Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH3:14])[C:9]=2[NH:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH2:13][CH3:14])[C:9]=4[NH:15][C:16]4[O:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4Nc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].CS(C)=O>O>[N:10]1[N:11]=[N:12][N:7]2[C:2]=1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Cl)nn1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc2nnnn2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.7 %

Procedure:
A mixture of 6-chloropyridazine-3-carbonitrile (291 mg, 2.12 mmol) (Szilagyi, G., et al; European J. Med. Chem. 19:111-117, 1984), sodium azide (149 mg, 2.29 mmol), and DMSO (0.9 mL) was stirred at rt for 20 min, then diluted with water (10 mL), and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine (1×10 mL), dried (Na2SO4), and the clear pink solution was passed through a silica plug (EtOAc eluent). Treatment with decolorizing charcoal, filtration, and concentration with rotary evaporation afforded the title compound as an off-white solid (243 mg, 1.69 mmol, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 8.66 (d, J=9.3 Hz, 1H), 7.81 (d, J=9.3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=1)([O-])=O>[Pd].CO>[N:12]1([CH2:11][CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cnn(CCCN2CCc3ccccc32)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(CCCN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 1-(3-(4-nitro-1H-pyrazol-1-yl)propyl)indoline (2.10 g, 7.70 mmol), Pd/C (210 mg) and MeOH (48 mL, degassed). The flask was evacuated and backfilled with H2 and the reaction mixture was stirred under H2-atmosphere at rt for 18 h. The reaction mixture was filtered over celite, washed with MeOH and the solvent was removed under reduced pressure to yield the title compound as a red oil. LC-MS conditions
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH:12][CH3:13].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[CH3:8][O:9][CH2:10][CH2:11][N:12]([CH3:13])[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A stirred solution of triethylamine (2.4 ml, 17.23 mmol) and N-(2-methoxyethyl)methylamine (1.5 g, 16.85 mmol) in DCM (20 ml) was cooled in an ice/water bath. A solution of 4-nitrobenzenesulphonyl chloride (3.2 g, 14.45 mmol) in DCM (20 ml) was added dropwise. The reaction was stirred for one hour the cooling bath was removed and the mixture stirred for further 3 hours. The reaction mixture was washed with 1M hydrochloric acid (40 ml), water (30 ml) and then brine. The volatiles were evaporated to give the title compound (3.8 g). M/z: 245.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:64][C:58]1[CH:59]=[CH:60][C:61]([F:63])=[CH:62][C:57]=1[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 55 %

Procedure:
DIPEA (186 mg, 1.44 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (119 mg, 0.37 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was added and the precipitate formed was collected to afford the residue. The residue was purified by preparative HPLC to afford 80 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457.14, 96.27%. 1H NMR (300 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.14 (s, 1H), 8.1 (t, 2H), 7.8 (d, 2H), 7.6-7.4 (m, 4H), 7.32 (d, 1H), 6.9 (t, 1H), 4.9 (bs, 1H), 4.2 (d, 2H), 3.8 (b, 2H), 3.55 (b, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=C.C=CC1C=CC=CC=1.C(C1C=CC=CC=1[C:23]([OH:25])=[O:24])=C>C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1)=[CH2:1]
Reactant: C=Cc1ccccc1C(=O)O
Reactant: C=Cc1ccccc1
Agent: C=C
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Product: C=Cc1ccc(C(=O)O)cc1
Reaction time: 0.08 h
Yield: 3062.6 %

Procedure:
40 g of an ethylene styrene interpolymer (35 wt percent Copolymer Styrene, 6.0 wt percent a tactic Polystyrene, ESI-2) was added to a Brabender mixer at 190° C. To the polymer melt, 1.2 g (8 mmol) of powdered vinylbenzoic acid was added. Finally, 107 μL of dodecylbenzenesulfonic acid was added and the molten mixture blended at 80 rpm for 5 minutes. After the allotted time, the Brabender was opened and the tan polymer melt was removed to yield 36.3 g of product. A 300 mg portion of the polymer was pressed between teflon sheets into a thin, clear, and creasable film at 210 C with 20,000 lbs of load. Analysis of the film by infrared spectroscopy showed a broad peak at 3500 to 3000 cm−1 due to the carboxylic acid group and a carbonyl stretch at 1695 cm−1. Dissolution of the polymer in warm xylene (15 mL/g of polymer) followed by precipitation into methanol did not change the IR spectrum of the product indicating that the vinylbenzoic acid was indeed grafted to the ethylene styrene copolymer and that the product was not simply a physical mixture of the two components.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (448 mg, 1.24 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (444 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na].[CH3:10][O:11][CH2:12][C:13]([C:16]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:18][O:17]1)([CH3:15])[CH3:14]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([OH:17])([C:13]([CH3:15])([CH3:14])[CH2:12][O:11][CH3:10])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COCC(C)(C)C1(Cn2cncn2)CO1
Agent: [Na]
Solvent: CCO
Product: COCC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.5 %

Procedure:
8.1 g (0.0633 mol) of 4-chlorophenol were added to a solution of 0.32 g (0.014 mol) of sodium in 100 ml of absolute ethanol. 10.3 g (0.0488 mol) of 2-(methoxy-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane, dissolve in 300 ml of absolute ethanol, were added, and the reaction mixture was heated under reflux for 48 hours. The reaction mixture was allowed to cool and was concentrated. The residue was taken up in ethyl acetate, and the solution was washed once with water, once with 1N sodium hydroxide solution, again with water, thereafter with 1N hydrochloric acid and 1N sodium hydroxide solution, again with water, and finally with saturated sodium chloride solution. The organic phase was dried over sodium sulphate, and concentrated. 10.7 g (64.6% of theory) of 2-(4-chlorophenoxymethyl)-3,3-dimethyl-4-methoxy-1-(1,2,4-triazol-1-yl)-butan-2-ol of refractive index nD20 =1.531 were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].O.Cl>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:5]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1

Procedure:
To a solution of ethyl 3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionate (6.00 g, 13.1 mmol) in THF (60 mL) and ethanol (30 mL) were added 5 M aqueous sodium hydroxide (3.14 mL, 15.7 mmol) and water (30 mL) and the resulting solution was refluxed for 1 hour. The reaction solution was cooled with ice. To the reaction solution were added 5 M hydrochloric acid (4.0 mL, 20.0 mmol) and water (100 mL). The obtained solid was collected by filtration, and recrystallized from water-containing acetone, to thereby yield 5.60 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C([O-])(O)=O.[Na+]>C(#N)C>[Br:16][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: Nc1ncccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Temperature: 23 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 3-fluoro-pyridin-2-ylamine (example C.29 step 2) (3 g, 26.8 mmol) in acetonitrile (50 mL) at 0° C. was added NBS (4.77 g, 26.8 mmol) and the mixture was stirred at 23° C. for 2 h. Poured on ice with sat. NaHCO3-sol., extracted thrice with AcOEt, dried over Na2SO4. Removal of the solvent in vacuum left a residue, which was purified by silica gel column chromatography with heptane/AcOEt 3:1 to give the title compound as a brown solid (3.1 g, 60%). MS (ISP) 191 [(M+H)+], 193 [(M+2+H)+].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:20]
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)O)c1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)NC2CCOCC2)c1
Yield: 87 %

Procedure:
As described for example 7b, 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) was converted (using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 276 mg, 87%) which was obtained as a white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:17]=4)[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(OCC)C.C(=O)(O)[O-].[Na+]>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:16]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][C:17]4=[O:47])[C:11]1([CH3:38])[CH3:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)[C@@H]2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of 3β-benzoyloxy-4,4-dimethyl-5α-cholest-8,14-diene (5.0 g, 10.2 mmol) in diethyl ether solution (300 mL) and 0.5 M aqueous sodium bicarbonate (300 mL) was added meta-chloro-perbenzoic acid (2.44 g, 11.3 mmol) (Aldrich). After 30 min, the ether fraction was separated from the sodium bicarbonate layer and the aqueous fraction was repeatedly extracted with diethyl ether (5×500 mL). The organic fractions were combined, washed with brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to about 150 ml. This ether solution of 38a was promptly cooled (0°) and treated dropwise with boron trifluoride etherate (26 mL, 22.5 mmol (Aldrich). After 30 min, the reaction was quenched with ice water (200 mL) and the aqueous phase was reextracted with ether (3×100 mL). The combined ether fractions were extracted with saturated sodium bicarbonate solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from isopropanol (75 mL) to afford 4.10 g of 3β-benzoyloxy-4,4-dimethyl-5α,14β-cholest-8-en-15-one (Compound 40a) in 75% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:27][CH:26]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccccc3F)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 25 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2-fluorobenzyl)-1-piperidinecarboxamide (0.50 g, 1.2 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.436 g, 1.08 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.21 g, 0.27 mmol).
Reaction SMILES: Cl.C[O:3][C:4]1[S:5][C:6]2[C:12]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][CH2:18][S:19][CH2:20][C:21](=[O:31])[NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:10]=[C:9]([O:33][CH3:34])[C:7]=2[N:8]=1>CO>[CH3:34][O:33][C:9]1[C:7]2[NH:8][C:4](=[O:3])[S:5][C:6]=2[C:12]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][CH2:18][S:19][CH2:20][C:21](=[O:31])[NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=1
Reactant: COc1nc2c(OC)ccc(CCNC(=O)CCSCC(=O)NCCc3ccccc3)c2s1
Agent: Cl
Solvent: CO
Product: COc1ccc(CCNC(=O)CCSCC(=O)NCCc2ccccc2)c2sc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Conc. hydrochloric acid (sg. 1.18, 1.5 ml) was added to the compound from step b) (3.3 g) in methanol (30 ml) and the mixture stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between chloroform and water. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic extracts were dried (MgSO4) and the solvents removed under reduced pressure to give the subtitled compound as an orange oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[C:8]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][C:22]3=[O:31])[CH2:17][CH2:16]2)[CH:7]=[C:6]([CH:32]2[CH2:34][CH2:33]2)[C:5]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[F:42]>C(O)C>[Cl:3][C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[C:8]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:22]3=[O:31])[CH2:19][CH2:20]2)[CH:7]=[C:6]([CH:32]2[CH2:33][CH2:34]2)[C:5]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[F:42]
Reactant: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(Cl)c3OC(C)C)CC2)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1c(CN2CCC(n3ccc(C(=O)O)cc3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Reaction time: 4 h
Yield: 27.3 %

Procedure:
A 2 M aqueous sodium hydroxide solution (2 mL) was added to an ethanol (8 mL) solution of methyl 1-(1-((2-chloro-6-cyclopropyl-2′,4′-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (590 mg), and the mixture was stirred at 80 C for 4 hours in a nitrogen atmosphere. The reaction mixture was concentrated to dryness under reduced pressure. The obtained residue was dissolved in water, and the solution was neutralized with 2 M hydrochloric acid. The resulting solid was collected by filtration and recrystallized (DMSO/ethanol) to obtain the title compound (157 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10]O)[CH:5]=[C:6]([I:8])[CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.O>[N:32]([CH2:10][C@@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([F:1])[CH:3]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(I)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1cc(F)cc(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(S)-tert-butyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate (4.8112 g, 12.62 mmol) was dissolved in DCM (100 mL) and cooled to 0° C. Et3N (2.62 mL, 18.93 mmol) was added next and then MsCl (1.180 mL, 15.15 mmol) was added dropwise. The reaction mixture was agitated at same temperature for 30 min after which RM quenched with Sat′d NaHCO3 and water. The product was extracted with DCM and the combined organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to afford the crude product which was dissolved in DMF (25 mL, ca 0.5 M). NaN3 (2.462 g, 37.9 mmol) was added next and the mixture heated at 70° C. After 6 h, the reaction mixture was cooled to room temperature and diluted with EtOAc and water and the product extracted with EtOAc. The combined organic extract was washed with water thrice and dried (magnesium sulfate), filtered and concentrated in vacuo and the residue purified by flash chromatography (0-50%) EtOAc/heptane to afford 4.03 g of (S)-tert-butyl (2-azido-1-(3-fluoro-5-iodophenyl)ethyl)carbamate as desired product. LCMS (m/z): 351.0 (MH+-56), 1.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
First, 50 g (0.29 mol) of 2-chloro-4-fluorobenzoic acid was dissolved in 150 ml of hydrochloric acid at room temperature, to which a mixed acid of 28 ml (0.31 mol) of fuming nitric acid and 56 ml of concentrated sulfuric acid was added dropwise at 35° to 45° C. Then, the solution was stirred at 40° C. for 1 hour and poured into 250 ml of ice-water. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of hexane and ethyl acetate, which afforded 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid. Then, 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid was dissolved in 50 ml of ethyl acetate, to which 33 g (0.28 mol) of thionyl chloride was added, and the mixture was heated under reflux for 3 hours and then allowed to stand for cooling to room temperature. Then, 20 ml of ethanol and 30 g of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded 57 g (0.23 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate. ##STR64##
Reaction SMILES: [CH2:1]([C@H:8]([C@H:12]([OH:16])[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.[Cu](Cl)Cl>[CH3:20][C:19]1([CH3:21])[O:16][C@@H:12]([C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([OH:11])=[O:10])[C:13](=[O:15])[O:14]1
Reactant: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@H]([C@@H](Cc2ccccc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of (2R,3S)-2-benzyl-3-hydroxysuccinic acid (1.70 g; 7.58 mmol; 1.0 eq.) in acetone (50.0 mL) was added 2,2-dimethoxypropane (1.86 g; 15.2 mmol; 2.0 eq.) and copper(II) chloride (102 mg; 0.76 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 2 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product as a greenish oil (1.46 g) used in the next step without further purification.