Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:28]1([NH:34][C:35]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35](=[O:36])[C:37]2[CH:38]=[CH:39][C:40]([C:41]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:27])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:43][CH:44]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCCC2)cc1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 215 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-piperidinylbenzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C32H29N5O2: 516.24; found: 516.07.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:3].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](OCC)=[O:21].[H-].[Na+].Cl>O.O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](=[O:21])[CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cccs1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Trifluoromethoxyacetophenone (4.1 g, 20 mM) and ethyl 2-thiophenecarboxylate (3.1 g, 20 mM) were placed in a 300 ml eggplant type flask, and 100 ml of dehydrated tetrahydrofuran was added thereto. After this mixture was stirred at room temperature, a 60% oil suspension of sodium hydride (1.1 g, 26 mM) was slowly added thereto. Thereafter, the resulting mixture was heated under reflux for 6 hours and allowed to cool to room temperature. After 100 ml of water was added to the reaction mixture under cooling with ice, the reaction mixture was adjusted to pH 1.0 with a concentrated aqueous solution of hydrochloric acid and then extracted with 100 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 6.2 g of 1-(2-thienyl)-3-(4-trifluoromethoxyphenyl)-1,3-propanedione in an almost quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH3:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH3:13]
Reactant: COCCCCN
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1c(F)cccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of 1,2-difluoro-3-nitrobenzene (5.15 g) and 4-methoxybutan-1-amine hydrochloride (5.42 g) in acetonitrile (100 ml) was added diisopropylethylamine (17 μl), and the mixture was stirred at 60° C. for 12 hr. 4-Methoxybutan-1-amine hydrochloride (1.00 g) was further added, and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with hexane-ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (7.70 g).
Reaction SMILES: C1(=O)C=CC(=O)C=C1.[Cl-].[Li+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][C@@H:23]2[O:28][C:27]3[C:29]([CH2:34][CH:35]=[CH2:36])=[C:30]([NH2:33])[CH:31]=[CH:32][C:26]=3[O:25][CH2:24]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][CH:23]2[O:28][C:27]3=[C:29]4[C:30](=[CH:31][CH:32]=[C:26]3[O:25][CH2:24]2)[NH:33][C:35]([CH3:36])=[CH:34]4)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C=CCc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C1C=CC(=O)C=C1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C)cc4c3O2)cc1
Reaction time: 0.08 h

Procedure:
Bis-acetonitrile (II) chloride (0.153 g, 0.60 mmole), 1,4-benzoquinone (0.64 g, 6.0 mmole) and lithium chloride (2.5 g, 60 mmole) were combined in 85 mL of tetrahydrofuran and the mixture stirred under argon for 5 minutes. A solution of (2R)-[8-allyl-7-amino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzene-sulfonate (2.2 g, 5.9 mmole) in 25 mL of tetrahydrofuran was added and the mixture stirred for 48 hours at room temperature. The mixture was then diluted with 300 mL of ethyl acetate and washed with 200 mL portions of 1 N aqueous HCl, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuum. Column chromatography on silica gel with methylene chloride as eluant gave 1.1 g of the (R)-enantiomer of the title compound as a gray foam. 1H-NMR (CDCl3): doublet 7.8 δ (2H); broad singlet 7.75 δ (1H); doublet 7.3 δ (2H); doublet 6.75 δ (1H); doublet 6.63 δ (1H); singlet 6.1 δ (1H); multiplet 4.5 δ (1H); multiplet 4.25 δ (3H); doublet of doublets 4.07 δ (1H); singlet 2.43 δ (3H); singlet 2.40 δ (3H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=O)[C:8]([F:23])=[CH:7][C:6]=1[Cl:24].P(Cl)(Cl)([Cl:29])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]2[Cl:29])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.98 g of N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, 1.5 ml of phosphorus oxychloride and 1.2 ml of pyridine in 10 ml of toluene is stirred at 80° C. for 3.5 hours. The mixture is then treated with 50 ml of ice-water and extracted three times with 80 ml of ethyl acetate each time. The combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and treated with 200 ml of n-hexane, and the mixture is filtered through 20 g of silica gel. The mixture is then concentrated and the product is left to crystallize out. In this manner there is obtained N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide, m.p. 183° C.;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:10]=1[NH2:11].Cl.[C:26](=N)(OC)[CH3:27].C(=O)([O-])O.[Na+]>CO>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:9]2[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:26]([CH3:27])=[N:11][C:10]=2[CH:12]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCc1ccccn1
Reactant: COC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1Cc1ccccn1
Yield: 93 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-picolyl)aminoanilin-5-yl)benzoxazole (see Working Example 79-1) (250 mg, 0.79 mmol) was added methyl acetimidate hydrochloride (100 mg, 0.87 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, after which it was filtered and concentrated to yield the title compound (250 mg, 93% yield) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22]([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 15 mL of DMF charged with (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid (8 mmol, 2.0 g), methyl iodide (15 mmol, 1.9 mL) and K2CO3 (15 mmol, 2.1 g), was stirred at ambient temperature for 16 h. The reaction mixture was poured into 50 mL of saturated NaHCO3, and the resulting solution was extracted with ether (3×50 mL). The combined organic phase was washed with 50 mL of H2O, dried with MgSO4, and the solvent removed under reduced pressure to yield the title compound as a slightly yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.26-7.38 (m, 5 H), 5.49 (br s, 1H), 5.13 (br s, 1H), 3.65 (s, 3H), 2.80-2.96 (m, 2H), 1.45 (s, 9H). MS (ESI): m/z 302 (M+Na).
Reaction SMILES: BrC1C=CC(C(=C2CCOCC2)C2C=CC(O)=CC=2)=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=O)=[CH:25][CH:24]=1.[CH3:38][C:39]1([CH3:48])[CH2:44][C:43](=O)[CH2:42][C:41]([CH3:47])([CH3:46])[O:40]1>[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[C:43]2[CH2:42][C:41]([CH3:47])([CH3:46])[O:40][C:39]([CH3:48])([CH3:38])[CH2:44]2)[C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Agent: [Zn]
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Yield: 76 %

Procedure:
Following the procedure described for compound 46, zinc powder (0.957 g, 14.6 mmole), TiCl4 (0.800 mL, 7.30 mmole), (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.512 g, 1.85 mmole) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.851 mL, 5.45 mmole), afforded 0.564 g (76%) of 53 as a white foamy solid. 1H NMR (CDCl3): δ 7.41 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.3 Hz, 2H), 4.99 (s, 1H), 2.24 (s, 2H), 2.20 (s, 2H), 1.22 (s, 6H), 1.21 (s, 6H).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-:28].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCCc2csc(C(F)(F)F)n2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (diastereomer A) in methanol with 1N sodium hydroxide solution. After the mixture has been neutralised with 1N hydrochloric acid it is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>O>[CH2:12]([NH:14][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:13]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CCN
Solvent: O
Product: CCNc1nc(Cl)ccc1C(=O)O
Yield: 62 %

Procedure:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a 70% solution of ethylamine in water is stirred at ambient temperature for 72 hours. The excess amine is then evaporated under reduced pressure and then a 10% aqueous acetic acid solution is added until the product precipitates. The beige solid is filtered off, rinsed with cold water and dried in an oven. 10.5 g of the expected product are obtained. Melting point: 158-160° C. Yield=62%.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:3]1=[O:20]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H](NC(=O)C=Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cinnamoyl chloride, and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 126°-140° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])O)[OH:10])[OH:8])[OH:6])[CH3:2].Cl.C(NC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O)C>O>[CH3:2][CH2:1][N:3]1[C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]([OH:6])[CH2:4]1
Reactant: CCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: CCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 24 h
Yield: 60 %

Procedure:
1.0 gram of N-ethylglucamine is suspended in 50 mL water and titrated to pH 5.0 with concentrated HCl (simultaneously dissolving the aminosugar). This solution is placed in a 500 mL shaker flask. To this solution is added 2.0 grams (wet weight) of washed Gluconobacter oxydans cells and the solution agitated at 100-120 rpm. After 24 hours, HPLC analysis indicates that 70% of the initial charge of N-ethylglucamine has been converted to 6-ethylamino-6-deoxy-α-L-sorbofuranose, and after 48 hours, at least 90% has been converted. After 72 hours, the supernatant is separated from the cells and sterile filtered. An aliquot (10 mL) of the supernatant is adjusted to pH 9.0 with concentrated NH4OH, chilled in an ice bath, and 100 mg NaBH4 is added. After standing in the ice bath overnight, the samples are acetylated and assayed by gas chromatography (GC)-mass spectroscopy. GC-mass spectroscopy indicates a 60% yield of N-ethyl-1-deoxynojirimycin from 6-ethylamino-6-deoxy-α-L-sorbofuranose (Chemical ionization mass spectroscopy of the acetylated product indicates that the GC peak corresponding to the reduced cyclized product has a parent peak mass of 360 (M+H), corresponding to tetra-acetylated N-ethyl-1-deoxynojirimycin).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=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.Br[C:64]1[CH:69]=[CH:68][N:67]([CH2:70][CH:71]2[CH2:73][CH2:72]2)[C:66](=[O:74])[CH:65]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:71]1([CH2:70][N:67]2[CH:68]=[CH:69][C:64]([N:13]3[CH2:14][CH2:15][CH:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:16])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)=[CH:65][C:66]2=[O:74])[CH2:72][CH2:73]1
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=c1cc(Br)ccn1CC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2CCN(c3ccn(CC4CC4)c(=O)c3)CC2)cc1
Temperature: 100 °C

Procedure:
4-Piperidin-4-ylbenzoic acid methyl ester (0.40 g, 1.81 mmol), palladium(II) acetate (0.015 g, 0.069 mmol) sodium tert-butoxide (0.34 g, 3.44 mmol) and BINAP (0.06 g, 0.096 mmol) were added to a stirred solution of intermediate D3 (0.31 g, 1.37 mmol) in toluene (10 ml). The reaction mixture was heated at 100° C. for 16 hours in a sealed tube. After cooling to room temperature the mixture was diluted with EtOAc and then filtered through diatomaceous earth, after which the solvent was evaporated in vacuo. The crude residue was treated with a mixture of DCM/methanol and then filtered off. The filtrate was evaporated to dryness in vacuo to yield crude D37 (0.48 g, 100%) that was used without further purification.
Reaction SMILES: O[N:2]=[C:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:12][C:4]1[C:3]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:2][O:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1onc(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 117.4 %

Procedure:
Ethyl 4-(hydroxyimino)-3-methyl-2-oxo-4-(pyridin-4-yl)butanoate (4.68 g, 18.7 mmol) and triethylamine (3.4 mL, 24.3 mmol) were added to 120 mL of CH2Cl2. Mesyl chloride (1.9 mL, 24.3 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with CH2Cl2 and saturated sodium bicarbonate solution was added. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was washed with brine and dried over MgSO4. The solvent was removed in vacuo to afford 5.1 g of the title compound. MS: (+) m/z 233.35 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:18][OH:19]>CO>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CON1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON1CCC(=NO)CC1

Procedure:
To a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (258 g, 2.0 mol) and triethylamine (305.2 ml, 221.9 g, 4.4 mol) in methanol (3000 ml) was added hydroxylamine hydrochloride (277.6 g, 4.0 mol), and the reaction mixture heated at reflux for 1.5 hours. The solvent was evaporated, the residue diluted with diethyl ether and the suspension filtered. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. Yield: 286.25 g of 1-methoxy-piperidin-4-one oxime as a colorless, viscous oil. This material was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:28][CH3:29])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine from Example 8 (199 mg, 0.984 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (219 mg, 1.08 mmol), HOAt (147 mg, 1.08 mmol), 4-methylmorpholine (0.238 mL, 2.16 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resulting residue was dissolved in AcOH (10 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated in vacuo and the residue was partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)propylcarbamate as a beige solid (234 mg, 64%). LCMS: RT 3.82 min [M+H]+ 370.5
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([O:13][C:12]([NH:11][C@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Temperature: 75 °C
Yield: 76 %

Procedure:
A solution of (R)-tert-butyl 6-bromo-2,3-dihydro-1H-inden-1-ylcarbamate (15.0 g, 48.07 mmol, 1.0 eq.) in a mixture of MeOH (200 ml) and DMSO (30 ml) was degassed with argon for 30 min followed by addition of palladium acetate (0.53 g, 2.40 mmol, 0.05 eq.), 1,3-bis(diphenylphosphino)propane (0.99 g, 2.40 mmol, 0.05 eq.) and TEA (20 ml, 144.21 mmol, 3.0 eq.). The reaction mixture was then sealed in an autoclave using CO pressure (80 psi) and heated at 75° C. for 16 h. The mixture was evaporated to dryness, diluted with water (150 ml) and extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4 and evaporated to give the crude product which was purified by column chromatography (silica gel; 5% ethyl acetate/hexanes) to yield the desired product as a white solid. Yield: 76% (10.6 g, 36.43 mmol).
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:25][C:24]3[C:15]([CH3:38])([CH:16]4[CH:21]([CH2:22][CH:23]=3)[CH:20]3[CH2:26][CH2:27][CH:28]([CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:30])[C:19]3([CH3:37])[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:39]([OH:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45].O1CCOCC1>CCCCCC>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:46][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:38])[C:24](=[CH:23][CH2:22][C@@H:21]3[C@@H:16]2[CH2:17][CH2:18][C@@:19]2([CH3:37])[C@H:20]3[CH2:26][CH2:27][C@@H:28]2[C@H:29]([CH3:30])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(C)C(=CCC4C3CCC3(C)C(C(C)CCCC(C)C)CCC43)C2)cc1
Reactant: OCCCCCCO
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 52 %

Procedure:
By use of the procedure described in the literature [Kosower, E. M. and Weinstein, S., J. Am. Chem. Soc., 78 (1956) 4347-4354; Davis, M., J. Chem. Soc., (1962) 178-181] cholesteryl p-toluenesulfonate and 1,6-hexanediol were condensed in boiling dioxane to give cholest-5-en-3β-yl 6-hydroxyhexyl ether in 52% yield as colorless plates (from hexane), m.p. 75.9°-81° C.