Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](F)[C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1.[NH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15].O.O.[Sn](Cl)Cl.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:12]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:23]([OH:24])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(N)CC
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)n1c(O)nc2ncc(Cl)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
In a 30 mL scintillation vial equipped with a stir bar was added ethyl acetate (10 mL), 5-chloro-3-fluoro-2-nitropyridine (101 mg, 0.56 mmol), and 3-aminopentane (74 mL, 0.63 mmol). The reaction was stirred at room temperature until starting material was consumed (TLC 25% ethyl acetate in hexanes). To this solution was added tin(II) chloride dihydrate (560 mg, 2.5 mmol), and the mixture was stirred until the aryl nitro was completely reduced (4 h to overnight). The solution was transferred from the scintillation vial to a 5 mL microwave tube, followed by the addition of carbonyldiimidazole (>10 equiv). The reaction was heated in a microwave reactor at 150° C. for 20 min. After cooling, water was added, and the organic layer was separated, concentrated, and purified by flash chromatography over silica gel (30-40% ethyl acetate in hexanes) to give 6-chloro-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol (93 mg, 0.390 mmol, 68% yield).
Reaction SMILES: C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC(N)=CC=1)C.CO.C(Cl)Cl.[CH2:28]([O:30][C:31](=[O:59])[C@@H:32]([NH:51]C(OC(C)(C)C)=O)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[N:48][CH:49]=3)[CH:44]=[CH:43][N:42]=2)=[CH:36][CH:35]=1)[CH3:29]>C(OC(O)C)C>[C:41]1([NH:40][C:37]2[CH:36]=[CH:35][C:34]([CH2:33][C@H:32]([NH2:51])[C:31]([O:30][CH2:28][CH3:29])=[O:59])=[CH:39][CH:38]=2)[C:50]2[C:45](=[CH:46][CH:47]=[N:48][CH:49]=2)[CH:44]=[CH:43][N:42]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(C)O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nccc3ccncc23)cc1

Procedure:
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino]propanoate (638 mg, 2.07 mmol) and Intermediate 12 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl)amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-coloured solid (420 mg, 60% over two steps). δ H (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br, s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Reaction SMILES: C[Mg]I.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)C(OC)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:22]1C[CH2:25][CH2:24][CH2:23]1>CCOCC>[CH2:4]([O:11][C:12]1[C:21]([CH2:25][CH2:24][CH2:23][OH:22])=[CH:20][CH:19]=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: C[Mg]I
Solvent: CCOCC
Product: OCCCc1ccccc1OCc1ccccc1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a 0° solution of 2.2 mole of methyl magnesium iodide in 1.5 l. ether is added a solution of 200 g. (1.06 mole) of methyl 3-benzyloxybenzoate in 500 ml. ether and 500 ml. tetrahydrofuran. The reaction mixture is stirred for 3 hours and then added to 1.5 l. ice cold saturated ammonium chloride and 2 l. ether. The organic extract is dried over magnesium sulfate and evaporated to an oil. Crystallization of the crude oil in petroleum ether gives 186 g. (93%) of the title compound.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.ClC1C=C([C@@H:20]2[C@@H:25]([C:26]3C=CC(Cl)=CC=3)[N:24]([CH:33]([CH2:36]C)[CH2:34]C)[C:23](=O)[C@:22](CC(NN)=O)(C)C2)C=CC=1>C(Cl)Cl>[CH:25]([N:24]([CH:33]([CH3:36])[CH3:34])[CH2:23][CH3:22])([CH3:26])[CH3:20]
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)NN)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C
Yield: 753.8 %

Procedure:
A solution of 56 mg (0.19 mmol) of triphosgene in DCM (1 mL) was added dropwise to a solution of 62 mg (0.13 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetohydrazide (obtained as a byproduct in Example 76, Step B) and 170 μL (0.98 mmol) of diisopropylethylamine in DCM (4 mL). The resulting light yellow solution was stirred at room temperature for 18 h, then was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase preparative HPLC (Sunfire™ Prep C18 OBD 10 μm column, (Waters, Milford, Mass.) gradient elution of 40% MeCN in water to 75% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:27]([N:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[C:31]([CH3:37])=[N:30]1)[CH3:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:35][C:32]3[C:31]([CH3:37])=[N:30][N:29]([CH2:27][CH3:28])[C:33]=3[CH3:34])=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCn1nc(C)c(C=O)c1C
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Solvent: CO
Product: CCn1nc(C)c(CC2=C(O)CC(CCc3ccc(OC(C)C)c(Cl)c3)(C3CCCC3)OC2=O)c1C
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 38.1 %

Procedure:
A solution of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (379 mg; 1.0 mmol from step 1 below) and 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (152 mg; 1.1 mmol) in methanol was heated at 40° C. overnight. The reaction mixture was treated with (CH3)2NHBH3 (65 mg, 1.1 equiv), and heated at 40° C. overnight again. The reaction was partitioned between EtOAc and H2O. The EtOAc layer was dried with Na2SO4, concentrated, and purified by reverse phase HPLC using 0.1% HOAc in H2O and CH3CN. (Column: Water's Bondapak, C18, particle size: 37-55 micron column size: 47×300 mm; Flow rate: 70 ml/min; Detector: was set at 254 nm; Buffer A: 0.1% HOAc in H2O; Buffer B: 0.1% HOAc in CH3CN. The column was equilibrated in A for 20 minutes. The sample was dissolved in 5 ml of DMSO, filtered, and injected onto the column. The gradient was held at 75% A/25% for 5 minutes and then increased linearly to 55% A/45% B in 15 minutes and then continued isocratically at 45% B for another 25 minutes. The desired product eluted at 28 minutes.) The product-containing fractions were lyophilized to afford the title compound as a powder (196.2 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, 3H), 1.26 (d, m overlap, 8H), 1.35-1.63 (m, 6H), 1.75 (m, 2H), 2.02 (s, 3H), 2.10 (s, 3H), 2.21 (m, 1H), 2.39 (m, overlap, 3H), 2.61 (d, J=16.4 Hz, 1H), 3.1 (m, 2H, overlap with H2O peak), 3.81 (q, 2H), 4.56 (7 line pattern, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.11 (s, 1H). LC-MS (APCI) calcd for C29H39ClN2O4: 514.26, found (M+H+): 515.3 m/z.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH3:14])[C:12]=1[OH:13])[C:8]#[N:9].Cl>CO>[OH:13][C:12]1[C:11]([CH3:14])=[CH:10][C:7]([C:8]([NH:2][OH:3])=[NH:9])=[CH:6][C:5]=1[CH3:4]
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1O
Yield: 30.7 %

Procedure:
To dry methanol (190 mL) is carefully added K-tert.-butylate (18.68 g, 166 mmol) followed by hydroxylamine hydrochloride (9.92 g, 143 mmol). The suspension is stirred for 30 min before 3,5-dimethyl-4-hydroxybenzonitrile (7.00 g, 147 mmol) is added. The mixture is refluxed for 32 h, then the suspension is diluted by adding 2 N aq. HCl. The solution is extracted twice with DCM (100 mL). The aq. layer is basified (pH 9) by adding solid NaHCO3 and extracted five times with DCM followed by four times with EA. The combined organic layers are dried over Na2SO4 and evaporated to dryness to give 4,N-dihydroxy-3,5-dimethyl-benzamidine (7.9 g) as a colourless solid; LC-MS: tR=0.62 min, [M+1]+=181.14.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH:35]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:32]([CH3:34])[CH3:33])[C:15]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH3:31])=[CH:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)=[O:16])[C@H:10]([CH2:35][NH:40][CH:37]2[CH2:39][CH2:38]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C=O)C(C)C)cc21
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COCCCn1cc(C)c2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3CNC3CC3)C(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,4R)-3-formyl-4-({isopropyl-[1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carbonyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 10.9 mmol) in dichloroethane (100 mL), cyclopropylamine (0.85 mL, 12 mmol) and NaBH(OAc)3 (4.32 g, 15.3 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. TLC, Rf (AcOEt)=0.1. MS (LC-MS): 541.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.52 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:33]#[N:34]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:3]5[CH:2]=[CH:11][N:34]([CH2:26][C:7]6[CH:6]=[CH:5][CH:10]=[CH:9][N:8]=6)[N:33]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#N
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3ccn(Cc4ccccn4)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The residue was dissolved in 1,4-dioxane (0.50 mL) and water (0.10 mL). To the solution was added 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.018 g, 0.043 mmol, Peak 1, Example 49, Step 7), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.916 mg, 0.00129 mmol), sodium carbonate (9.14 mg, 0.0862 mmol). and the mixture was vacuumed and refilled with N2 for 3 times. The reaction was stirred at 90° C. overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=496.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][SiH2:5][CH:6](Cl)Cl.[CH:9]([Mg]Cl)=[CH2:10].[CH2:13]1COC[CH2:14]1>>[Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:6])([CH:9]=[CH2:10])[CH:13]=[CH2:14]
Reactant: C=C[Mg]Cl
Reactant: ClCCC[SiH2]C(Cl)Cl
Reactant: C1CCOC1
Product: C=C[Si](C)(C=C)CCCCl
Reaction time: 2 h
Yield: 91 %

Procedure:
The above-synthesized 3-chloropropyldichloromethylsilane (3) (9 g, 52.2 mmol) was dissolved in 50 mL of THF, to which 1.6 M vinylmagnesium chloride (98 mL, 157 mmol) was then slowly added at 0°, and the mixture was stirred for 2 hours. After the reaction, the organic layer was extracted with NH4Cl aqueous solution and ether, and washed with saturated NaCl. The washed organic layer was dried with anhydrous MgSO4 and then filtered through celite to remove MgSO4. After evaporating the solvent, and the resulting residue was purified by column chromatography (n-Hexane, Rf=0.36) to give 8.3 g (91% yield) of pure 3-chloropropylmethyldivinylsilane (4).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1C=O.[C:8](=[O:11])([O-])[O-].[Na+].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:3]1[CH:4]=[C:5]([CH:8]=[O:11])[N:1]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ncc[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(Cc2ccccc2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of imidazolecarboxaldehyde (1.0 g, 10.4 mmol) in DMF (10 mL) was added sodium carbonate (2.2 g, 20.8 mmol). The mixture was then treated with a solution of benzyl bromide (1.77 g, 10.4 mmol) in DMF (5 mL) dropwise and stirred for 1 h at 100° C. The reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried with MgSO4, filtered, and concentrated to yield a dark brown oil (1.14 g). (m/z): [M+H]+ calcd for C11H10N2O 187.21; found, 187.3. 1H NMR (d6-DMSO, 400 MHz) δ (ppm): 9.67 (s, 1H), 8.22, 8.08, 7.96, 7.90 (4 sets of singlets, total 2H), 7.30-7.24 (m, 5H), 5.49 (s, 1H), 5.25 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:42])[O:37][CH2:38][CH2:39][O:40][CH3:41].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:36](=[O:42])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: COCCOC(=O)Cl
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and 2-methoxyethyl carbonochloridate (99 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH3:4][CH:3]([CH3:5])[CH:2]([P:6](=[O:8])([OH:7])[OH:9])[NH:1][C:20](=[O:21])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C(N)P(=O)(O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
1-Amino-2-methylpropylphosphonic acid (2.7 g) described in Synthesis 370(1988) was dissolved in water (27 ml), and the solution was added with 5 N aqueous sodium hydroxide (10.5 ml) and 3-phenylpropanoyl chloride (2.6 ml) and stirred at room temperature for 16 hours. The reaction mixture was washed with diethyl ether and acidified with hydrochloric acid. The organic substances were extracted with ethyl acetate, and the extract was washed with saturated brine to obtain 2-methyl-1-(3-phenylpropanoylamino)propylphosphonic acid (554 mg, 11%).
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4]([OH:6])=O.C[N:24]([CH3:27])C=O.[C:28](Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[CH2:27]([NH:24][C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])[CH3:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Reactant: CN(C)C=O
Solvent: c1ccccc1
Product: CCNC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Reaction time: 1 h
Yield: 48 %

Procedure:
A suspension of 0.25 g. (0.78 mmole) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid in 15 ml. of dry benzene was stirred at 23° C. under argon while about 5 mg. of dimethylformamide were added thereto followed by 0.20 g. (1.57 mmole) of oxalylchloride in 5 ml. of dry benzene. After one hour of stirring, dry ethylamine was bubbled into the resulting orange solution until a bright yellow color persisted. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered and evaporated to give a crude orange solid. This material was purified by chromatography on silica gel using ethyl acetate-hexane (1:1 parts by volume) as elutant. One crystallization from ethyl acetate-hexane (1:1 parts by volume) gave 130 mg. (48% yield) of pure N-ethyl (2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenamide, m.p. 167°- 171° C.
Reaction SMILES: C([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][C:14]=2[Cl:24])[C:7]([CH:10]=O)=[CH:8][N:9]=1)CCC.N1[CH2:30][CH2:29][CH2:28][CH2:27]C1.[C:31]1([CH3:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:30][CH:29]([N:9]1[CH:8]=[C:7](/[CH:10]=[C:16](\[CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)/[C:19]([OH:21])=[O:20])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=2[Cl:24])[CH2:5]1)[CH2:28][CH3:27]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Reactant: C1CCNCC1
Reactant: Cc1ccccc1
Product: CCC(C)N1C=C(/C=C(\Cc2ccccc2)C(=O)O)N(Cc2ccc(C(=O)O)cc2Cl)C1

Procedure:
A solution of this half-acid half-ester in toluene is added to a refluxing solution of 2-n-butyl-1-(4-carboethoxy-2-chlorobenzyl)imidazole-5-aldehyde and piperidine in toluene. Twice at 1 hour intervals an additional amounts of the half-acid, half-ester is added, and the solution is then refluxed for 17 hours. Evaporation of the toluene and chromatography of the residue over silica gel using 2:3 ethyl acetate-hexane for elution gives the diester of the title product. This diester is hydrolyzed in 2:1 ethanol-water with 5 equivalents of potassium hydroxide for 18 hours and worked up in the usual manner to give the final product.
Reaction SMILES: [NH4+:1].[OH-:2].[OH-].[Na+].O[C@@H:6]1[C@@H:11](Br)[CH2:10][CH2:9][C@H:8]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:7]1>>[NH2:1][C@H:6]1[C@H:11]([OH:2])[CH2:10][CH2:9][C@H:8]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:7]1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Reactant: [NH4+]
Reactant: [OH-]
Agent: [Na+]
Product: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](N)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A 28% ammonia aqueous solution (1563 ml) was added to an aqueous solution (500 ml) of (1S,3S,4S)-3-hydroxy-4-bromo-N,N-dimethylcyclohexanecarboxamide (274.5 g), and the obtained solution was then heated to 40° C., followed by stirring the reaction solution for 8 hours. Thereafter, the reaction solution was further stirred at room temperature for 6 hours. Thereafter, 48% sodium hydroxide (67.3 ml) was added to the reaction mixture, and the obtained mixture was then concentrated to 500 ml to obtain the title compound (184.0 g, yield: 81%) in the form of an aqueous solution (572 g).
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])[CH3:30]>C(Cl)Cl>[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:7])[CH2:36][CH2:35]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a stirred solution of 1-methyl-cyclopropanecarboxylic acid (14.4 g, 0.144 mol) in 200 mL of CH2Cl2 was added (27.10 g, 0.141 mol) of EDC, (19.10 g, 0.141 g) of HOBt and Et3N (35.93 mL, 0.259 mol). After one hour at RT, was added piperidine-4-carboxylic acid ethyl ester (18.90 g, 0.120 mol). The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1:1) yielded 26.1 g (92%) of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].ClC([O-])=O.Cl[C:17]([O:19][CH3:20])=O.N1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCC>[CH2:17]([O:19][C:20]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:4][CH2:3][CH2:2][CH2:10][CH3:9]
Reactant: COC(=O)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: c1ccncc1
Agent: O=C([O-])Cl
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOc1nc2ccc(C)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 31 %

Procedure:
2-Amino-5-methylbenzoic acid (2.71 g, 17.9 mmol, 0.87 eq.) was dissolved in pyridine (24 ml) and added to the chloroformate solution prepared above. The mixture was stirred at room temperature for 1.75 hours. Methyl chloroformate (13.6 ml, 176 mmol, 8.5 eq) was added slowly, then the mixture was left to stir at ambient temperature overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (15 ml) and 10% aqueous citric acid (20 ml). The combined aqueous phases were extracted with ethyl acetate (20 ml). The organic extracts were combined and washed with water (20 ml) and brine (20 ml) then concentrated to give a solid. This was slurried in pentane (5 ml), filtered, then slurried in acetonitrile (5 ml), filtered and purified by flash chromatography on silica (1.5% diisopropylethylamine in dichloromethane) to give a white solid (2.51 g, 31%) δH (400 MHz, CDCl3) 0.87 (3H, t, J 6.8, CH2CH3), 1.24-1.45 (26H, m, 13×CH2), 1.75-1.83 (2H, m, OCH2CH2), 2.41 (3H, s, ArCH3), 4.41 (2H, t, J 6.7, OCH2), 7.30 (1H, d, J 8.3, ArH), 7.51 (1H, dd, J 8.5, 2.0, ArH), 7.90 (1H, d, J 1.1, ArH); m/z (ES+) 402 (MH+); MPt. 72-73° C.