. This was allowed to cool and was concentrated in vacuo to give a dark oil. The oil was taken up in ethyl acetate and washed with water, sodium bicarbonate (3×, until remained slightly basic), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile as pale yellow solid (7.2 g, 62%). LCMS calculated for C10H9INO2(M+H)+: m/z=301.9; found: 301.9.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.419 mmol), 5-methylpyridine-3-boronic acid (348 mg, 2.54 mmol), PdCl2(PPh3)2 (170 mg, 0.242 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL) at 95° C. for 22 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: C([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])(OC(C)(C)C)=O.[OH:14][C:15]([CH:17]([C:19]1[CH:32]=[CH:31][CH:30]=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:20]=1)[CH3:18])=[O:16].[ClH:33].C(OCC)(=O)C.C(OCC)C.CCCCCC>ClCCl>[NH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11].[ClH:33].[OH:16][C:15]([CH:17]([C:19]1[CH:32]=[CH:31][CH:30]=[C:21]([C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:20]=1)[CH3:18])=[O:14]
Reactant: CC(C)(C)OC(=O)NC(CO)CO
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(CO)CO
Reaction time: 2 h

Procedure:
Boc-serinol-ketoprofen (0.428 mmol) was dissolved in dichloromethane (1 ml), and 4 N hydrochloric acid/ethyl acetate (4 ml) was added thereto under ice-cooling, followed by stirring for 2 hours while gradually returning to room temperature. After confirming disappearance of Boc-serinol-ketoprofen by TLC, diethyl ether and hexane were added thereto, and the resulting precipitate was centrifuged. The thus obtained precipitate was dried under reduced pressure to give the titled compound (243.6 mg, qu.). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: O.[NH2:2][NH2:3].N1C=CC=CC=1.C[O:11][C:12](=O)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][CH2:13][C:12]([NH:2][NH2:3])=[O:11])=[CH:17][CH:18]=1
Reactant: NN
Reactant: COC(=O)COCc1ccc(OC)cc1
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(COCC(=O)NN)cc1
Yield: 79.7 %

Procedure:
Add hydrazine hydrate (2.1 mL, 42.1 mmol) and pyridine (0.3 mL, 3.8 mmol) to a solution of (4-methoxy-benzyloxy)-acetic acid methyl ester (8.05 g, 38.3 mmol) in ethanol (100 mL, absolute). Heat the reaction to reflux under N2 overnight. Concentrate; add toluene and concentrate (2 times). Purify the residue by flash chromatography on silica gel eluting with 0-40% ACN/CH2Cl2 to afford the title compound (6.42 g, 80%) as clear oil. 1H NMR (400 MHz, DMSO) δ 3.73 (s, 3H); 3.84 (s, 2H); 4.24 (bs, 2H); 4.42 (s, 2H); 6.89 (d, 2H, J=8.3 Hz); 7.27 (d, 2H, J=8.3 Hz); 9.00 (bs, 1H). MS(IS) 209 (M−).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14]Cl)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12].[SH:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CC(O)C>[NH:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[S:16][CH2:14][C:3]1[C:2]([Cl:1])=[C:7]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][N:4]=1
Reactant: CN(CCCO)c1ccnc(CCl)c1Cl
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: CN(CCCO)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Temperature: 4 °C

Procedure:
A solution of 3-[(3-chloro-2-chloromethyl-pyridin-4-yl)-methyl-amino]-propanol isolated in step a) (5.3 g) and 2-mercapto-benzimidazole (2.2 g, 14.6 mmol) in 2-propanol (150 ml) is boiled under reflux for 2 h. After cooling to 4° C. the precipitate is filtered, washed with 2-propanol and dried in vacua. The residue is dissolved in water, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from ethyl acetate to give the title compound as an off-white solid, 3.6 g (46%). M.p. 127-30° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])=[CH:9][C:8]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 61.6 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (19 mg, 0.019 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (18 mg, 0.019 mmol) and cesium carbonate (454 mg, 1.4 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-(2,4,5-trifluoro-phenyl)-quinoline (compound of example 21) (400 mg, 0.93 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (97 mg, 1.11 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (250 mg, 62%). MS: m/z=437 (M+H).
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)=O)(=[O:16])=[O:15]>C1COCC1>[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH2:22][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)(=[O:16])=[O:15]
Reactant: COc1cccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cccc(NCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 11.6 %

Procedure:
BH3.THF (15 ml, 1M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl]thiophene-3-sulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70°-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](/[N:17]=[CH:18]/[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: COc1cc(/C=N/c2ccc(C)cc2NC(=O)c2ccccc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNc2ccc(C)cc2NC(=O)c2ccccc2)cc(OC)c1OC

Procedure:
A suspension of compound (E)-N-(5-methyl-2-(3,4,5-trimethoxybenzylideneamino)phenyl)benzamide (3 mmol) in methanol was cooled with an ice bath. Sodium borohydride was added until the color turned white. Excess sodium borohydride was quenched by the addition of distilled water. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuum to obtain N-(5-methyl-2-(3,4,5-trimethoxybenzylamino)phenyl)benzamide as a solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]([C@@H:11]1[CH2:16][CH2:15][C:14](=[N:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[BH4-].[Na+].[OH-].[Na+]>O.C(OCC)(=O)C.C(#N)C.O1CCCC1>[CH2:26]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([C@@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:13][NH:12]1)=[O:10])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C([C@@H]1CCC(=NOCc2ccccc2)CN1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C([C@@H]1CC[C@@H](NOCc2ccccc2)CN1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -10 °C
Reaction time: 22 h
Yield: 81.9 %

Procedure:
Under nitrogen atmosphere, tetrahydrofuran (1.6 ml) and acetonitrile (0.4 ml) were added to (2S)-5-benzyloxyimino-piperidine-2-carboxylic acid dibenzylamide (0.214 g, 0.50 mmol), and the obtained mixture was cooled down to −10° C. Sulfuric acid (0.302 g, 3.06 mmol) was added to the mixture, and then sodium borohydride (0.0757 g, 2.00 mmol) was added. After 22 hours of stirring, ethyl acetate (10 ml) and water (5 ml) were added to the mixture, the pH of the mixture was adjusted at 11 with 30% by weight sodium hydroxide aqueous solution, and the obtained mixture was separated. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.176 g of the title compound (yield: 82%). The diastereo selectivity was (2S,5R)/(2S,5S)=87.7/12.3 (75.4% de).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:18]/[C:19](/[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[N:39]\[OH:40])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)c2ccccc2C(F)(F)F)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 3-(4′-methanesulfonyl-biphenyl-4-yl)-1-(2-methyl-pyridin-4-yl)-3-(2-trifluoromethyl-phenyl)-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=539.2 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)ccn2)CC1
Yield: 95.5 %

Procedure:
Subject a slurry of 4-(4-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 9.28 mmol) and 5% Pd/C (151 mg) in EtOAc (150 mL) to an atmosphere of hydrogen at 60 psi (Parr shaker) overnight at ambient temperature. Filter the reaction mixture through a pad of Celite® and concentrate under reduced pressure to provide the title compound as a white solid (2.6 g, 95% yield). LCMS ES+(m/z) 294 [M+H].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:19]([N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1onc(-c2cc(C(F)(F)F)ccn2)n1Cc1ccccc1
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.04 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.22 g of benzyl bromide was added, and the mixture was stirred for 3 hours. Thereafter, the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.08 g of 4-benzyl-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (5)).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])[C:6]2=O.[ClH:20]>CO>[ClH:20].[CH3:1][C:2]1[C:3]2[CH2:4][C:5]3[N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[C:17](=[O:18])[NH:19][C:6]=3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc2c1CC(n1ccnc1C(N)=O)C2=O
Agent: Cl
Solvent: CO
Product: Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12

Procedure:
The procedure is carried out as in Example 1 but starting with 2 g of 1-(4-methyl-1-oxo-2-indanyl)imidazole-2-carboxamide, a total of 60 ml of methanol and 25 ml of 12N aqueous hydrochloric acid solution. 1.45 g of 9-methyl-5H, 10H-imidazo [1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride are thus obtained which decompose without melting above 300° C. [NMR spectrum: (300 MHz; DMSO-d6 plus a few drops of CD3COOD-d4 ; δ in ppm): 2.40 (s, 3H: --CH3); 4.01 (s, 2H: --CH2-- in position 10); 7.23 (d, J=8 Hz 1H: --H8); 7.36 (t, J=8 Hz, 1H: --H7); 7.8 (d, J=8 Hz, 1H: --H6); 8.17 and 8.36 (2d, J=1 Hz, 1H each: --H of imidazole).