Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:23])([F:24])[F:25])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])=[O:4]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), (S)-1-aminopropan-2-ol (10.47 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to DMF (1 mL). It was stirred for 20 min before additional HATU (35.3 mg, 0.093 mmol) was added. After stirring for an additional 10 min, it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min, 20 mL/min, 220 nM, product retention 15.1 min) to provide (R/S)-2-hydroxy-N-((S)-2-hydroxypropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.041 mmol, 43.8% yield) as a mixture of diastereomers: LCMS=488.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.52-7.72 (7 H, m), 5.14 (1 H, s), 3.78-3.94 (1 H, m), 3.13-3.34 (2 H, m), 1.13 (3 H, d, J=7.47 Hz); HPLC peak RT=7.0 min (Method A).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:5]([O:4][C:3]([N:2]([CH3:1])[CH2:10][CH2:11][CH2:12][N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:19][CH2:18]1)=[O:9])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C(OCc1cc(Cl)cc(Cl)c1)N1CCNCC1
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl methyl(3-oxopropyl)carbamate (step 3) (1.528 g, 8.16 mmol) was solubilised in DCM (50 ml) and added to 3,5-dichlorobenzyl piperazine-1-carboxylate (step 2) (3.09 g, 9.82 mmol). The resulting mixture was treated with acetic acid (56 μl, 0.982 mmol) and after stirring for 1 hr at RT, sodium triacetoxyborohydride (4.16 g, 19.64 mmol) was added. The reaction mixture was stirred at RT overnight and then quenched by addition of 2M NaOH (aq.). The aqueous layer was basified to pH 14 with conc NaOH solution. The organic layer was separated and the aqueous layer was extracted with more DCM. The organic portions were combined, dried over MgSO4 (anh), filtered and evaporated under reduced pressure, yielding a yellow oil. The crude product was purified by chromatography on silica eluting with 0-10% MeOH (with ammonia) in DCM to afford the title compound;
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[N:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:11]1=[O:24].[CH3:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH:35]=[O:36]>O1CCCC1>[OH:36][CH:35]([C:18]1[S:19][C:13]2[N:12]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:11](=[O:24])[N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:27]1[N:26]([CH3:25])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3nc4ccccc4n3C)sc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
A solution of lithium diisopropylamide (3.15 mmol) in anhydrous tetrahydrofuran (5 ml) was added to a solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (500 mg) in anhydrous tetrahydrofuran (20 ml) at −78° C. After 10 minutes, 1-methylbenzimidazole-2-carboxaldehyde (600 mg) was added and the resultant solution kept at −78° C. for 1 hour. The reaction mixture was allowed to warm to ambient temperature and quenched with saturated sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate and washed with saturated sodium hydrogen carbonate and then brine, then dried over a mixture of magnesium sulfate and silica, filtered, and evaporated. Purification by HPLC over silica eluting with an isohexane:ethyl acetate gradient (4:1 to 0:1) gave the title compound (0.13 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Temperature: 60 °C
Reaction time: 60 h
Yield: 24 %

Procedure:
To a solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1 eq), 4-hydroxybenzoic acid (1.1 eq), N-methylmorpholine (3 eq) in dry DMF (0.16 M), was added PyBop (1.5 eq). The reaction mixture was heated at 60° C. with stirring for 60 h. At this time the reaction was allowed to cool to RT partitioned between EtOAc and 1N aqueous HCl. The aqueous fraction was extracted with EtOAc and the combined organics washed with saturated aqueous Na2CO3, brine, before being dried over Na2SO4, filtered and evaporated in vacuo. Purification was by flash chromatography on silica gel (4:6) EtOAc/PE) to afford the title compound (24%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[NH2:13][C:12]1[C:14]([CH3:27])=[CH:15][C:16]([C:2]2[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)=[CH:17][C:11]=1[CH3:10]
Reactant: Cn1ncc(Cl)cc1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Product: Cc1cc(-c2cnn(C)c(=O)c2)cc(C)c1N
Temperature: 60 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 5-chloro-2-methylpyridazin-3(2H)-one and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 60° C. LC (method 9): tR=0.79 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CN1CCCCC1)C2

Procedure:
The title compound was prepared (0.074 g, 69%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.12 g, 0.26 mmol) and piperidine (0.22 g, 2.6 mmol). mp 184-186° C.
Reaction SMILES: [CH3:1][SH:2].F[C:4]1[CH:18]=[CH:17][C:7]([C:8]([C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]=2[CH3:16])=[O:9])=[CH:6][CH:5]=1>C(O)C>[CH3:16][C:11]1[NH:12][C:13](=[O:15])[S:14][C:10]=1[C:8](=[O:9])[C:7]1[CH:17]=[CH:18][C:4]([S:2][CH3:1])=[CH:5][CH:6]=1
Reactant: CS
Reactant: Cc1[nH]c(=O)sc1C(=O)c1ccc(F)cc1
Solvent: CCO
Product: CSc1ccc(C(=O)c2sc(=O)[nH]c2C)cc1
Temperature: 25 °C

Procedure:
Gaseous methylmercaptan is added to a solution of 5(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone (4.7 g) in ethanol (200 ml) to saturation. The mixture is heated at 120° C. in a sealed stainless steel container for 16 hours. After cooling to ambient temperature, the mixture is evaporated to dryness. The residue is recrystallized twice from ethanol to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: OCc1ccc(Oc2ccc(F)cc2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(F)cc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-(4-fluorophenoxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[C:4]([CH3:19])[N:3]=1.C(N(CC)CC)C.[CH2:27]([NH:29][C:30]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:28]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[C:4]([CH3:19])[N:3]=[C:2]([N:33]3[CH2:32][CH2:31][C:30]([NH:29][CH2:27][CH3:28])([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34]3)[N:7]2[N:8]=1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Reactant: CCNC1(C(N)=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)CC1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
To a solution of 4-chloro-7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-1A-1e; 28 mg, 0.069 mmol) and triethylamine (14 μl, 0.10 mmol) in tetrahydrofuran (1 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1h; 13 mg, 0.076 mmol) and the mixture was stirred overnight. The mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-20-30% acetonitrile in methylene chloride as eluant afforded product I-1A-1i (20 mg, 54%): +APcI MS (M+1) 540.8; 1H NMR (400 MHz, CD2Cl2) δ 7.54 (d, J=7.9 Hz, 1H), 7.47-7.38 (m, 3H), 4.83-4.65 (br m, 2H), 4.20-4.05 (br m, 2H), 2.55 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 2.26-1.98 (m, 2H), 1.78-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[N+:27]([O-])([OH:29])=[O:28]>S(=O)(=O)(O)O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:20]([N+:27]([O-:29])=[O:28])=[CH:19][CH:18]=[CH:17][C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cccc([N+](=O)[O-])c3nc2-1

Procedure:
Japanese Kokai Patent Application No. 59-51288 provides one method of making 9-nitro-camptothecin by treating camptothecin with a slight excess of concentrated nitric acid in concentrated sulfuric acid. However, when following this procedure, a yield of about 3% to about 7% of the 9NC product which is capable for medicinal use is obtained. Further, this procedure results in unwanted byproducts such as the inactive isomer, 12-nitrocamptothecin (12NC), in a ratio of about 1 to 3 of 9NC to 12NC. The following scheme shows the reaction from the use of nitric acid and sulfuric acid. ##STR1##
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:15]([C:12]1[O:11][C:10]([CH2:9][CH2:8][NH2:7])=[N:14][N:13]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nnc(CCN)o1

Procedure:
4.00 g (15.67 mmol) tert-butyl[2-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamate and 20 ml trifluoroacetic acid are stirred in 200 ml dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:11]N(C)C)[CH:9]=O.[NH2:15][C:16]([NH2:18])=[O:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:11]=[N:15][C:16](=[O:17])[NH:18][CH:9]=1
Reactant: NC(N)=O
Reactant: CN(C)C=C(C=O)c1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: O=c1ncc(-c2ccccc2Cl)c[nH]1

Procedure:
10 g of 2-(2-chlorophenyl)-3-dimethylaminoprop-2-enal (Example 1a) and 6 g of urea are heated under reflux in 40 ml of ethanol, in the presence of 10 ml of hydrochloric acid, for 4 hours.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]OS(C)(=O)=O.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K].O>CN(C=O)C>[F:1][CH2:2][CH2:3][CH2:4][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: CS(=O)(=O)OCCCF
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCF
Temperature: 75 °C
Yield: 99.1 %

Procedure:
A solution of methanesulfonic acid 3-fluoro-propyl ester (34.5 g, 221 mmol) in 250 mL of anhydrous DMF was treated with solid potassium phthalimide (49 g, 265 mmol, 1.2 equiv) at 25° C. The resulting suspension was warmed to 70-80° C. for 2 hours. When 1H NMR showed that the reaction was complete, the reaction mixture was treated with H2O (200 mL). The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired 2-(3-fluoro-propyl)-isoindole-1,3-dione (45.4 g, 45.5 g theoretical, 99.7% yield) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Li]CCCC.[C:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][C:25]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)([OH:28])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C#N)c2)CC1
Temperature: -15 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A solution of 3-Bromobenzonitrile (0.48 g, 2.64 mmol) in THF (20 mL) was stirred under nitrogen at −78° C. To this was added dropwise a solution of 2.0M nBuLi in hexanes (1.38 mL, 2.72 mmol). The solution was allowed to warm to −15° C. over 1.5 hours. The solution was recooled to −78° C. and a solution of N-Boc-4-piperidone (0.53 g, 2.64 mmol) in THF (5 mL) was added dropwise. The reaction mixture was allowed to warm to −10° C. and stirred at this temperature for three hours. The reaction was quenched with ½ saturated ammonium chloride solution (30 mL) and stirred 15 minutes. The THF was removed by evaporation and the residue extracted with methylene chloride (3×50 mL). The organic extracts were combined, dried over sodium sulfate, evaporated to give an orange oil which was purified by flash chromatography 3:5:2 methylene chloride: heptane: ethyl acetate to give the title compound (0.30 g) as a clear oil. 1H NMR [(CDCl3]: δ 7.82 (s, 1H), 7.72 (d, 1H), 7.58 (d, 1H), 7.55-7.42 (m, 1H), 4.20-3.95 (m, 2H), 3.35-3.10 (m, 2H), 2.08-1.83 (m, 2H), 1.80-1.66 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:21])=[CH:10][CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(Oc2ccc(CBr)cc2)c1
Temperature: 0 °C

Procedure:
Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 1 to obtain 4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure as in Reference Example 189 was followed using sodium borohydride in place of the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzyl alcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide (2.75 g), was dissolved in methylene chloride (30 mL). While this solution was stirred at 0° C., triphenyl phosphine (2.17 g) was added. The mixture was stirred at 0° C. for 1 hour and at room temperature for the subsequent 30 min. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired product as a colorless oil (3.12 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:17]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:18]1>C(#N)C>[O:10]([CH2:9][CH2:8][N:17]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)/C=C/c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cnn(CCOc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
Cesium carbonate (0.490 g, 1.5 mmol) and 1-(2-bromoethoxy)benzene (0.261 g, 1.30 mmol) were added to a solution of (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room temperature. The suspension was stirred overnight at 80° C. The reaction mixture was then cooled down to room temperature and the precipitated solids were filtered off. The filtrate was concentrated and purified by silica gel column chromatography using a gradient of 0-60% of EtOAc in hexanes to provide the title compound (0.203 g, 71%) as a colorless oil. ES+(M+H)+287
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]([C:19]#N)(C)[C:15](N)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([OH:16])=[O:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C#N)(C(N)=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of 106.4 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide, 200 ml. of 40% aqueous sodium hydroxide and 400 ml. of alcohol is boiled under stirring for 20 hours. The alcohol is then distilled off and the residue is diluted with 200 ml. of water. The aqueous solution is acidified to pH=1 by adding concentrated hydrochloric acid. The separating oil is extracted with 3×500 ml of benzene. The benzene solution is evaporated after drying above sodium sulphate. Thus 96 g. (98.5%) 2-(3-phenoxy-phenyl)-propionic acid are obtained; the product is suitable for the preparation of salts without further purification.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[CH2:21]1)(=O)=O.C(#N)C>>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]3[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=3)[CH2:21]2)[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1ccc([C@@]2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Solvent: CC#N
Product: COc1ccc([C@]2(CCN3CCC(N4CCCCC4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dimethoxyphenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>C(O)C>[NH2:15][CH2:14][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=2[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CN
Yield: 82.3 %

Procedure:
A mixture of 2-methyl-7-nitro-3-phthalimidomethylbenzo[b]furan (575 mg) and hydrazine monohydrate (172 mg) in ethanol (10 ml) was refluxed for 5 hours. The reaction mixture was cooled, acidified with 1N-hydrochloric acid and filtered. The filtrate was neutralized with aqueous saturated sodium bicarbonate and the ethanol in the mixture was evaporated in vacuo. The separated solid was collected, washed with water and dried to give 3-aminomethyl-2-methyl-7-nitrobenzo[b]furan (290 mg).