Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]#[N:12])[CH2:8]2.C([N-]C(C)C)(C)C.[Li+].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[C:11]([C:2]1([C:22]([O:24][CH3:25])=[O:23])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)#[N:12]
Reactant: N#CC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C#N)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of adamantane-2-carbonitrile (1.17 g, 7.23 mmol) in anhydrous tetrahydrofuran (75 mL) was added lithium diisopropylamide (2.0 M solution in tetrahydrofuran, ethylbenzene and heptanes, 5.4 mL, 11.00 mmol)-78° C. The reaction mixture was stirred under a nitrogen atmosphere for 30 minutes, and then methyl chloroformate (0.83 mL, 11.00 mmol) was added. After 1.5 hour, the reaction was warmed to ambient temperature and quenched by addition of 1 M hydrochloric acid (150 mL). The mixture was diluted with ethyl acetate (200 mL), washed with 1 M hydrochloric acid (150 mL), brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound as a colorless oil (0.95 g, 60%): 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 2.51 (br s, 2H), 2.23-2.18 (m, 2H), 1.93-1.91 (m, 1H), 1.85-1.71 (m, 9H); MS (ES−) m/z 220.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9].[H-].[Na+].Cl.Cl[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>CN(C)C=O>[NH:24]1[CH:25]=[C:21]([CH2:20][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]#[N:9])[N:22]=[CH:23]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccccc1)c1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccccn1
Reaction time: 1 h

Procedure:
A 19.42 g. portion of 2-(2-pyridyl)-2-phenylacetonitrile was stirred with 4.8 g. of 50% sodium hydride in 50 ml. of dimethylformamide, and reacted with 7.65 g. of 4-chloromethylimidazole hydrochloride in 25 ml. of dimethylformamide as described in Example 1. The mixture was stirred at 80°-90° C. for 1 hour, the solvent was removed by evaporation under vacuum, and wthe residue was worked up as described in Example 1 to obtain 11.87 g. of the free base named in the heading above, m.p. 111°-115° C. dec. The product was triturated twice with portions of diethyl ether, and was dissolved in chloroform. The solution was extracted with water and dried over sodium sulfate. Evaporation of the solvent under vacuum gave 11.84 g. of purified free base, m.p. 111°-115° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[NH:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.C([O:30][CH:31]=[CH:32][C:33](OCC)=O)C>FC(F)(F)C(O)=O>[CH2:19]([C:18]1[N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[C:6]([OH:5])=[O:7])=[CH:15][CH:14]=2)[C:31](=[O:30])[CH:32]=[CH:33][N:23]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCOC=CC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nccc(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound is prepared form N-(2'-t-butoxycarbonylbiphen-4-yl)methylvaleramidine and ethyl 3-ethoxyacrylate (Aldrich) similarly to that in Example 10. The t-butyl ester is hydrolyzed in neat trifluoroacetic acid to give the title compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.[CH2:21]([O:23][C:24](=[O:32])[CH:25](Cl)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH3:22]>O>[CH2:21]([O:23][C:24]([CH:25]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:9]([F:19])([F:20])[F:8])=[CH:11][CH:12]=1)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:32])[CH3:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OC(=O)c1ccc(C(F)(F)F)cc1)C(=O)C(C)C
Temperature: 90 °C

Procedure:
Sodium Hydride, 60% mineral oil (1.9 g, 46.3 mmol) and dimethylformamide (50 mL) are stirred at room tmperature and 4-(trifluoromethyl)benzoic acid (8.0 g, 42.1 mmol) is added. To the resulting slurry is added 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (8.5 g, 44.2 mmol) and the resulting mixture is heated to 90° C. for 3 hr. The reaction mixture is cooled, diluted with water (100 mL), and product is extracted with ethyl acetate (100 mL). The organic layer is washed with water (three 100 mL portions) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to constant weight to give 4-trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butyl ester as a colorless oil, 14.6 g, 100%. The resulting oil is stirred in a mixture of acetic acid (100 mL) and ammonium acetate (9.75 g, 126.5 mmol) at reflux 1 hr, then 20 hr at room temperature. The solvent is removed in vacuo and the residue is partioned between aqueous saturated sodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL. The layers are separated, the aqueous layer is washed with ethyl acetate (100 mL). The organic extracts are combined, washed with water and brine (100 mL each) dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is purified over silica eluting with 9:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester as a white solid, 8.1 g, 60%. MS (M++1) 328.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].C(N[C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23]OC(=O)C)[O:11][C@H:10]1[N:28]=[N+:29]=[N-:30])(=O)C>CN(C)C=O>[C:16]([O:18][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH3:23])[O:11][C@H:10]1[N:28]=[N+:29]=[N-:30])(=[O:15])[CH3:17]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N=[N+]=[N-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])O[C@H](C)[C@@H]1OC(C)=O
Temperature: 50 °C

Procedure:
A solution of diphenyl(2,3,4-tri-O-acetyl-α-D-fucopyranosyl)-phosphate (2.0 g) in anhydrous dimethylformamide (80 mL) containing sodium azide (2.0 g) was heated to 50° C. for 2 h and processed as described in the synthesis of Compound 5, part c (Experiment 4). The product was purified by chromatography on a column of silica gel using ethyl acetate--hexane (3:8) as eluant to obtain the title compound (1.13 g).
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:5](=[O:8])[CH2:6][NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1N(C(=O)CBr)C(C)C
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(C(=O)CNc1ccccc1Nc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-Isopropyl-N-(2-methoxy-phenyl) bromoacetamide, prepared as in Part B, (10.0 g 34.9 mmol), N-phenyl phenylenediamine (6.41 g, 34.9 mmol) and potassium carbonate (4.82 g) in DMF (100 mL) is stirred at RT for 48 h. The reaction mixture is filtered through celite and the filtrate concentrated in vacuo. Purification by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent gave N-Isopropyl-N-(2-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamideas a light brown foam (4.50 g): 1H NMR (300 MHz, CDCl3) δ7.46 (t, 1H, J=7.9), 7.030-7.05 (m, 8H), 6.98 (t, 1H, J=6.8), 6.84 (m, 2H), 6.70 (t, 1H, J=7.6), 6.37 (d, 1H, J=8.0), 5.4 (s, br, 1H), 4.95 (m, 1H, J=6.8), 3.84 (s, 3H), 3.45 (dd, 2H, J=23.2, 6.6), 1.20 (d, 3H, J=6.8), 1.01 (d, 3H, J=6.8).
Reaction SMILES: C(O)(=O)C.C(O[C:8]1(O[Si](C)(C)C)[CH2:10][CH2:9]1)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[N:27][N:26]3[C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[N:40][CH:39]=2)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO.O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:32][CH2:33][N:34]([CH:8]5[CH2:10][CH2:9]5)[CH2:35][CH2:36]4)=[N:27][N:26]3[C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[N:40][CH:39]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(-c2nc3ccc(N4CCNCC4)nn3c2-c2ccnnc2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc3ccc(N4CCN(C5CC5)CC4)nn3c2-c2ccnnc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
0.15 ml of acetic acid and 0.32 ml (1.6 mmol) of (1-ethoxycyclopropoxy)trimethylsilane are added, in a reactor, to 0.10 g (0.27 mmol) of 2-(4-fluorophenyl)-6-(piperazin-1-yl)-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine in 3 ml of methanol. 1.2 ml (1.2 mmol) of a molar solution of sodium cyanoborohydride in tetrahydrofuran are then added. After stirring for 15 minutes, the mixture is heated at 50° C. for 2 hours. After cooling, the product is extracted with dichloromethane, and the organic phase is filtered over a hydrophobic cartridge and then concentrated under reduced pressure. The residue is chromatographed on a silica gel column, to give 0.064 g of product. The latter is crystallized from diisopropyl ether, to give 0.053 g of light yellow crystals after drying.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH:10]([OH:20])[CH2:11][C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1.[H][H]>C(O)C.CO.[Pt]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1
Reactant: [H][H]
Reactant: OC(CC#Cc1cccnc1)CC#Cc1cccnc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CO
Product: OC(CCCc1cccnc1)CCCc1cccnc1
Yield: 98.9 %

Procedure:
A suspension of platinum oxide (280 mg) in absolute ethanol (1 mL) was diluted with absolute methanol (10 mL) followed by the addition of compound 1 (2.81 g, 10.73 mmol). The suspension was placed under 40 psi of hydrogen gas. After hydrogen consumption ceased, the hydrogen was replaced with nitrogen and the reaction was filtered and concentrated to provide 2.87 g of compound 2 as a viscous oil.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc2c(c1)CNCCN2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCNc2ccccc2C1
Temperature: 0 °C
Yield: 83 %

Procedure:
2,3,4,5-Tetrahydro-1H benzo[e][1,4]diazepine (5 g, 33.7 mmol) was dissolved in THF (168.5 mL and cooled to 0° C. with an ice bath. Hunig's base (8.81 mL, 50.6 mmol) and benzyl chloroformate (5.30 mL, 37.1 mmol) was added dropwise with stirring. After 7 hours stirring, THF was removed, and water and ethyl ether were added to the flask. The reaction mixture was extracted with diethyl ether (4×), and the combined organic extracts were washed with aqueous sodium bicarbonate (1×) and brine (1×). The organic extracts were then dried with magnesium sulfate, filtered and concentrated to give a yellow oil. Further purification (25:75 ethyl acetate/hexane, then 30:70 ethyl acetate/hexane) yielded 7.9 g of desired product (83%).
Reaction SMILES: ClC1N=[C:4]([NH:18][C:19]2[C:24]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]([Cl:31])=[CH:21][N:20]=2)[C:5](=[O:17])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:31][C:22]1[CH:21]=[N:20][C:19]2[NH:18][C:4]3[C:5](=[O:17])[N:6]([CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)[CH:7]=[C:26]([Si:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=3[C:24]=2[CH:23]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(Cl)cc3C#C[Si](C)(C)C)c2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(Cl)cc43)c2=O)cc1
Yield: 86.8 %

Procedure:
Compound 66 (5.8 g, 12.3 mmol) and DIEA (3.2 mL, 18.4 mmol) were dissolved in toluene (600 mL), and the solution was heated at reflux under N2 for four days. The solution was concentrated and purified by flash chromatography (30% EtOAc/CH2Cl2) to give 4.4 g (87%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 8.54 (d, 1H, J=2.4 Hz), 8.20 (d, 1H, J=2.4 Hz), 7.37 (s, 1H), 7.32 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.8 Hz), 5.25 (s, 2H), 3.71 (s, 3H), 0.39 (s, 9H). MS (ES) [m+H] calc'd for C21H22ClN3O2Si, 412, 414; found 412, 414.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[N:14]([CH:21]3[CH2:23][CH2:22]3)[C:13]2=[O:24])[CH2:9]1)(C)(C)C.[ClH:26].O1CCOCC1>CO>[ClH:26].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[N:14]([CH:21]3[CH2:22][CH2:23]3)[C:13]2=[O:24])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a round bottomed flask was added tert-butyl(trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)carbamate (1.905 g, 5.52 mmol) and hydrogen chloride, 4.0M solution in 1,4-dioxane (1.915 ml, 55.2 mmol) to stir at room temperature. The reaction was monitored by TLC until completion (10% MeOH/90% DCM). The reaction mixture was filtered and solids were washed with diethyl ether and dried in a vacuum oven to give the title compound (1.0201 g, 3.62 mmol, 65.6% yield). LCMS showed product peak at 0.997 min (m+1=246.1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.06 (m, 4 H) 2.52-2.60 (m, 2 H) 2.90-2.99 (m, 1 H) 3.16 (ddd, J=14.52, 8.66, 7.34 Hz, 2 H) 3.96-4.08 (m, 1 H) 5.21-5.33 (m, 1 H) 7.92-8.01 (m, 2 H) 8.34 (br. s., 3 H).
Reaction SMILES: [Mg].CI.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: C[Si](C)(C)Oc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
5.35 g (0.22 mole) magnesium was added to 10 ml tetrahydrofuran and 0.35 ml CH3I under N2 and heated to initiate the Grignard reaction. A solution of 49.0 g (0.2 mole) p-bromophenyoxytrimethylsilane and 63 ml tetrahydrofuran was added over a 11/2 hour period. The reaction mixture was refluxed one additional hour and then cooled to room temperature. 22.8 g (0.21 mole) chlorotrimethylsilane was added to the reaction mixture. Once again the mixture was refluxed 1 hour and then cooled. 100 ml distilled water was slowly added, stirred, and separated. The organic phase was washed with two 50 ml portions of water and finally 50 ml of brine. The organic solution was dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator under reduced pressure. Vacuum distillation gave 28.7 g of p-trimethylsilylphenoxytrimethylsilane, bp 132 degrees Celsius at 27 mm Hg.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N=C=N>>[CH:22]1([N:21]=[C:20]([NH:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH3:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CNCCC[Si](OC)(OC)OC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C=N
Product: CO[Si](CCCN(C)C(=NC1CCCCC1)NC1CCCCC1)(OC)OC
Reaction time: 2 h

Procedure:
A mixture of 23.23 g of N-methyl-(3-(trimethoxysilyl)propyl)amine (0.12 mol, 20% excess) and of 20.65 g of dicyclohexylcarbodiimide (0.1 mol) was heated for 6 h at 100° C. (carbodiimide conversion of 94%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 41.3 g of a colorless, moderately viscous liquid corresponding to the expected guanidine, containing 6% of the initial amine.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[N:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3cccnc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
The mixture of 2-[(quinoline-8-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (47) (190 mg, 0.53 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give the pure product (48) as white solid (152 mg, 86%).
Reaction SMILES: O.[OH-].[Li+].[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][C:15]=2[CH3:25])=[CH:10][CH:9]=1.C(O)C.Cl>O.O1CCOCC1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:15]=2[CH3:25])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCO)cc2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Lithium hydroxide monohydrate (0.19 g) was added to a mixture of ethyl 4′-(2-hydroxyethoxy)-2-methylbiphenyl-4-carboxylate (0.136 g), ethanol (2 mL), 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (2.3 mL). The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=2/1-4/1) to afford the title compound (0.066 g).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[Br-].[C:11]([C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13]C)=[O:12].[CH3:41][C:42]1[CH:43]=[C:44]([CH:56]=[CH:57][CH:58]=1)[CH:45]=[CH:46]C1C(C(O)=O)=CC=CC=1>C(#N)C>[CH2:9]([C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[CH:7]=[O:8])[CH3:11].[CH2:45]([C:44]1[CH:43]=[C:42]([CH:58]=[CH:57][CH:56]=1)[CH:41]=[CH:17][C:16]1[C:15]([C:11]([OH:13])=[O:12])=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:46]
Reactant: Cc1cccc(C=Cc2ccccc2C(=O)O)c1
Reactant: COC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C=O)c1
Agent: [Br-]
Solvent: CC#N
Product: CCc1cccc(C=Cc2ccccc2C(=O)O)c1
Product: CCc1cccc(C=O)c1

Procedure:
116.5 Gm. of 1,5-diazabicyclo[3.4.0]nonene-5 is added to 107.5 gm. of m-tolualdehyde and 400 gm. of o-carbomethoxybenzyltriphenylphosphonium bromide in 2000 ml. of acetonitrile. The mixture is refluxed briefly then cooled and the solvent removed under vacuum. The residue is dissolved in chloroform and washed with dilute hydrochloric acid, and the solution dried and evaporated. The product is refluxed for 11 hours in a solution of 111 gm. potassium hydroxide in 1,000 ml. of water and 150 ml. of methanol. The solution is cooled and extracted with chloroform. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with chloroform. The extract is dried and evaporated to give 177.5 gm. (91%) of 3'-methylstilbene-2-carboxylic acid (ca. 60:40 cis:trans). Use of m-ethylbenzaldehyde instead of m-tolualdehyde gives a similar yield of 3'-ethylstilbene-2-carboxylic acid.
Reaction SMILES: [N:1](CCOCCON)=[N+:2]=[N-:3].[OH:11][C:12]([CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]1[C@@H:26]2[C@@H:21]([NH:22][C:23]([NH:25]2)=[O:24])[CH2:20][S:19]1)=[O:13].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]([CH:14]([CH2:15][CH2:16][CH2:17][C@H:18]1[C@@H:26]2[C@@H:21]([NH:22][C:23]([NH:25]2)=[O:24])[CH2:20][S:19]1)[C:12](=[O:11])[OH:13])=[N+:2]=[N-:3]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: [N-]=[N+]=NCCOCCON
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of O-(2-(2-azidoethoxy)ethyl)hydroxylamine (10 mg, 0.068 mmol), biotin (225 mg, 0.103 mmol) and DIPEA (29 mg, 0.206 mmol) in 0.8 mL of DMF was added PyBOP (54 mg, 0.103 mmol). The reaction was allowed to stir at room temperature for 2 h. Solvent was then removed in vacuo, and the crude product was purified by silica gel column chromatography (ethyl acetate: methanol 4:1) to afford azido-biotin (22 mg, 0.059 mmol, 88%) as a pale yellow solid. 1H NMR (CD3OD, 500 MHz) δ (ppm): 1.35 (m, 1H), 1.43 (m, 2H), 1.68 (stack, 4H), 2.11 (t, J=7.3 Hz, 2H), 2.70 (d, J=12.8 Hz, 1H), 2.92 (dd, J=5.0, 12.8 Hz, 1H), 3.20 (m, 1H), 3.43 (m, 2H), 3.67 (m, 2H), 3.72 (m, 2H), 3.98 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:5][CH2:4]1.[H-].[Na+].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>C1COCC1>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH2:2][C:3]1([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])[CH2:4][CH2:5]1
Reactant: N#Cc1c(N)cccc1F
Reactant: CCCNC(=O)C1(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)C1(COc2cccc(N)c2C#N)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of 1-(hydroxymethyl)-N-propylcyclopropanecarboxamide (Example 198c) (0.67 g, 4.25 mmol) in anhydrous THF (10 mL) was treated with NaH (0.17 g, 4.25 mmol, 60% suspension in mineral oil) at 0° C., under a nitrogen atmosphere. The obtained mixture was stirred at 0° C. for 10 min and at rt over 30 min. Then, a solution of 2-amino-6-fluorobenzonitrile (0.53 g, 3.86 mmol) in THF (5.0 mL) was added and the obtained mixture was heated at reflux overnight. The cold mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (3×50 mL). The combined extract was washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel using gradient hexanes→hexanes/EtOAc (4:6), to give 0.75 g (71%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.51 (t, J=6.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 5.97 (broad s, 2H), 4.13 (s, 2H), 3.04 (q, J=6.4 Hz, 2H), 1.43 (hex, J=6.8 Hz, 2H), 1.05-1.11 (m, 2H), 0.78-0.86 (m, 5H).