Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CC(C)=O>[C:7]([CH:9]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 42.5 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL), and the mixture was stirred at 40-45° C. for 45 min. A solution (100 mL) of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1→1:1) to give the title compound as a pale-yellow oil (yield 10.41 g, 90%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl.[C:5]1([C:11]2([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>CO>[CH3:19][CH:18]([NH:3][CH2:1][CH3:2])[CH2:17][C:11]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]1
Reactant: CCN
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 5.3 g. (about 8 equivalents) of ethylamine and 10 g. of molecular sieve 3A in 100 ml. absolute methanol are added at 0° C. 5.6 ml. of 5 N methanolic hydrochloric acid (2 equivalents) and then 3 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in a small amount of absolute methanol. 0.63 g. (0.7 equivalent) of sodium cyanoborohydride is then added and the mixture is stirred at room temperature for 5 days. The mixture is worked-up in exactly the same manner as described in Example 16. The crude product is chromatographed on silica gel with methylene chloride/methanol (10:1). There is obtained α-methyl-N-ethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine as an oily product. This product is converted as usual into the hydrochloride which, after crystallization from methylene chloride/ether, has a melting point of 151°-153° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([Cl:19])[CH:10]=1)[CH2:2][CH2:3][CH3:4].C>[Br-].[Zn+2].[Br-].[Pd].CC(=O)OCC>[CH2:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[C:11]([Cl:19])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C=Cc1ccc(C(F)(F)F)c(Cl)c1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CCc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of 3-(3-chloro-4-trifluoromethyl-phenyl)-acrylic acid butyl ester (7.030 g; 22.921 mmol), zinc bromide (1.031 g; 4.584 mmol), and 10% palladium over activated charcoal (0.403 g) was placed under nitrogen before EA (150 ml) was added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 9 h. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3-(3-chloro-4-trifluoromethyl-phenyl)-propionic acid butyl ester as a yellow oil which was further dried under HV (8.430 g; 100%). LC-MS: tR=1.16 min.; [M+H]+: no ionisation.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:15]([O:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](Br)[CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:26]=[N:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Brc1cncc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(OCc2ccccc2)c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611) and 3-(benzyloxy)-5-bromopyridine, prepared as described in (U.S. Pat. No. 5,733,912) were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [C:1]1([S:21]([O-:24])(=[O:23])=[O:22])[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[C:8](S([O-])(=O)=O)[C:7]=3[C:6](=[O:20])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na+:25].[Na+].[N+:27]([C:30]1[CH:31]=C(S([O-])(=O)=O)C=[CH:34][CH:35]=1)([O-])=O.[Na+].[O-2].[Mg+2].C(N)(CC)C.Cl>S([O-])([O-])(=O)=O.[Cu+2].O>[CH:30]([NH:27][C:8]1[C:7]2[C:6](=[O:20])[C:5]3[CH:4]=[CH:3][CH:2]=[C:1]([S:21]([O-:24])(=[O:23])=[O:22])[C:14]=3[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([CH2:35][CH3:34])[CH3:31].[Na+:25]
Reactant: O=C1c2cccc(S(=O)(=O)[O-])c2C(=O)c2cccc(S(=O)(=O)[O-])c21
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Cu+2]
Agent: CCC(C)N
Agent: Cl
Solvent: O
Product: CCC(C)Nc1cccc2c1C(=O)c1cccc(S(=O)(=O)[O-])c1C2=O
Yield: 92 %

Procedure:
110 Parts sodium anthraquinone-1,5-disulphonate are heated together with 44 parts sodium m-nitrobenzene-sulphonate, 13 parts magnesium oxide, 1.3 parts copper sulphate. 5 H2O, 386 parts of water and 43.6 parts of sec. butylamine in an autoclave at 130° for 48 hours while stirring. After cooling, the reaction mixture is acidified with hydrochloric acid, the product is filtered off with suction and washed with a 2% sodium chloride solution until neutral. The moist filter cake is dissolved hot in 2700 parts of 2.5% hydrochloric acid. The solution is filtered off with suction while hot and the filtrate mixed with 50 parts sodium chloride. After cooling, the mixture is suction-filtered, the filtrate washed with a 2% sodium chloride solution until neutral, and dried. There are thus obtained 76.8 parts sodium 1-sec. -butylamino-anthraquinone-5-sulphonate containing about 92% of pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1CCCCC1)C1CCCCC1.[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[CH:17][C:16](/[CH:36]=[CH:35]/[C:34]([O:38][CH3:39])=[O:37])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ccc(Br)cc1
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a degassed solution of (S)-2-(4-bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (44.0 g, 128 mmol) in 1,4-dioxane (500 mL) in a sealed pressure vessel was sequentially added N-methyldicyclohexylamine (32.9 mL, 154 mmol), (t-Bu)3HBF4 (1.19 g, 4.10 mmol), methyl acrylate (34.8 mL, 385 mmol) and Pd2(dba)3 (1.19 g, 1.29 mmol). The reaction mixture was heated to 150° C. in a sealed pressure vessel for 4.5 h then cooled in ice bath and placed in refrigerator for 16 h. The reaction mixture was filtered through a Celite pad, the filter cake was washed with 250 mL ethyl acetate, and the combined organics were concentrated in vacuo to a yellow oil. The oil was taken up in 20% ethyl acetate in heptane, sonicated and filtered, and the filtrate was concentrated again in vacuo. The residue was dissolved in ethyl acetate and the organic solution was washed sequentially with 10% citric acid, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (ethyl acetate/heptane) or recrystallized from 20% ethyl acetate in heptane. Total recovery is 42.1 g (99% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:9]=[C:8]([C:31](OCC)=[O:32])[N:7]=1)=O)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[H][H]>C(O)C>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][C:10]1[CH:11]=[C:6]([CH2:4][OH:3])[N:7]=[C:8]([CH2:31][OH:32])[CH:9]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1cc(OCCOCCOCCOCCC(=O)OC(C)(C)C)cc(C(=O)OCC)n1
Reactant: [H][H]
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOc1cc(CO)nc(CO)c1
Yield: 63.7 %

Procedure:
To a solution of 4-(2-{2-[2-(2-tert-Butoxycarbonyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridine-2,6-dicarboxylic acid diethyl ester (1.36 g) in absolute ethanol (72 mL) was added sodium borohydride (309 mg) and calcium chloride (921 mg). After stirring for 30 mn, hydrogen evolution ceased, and reaction was quenched with water. After concentration under reduced pressure, ammonium chloride was added and the aqueous phase was extracted three times with ethyl acetate. The combined organic solutions were dried over magnesium sulfate, and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Analogix Super Flash SiO2 SF25-80 g), using gradient elution with a mixture of DCM (A) and MeOH (B) (gradient: 100% A down to 90% A: 10% B) to give 3-(2-{2-[2-(2,6-Bis-hydroxymethyl-pyridin-4-yloxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid tert-butyl ester (720 mg): LC/MS (Method A3): ES: m/z 416 (M+H)+; RT=0.52 min
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:12][C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO.O>[C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][C@@H:20]([C:18]([NH:17][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:10][CH:9]=3)[CH2:12][C:13]([OH:15])=[O:14])=[O:19])[CH2:21]2)=[O:42])[CH2:34][CH2:33]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(OCCF)cc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3ccc(OCCF)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 70 h
Yield: 100.6 %

Procedure:
96 mg (0.16 mmol) tert-butyl 4-{3-[(3R)-3-({1-[4-(2-fluoroethoxy)phenyl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 20 ml methanol. 512 mg (1.62 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 70 hours and then diluted with 20 ml water. The mixture was acidified with 1 N hydrochloric acid to pH 4 and extracted with 2×40 ml dichloromethane. Concentration of the organic phase gave 93 mg (99%) 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[4-(2-fluoroethoxy)phenyl]propanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][CH:20]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccn2C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (400 mg, 1.16 mmol) and 1-methyl-2-tributylstannanyl-1H-pyrrole (643 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (124.5 mg, 0.15 equiv) was added and the flask was closed by a septum. Dioxane (16 mL) was added and the mixture was stirred for 1 h (TLC control) at 100° C. After 1 h, 1-methyl-2-tributylstannyl-1H-pyrrole (429 mg, 1 equiv) was added and the mixture was stirred for 35 h (TLC control) at 100° C. The solvent was removed in vacuo, the residue was taken in DCM and washed with a saturated solution of NaHCO3, water and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to furnish 2-amino-5-(1-methyl-1H-pyrrol-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (50 mg, 14.5%) as a yellow oil. ESI-MS: m/z 299 [M+H]+, rt 5.78 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=O)[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3>CCOCC.C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COc1ccc2c(=O)c3ccccc3oc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc2c(c1)Oc1ccccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a suspension of lithium aluminum hydride (0.524 g, 13.8 mmole) in Et2O (30 ml) at 0° was added, dropwise, a solution of xanthone 8 (1 g, 4.42 mmole) in toluene (25 ml). The resulting mixture was stirred at room temperature for 30 min, then refluxed vigorously for 17 hrs. After cooling in an ice bath, the reaction was quenched carefully with EtOAc (1.5 ml), MeOH (1.5 ml) and finally with dilute HCl solution until the aqueous layer was acidic. The reaction mixture was partitioned between 10% EtOAc-hexanes and water. After the organic layer was separated, the aqueous layer was extracted two more times with 10% EtOAc-hexanes. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and filtered through a silica gel plus. After concentration of the filtrate, 3-methoxy-9H-xanthene 9 (0.806 g, 86%) was isolated as a slightly yellow solid: m.p. 72-74° C.; 1H NMR (CDCl3): delta 7.13-7.20 (2H, m), 6.98-7.06 (3H, m), 6.58-6.62 (2H, m), 3.97 (2H, s) and 3.79 (3H, s); 1R (CHCl3): 3000, 2935, 2836, 1625, 1596, 1520, 1480, 1455, 1438, 1275, 1227, 1150, 1119, 1092, 1031, 962 and 837 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@H:10]3[O:19][C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]3[CH2:20][CH2:21][N:22]3[C:23](=[O:32])[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]3=[O:31])=[CH:6][CH:7]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(Br)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ccc(/C=C/[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step d above (1 g), 2-methoxy-5-pyridine boronic acid (0.614 g), tetrakistriphenylphosphinepalladium (0) (0.115 g), and potassium carbonate (0.832 g) was dried under high vacuum for 10 minutes, and dry dimethylformamide (8 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluant to afford the title compound (0.62 g).
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Br-].C1(C[Zn+])CCCCC1>>[ClH:1].[CH:4]1([CH2:5][C:6]2[N:11]=[CH:10][C:9]3[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=3[CH:7]=2)[CH2:3][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Agent: Cl
Agent: [Br-]
Agent: [Zn+]CC1CCCCC1
Product: CC1(C)CNc2cc(CC3CCCCC3)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using cyclohexylmethylzinc bromide instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=245.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]([O:14][CH2:15][CH3:16])=O.C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1nc2ccccc2c(=O)o1
Reaction time: 2 h

Procedure:
To a solution of anthranilic acid (0.1 mol., 13.71 gm) in dry pyridine (100 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (4 equiv., 38.25 ml) in a dropwise manner over 15 minutes. After stirring for 2 hours, excess pyridine was removed under reduced pressure at 40° C. (bath temperature) and the residue was stirred vigorously in ice cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml), and air-dried to give 18.6 gm of crude product. The crude product was treated with active charcoal (2 gm) in ethyl acetate (150 ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc-ether gave 17.02 (89%) of the title compound, 2-ethoxy-4H-3,1-benzoxazin-4-one, as colorless crystals; m.p. 88°-90.5° C.; IR (KBr): νmax 1760 cm-1 (C=O), 1630 cm-1 (C= N); H"NMR (CDCl3); δ 1.46 ppm (t, J=7.1 Hz, 3H,)CH2CH3), 4.53 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 7.30-8.20 ppm (m, 4H, aromatic protons).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33]C2CCCCO2)=[CH:26][CH:25]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl.[N-:41]=[N+:42]=[N-].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.N1C=CC=CC=1.O>[N:8]([C@@H:9]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOC3CCCCO3)cc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCO)cc2)N=[N+]=[N-])CC1
Temperature: 23 °C
Reaction time: 9 h

Procedure:
To a stirring solution of the amide 143 (8.8 g, 16 mmol) in dioxane (20 mL) at 23° C. was added a solution of 4 M HCl in dioxane (320 mL). The mixture was stirred for 9 h and concentrated in vacuo to afford a crude, clear, viscous pale-yellow oil. A slurry of NaN3 (1.56 g, 24 mmol) in pyridine (25 mL) was then cooled to 0° C. and trifluoromethanesulfonic anhydride (4 mL, 24 mmol) was added dropwise before allowing the mixture to warm to 23° C. and stir for 3 h. A solution of the amine hydrochloride (6.4 g, 16 mmol) in H2O (11 mL) was then added followed by CuSO4.5H2O (600 mg, 2.4 mmol). The combined mixture was allowed to stir at 23° C. overnight. An aqueous saturated solution of NaHCO3 was then added and the organic layer was extracted 3×EtOAc. The combined organic extracts were washed 1×10% CuSO4, 2×1 M HCl, 1×brine, and dried over MgSO4. Solvents were removed in vacuo and the crude residue purified by flash chromatgraphy on silica gel using hexanes/ethyl actetate on a Biotage purification system yielding the azide 144 as a colorless, viscous oil (3.3 g, 53%).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])C.Cl.[CH:18]([NH:21]N)([CH3:20])[CH3:19]>>[CH3:19][CH:18]([N:21]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][CH:4]=[N:2]1)[CH3:20]
Reactant: CC(C)NN
Reactant: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: CC(C)n1ncnc1-c1ccccc1[N+](=O)[O-]

Procedure:
N-[(Dimethylamino)methylene]-2-nitrobenzamide, prepared in Example 90, and isopropylhydrazine hydrochloric acid salt were reacted as in Example 90 to give 1-(2-propyl)-5-(2-nitrophenyl)-1,2,4-triazole, which was reduced and coupled with CMI similarly to give the fumaric acid salt of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(2-propyl-1H-1,2,4-triazol-5-yl)aniline.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][O:9][CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O)=[C:6]([I:20])[C:5]([CH2:21][O:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)=[C:4]([I:33])[C:3]=1[CH2:34][O:35][CH2:36][CH2:37][NH:38]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C(OCC)C.[OH-].[Na+]>ClCCl.O>[I:1][C:2]1[C:3]([CH2:34][O:35][CH2:36][CH2:37][NH2:38])=[C:4]([I:33])[C:5]([CH2:21][O:22][CH2:23][CH2:24][NH2:25])=[C:6]([I:20])[C:7]=1[CH2:8][O:9][CH2:10][CH2:11][NH2:12]
Reactant: CC(C)(C)OC(=O)NCCOCc1c(I)c(COCCNC(=O)OC(C)(C)C)c(I)c(COCCNC(=O)OC(C)(C)C)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NCCOCc1c(I)c(COCCN)c(I)c(COCCN)c1I
Temperature: 0 °C
Reaction time: 3 h

Procedure:
24.4 g (25 mmol) of 2,4,6-triiodo-1,3,5-tris-(2-tert-butoxycarbonylaminoethoxymethyl)benzene is dissolved in 100 ml of dichloromethane, mixed at 0° C. with 100 ml of trifluoroacetic acid and stirred for 3 hours at 0° C. The batch is poured into 500 ml of diethyl ether, the solid that accumulates in this case is suctioned off and rewashed several times with diethyl ether. The residue is dissolved in 100 ml of water and 100 ml of dichloromethane while being stirred vigorously, and 32% NaOH solution is added until a pH of 10 is reached. The organic phase is separated, the aqueous phase is extracted three times with 50 ml each of dichloromethane, the combined organic phases are dried on magnesium sulfate and evaporated to the dry state.