Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[C:25]([N:27]=[O:28])[CH:24]=[C:23]([CH3:29])[C:22]=1[OH:30]>ClCCl>[OH:28][N:27]([C:25]1[CH:24]=[C:23]([CH3:29])[C:22]([OH:30])=[C:21]([CH3:20])[CH:26]=1)[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(N=O)cc(C)c1O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(N(O)C(=O)c2ccccc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 2,6-dimethyl-4-nitrosophenol (151 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.CO.[O:21]=[O+][O-]>ClCCl>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:21])[C:17]=2[N:16]=1
Reactant: Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(=O)CCC2

Procedure:
Intermediate 200A2 in dichloromethane (100 mL)/methanol (200 mL) was cooled to −78° C. Ozone was passed through the mixture for 1-2 h until the mixture had a light blue color. The reaction mixture was purged with nitrogen followed by the addition of dimethyl sulfide (10 mL). The mixture was stirred for 30 m and evaporated. The residue was partitioned between ether and 1M HCl. The organic layer was extracted with 1N HCl (2×) and the acidic, aqueous layers were pooled, washed with ether (3×), cooled with crushed ice, and carefully basified with solid NaOH. The basic layer was extracted with chloroform, freed of solvent, and the residue was passed through a column of SiO2 with 80% ethyl acetate/hexane to give impure Intermediate 200A3 as a yellow solid. Further purification of this mixture was conducted by oxidation of the minor product: (˜3%) 8-oxo-5,6,7,8-tetrahydro-quinoline-2-carbaldehyde in formic acid (15 mL) at 0° C. by dropwise addition of H2O2 (2.1 mL, 30% solution). The mixture was stirred for 1.5 h, quenched with crushed ice, diluted with chloroform, and basified with 2 M NaOH to pH>8. The chloroform layer was dried, filtered and evaporated to give pure 2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A3), 15.1 g (˜50% over two steps).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].FC(F)(F)S(O)(=O)=O>CSC.C(Cl)Cl>[C:1]([S:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([OH:24])=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCC1(C(=O)NCC(O)C(=O)OCc2ccccc2)CCc2ccccc2C1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)SCC1(C(=O)NCC(O)C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (882 mg, 2.00 mmol) in dimethylsulfide (2 mL) and add trifluoromethane sulfonic acid (0.2 mL). Stir at ambient temperature under an atmosphere of argon for 1 hour. Dilute to a volume of 50 mL with methylene chloride and extract with brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the crude product. Purify the residue by column chromatography (acetic acid:ethyl acetate:hexane) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[C:6]=2[CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[C:6]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3ccc(Br)cc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2ncn(C3CCNC3)c2c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (crude) in DCM (9 mL) was added TFA (3 mL). After stirring for 2 h, the solution was concentrated to give the desired crude product which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C.O=[Pt]=O>[CH3:1][C:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc2ccncc2c1C
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)c1sc2c(c1C)CNCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.5 %

Procedure:
A mixture of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (4 g, 0.018 mol) and PtO2 (0.5 g, 0.002 mol) in ethanol (100 mL) was stirred under an H2 atmosphere (3 atmospheres) for 72 hours at room temperature. The PtO2 was removed by filtration, the filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel chromatography (DCM/EtOH=10:1) to afford ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (1.6 g, 40%). ES+ 226; 1H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1 Hz, 2H), 3.93 (s, 2H), 3.21 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.55 (s, 1H), 2.34 (s, 3H), 1.26 (t, J=6.0 Hz, 3H).
Reaction SMILES: ClC1C=C(C2C=C(C(N3CCNC(=O)C3)=O)O[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)C=CC=1.Br[C:30]1[CH:31]=[C:32]([C:42]([N:44]2[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]2)=[O:43])[O:33][C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1>>[Cl:41][C:37]1[CH:36]=[C:35]([C:34]2[O:33][C:32]([C:42]([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=[O:43])=[CH:31][C:30]=2[C:17]2[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:12])[CH:18]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1cccc(-c2oc(C(=O)N3CCNC(=O)C3)cc2-c2cccc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Product: Cc1cc(C)cc(-c2cc(C(=O)N3CCNC(=O)C3)oc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 18 starting with the compound from Example 27A. 15.0 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:37]3[CH2:38][CH2:39][N:34]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:35][CH2:36]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: COC(=O)CCN1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (5 mL) was added methyl 3-(piperazin-1-yl)propanoate hydrochloride (44 mg, 0.21 mmol), DIEA (90 mg, 0.70 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (40.0% up to 51.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This resulted in 56.1 mg (49%) of the formic acid salt of methyl 3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate as a light yellow solid. LCMS (Method 25) [M+H]+=617.1, RT=1.51 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.60 (s, 3H), 3.49-3.41 (m, 4H), 2.59 (t, 2H, J=6.4 Hz), 2.51 (t, 2H, J=6.4 Hz), 2.39-2.33 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.N1CCOCC1>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCN1CCC(O)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(3-chloro-5-fluorophenyl)-pyrrolidin-3-ol (0.1 g, 0.33 mmol) iodoethane (1 mL, 12.37 mmol), dimethyl formamid (2 mL), morpholine (2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.05 g. [α]D=+16.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 113-114° C.; MS m/z (relative intensity, 70 eV) 243 (M+, 6), 157 (7), 129 (11), 72 (33), 71 (bp).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[N:16]([CH3:21])[N:17]=[CH:18][C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[CH3:21][N:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[C:19]([CH3:20])[CH:18]=[N:17]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cnn(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2c(C)cnn2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,4-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate I, 40 mg, 0.106 mmol) and 2-methoxy-5-pyridineboronic acid (Aldrich, Buchs, Switzerland, 20 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: tR 2.69 min (Method A); M+H=401 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.03 (s, 1H), 8.27-8.21 (m, 1H), 8.16-8.09 (m, 1H), 7.96-7.89 (m, 1H), 7.84-7.77 (m, 1H), 7.65 (s, 1H), 7.00-6.88 (m, 2H), 3.88 (s, 3H), 3.61 (s, 6H), 1.82 (s, 3H))
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH2:22][O:23][CH3:24])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)(Cl)[Cl:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH2:22][O:23][CH3:24])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25][Cl:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
From 27: A solution of 27 (55 mg, 0.16 mmol) in 3 mL anhydrous CH2Cl2 was treated with CCl4 (155 μL, 1.6 mmol) and Ph3P (212 mg, 0.81 mmol) and the mixture was stirred at 25° C. for 2 h. The solution was concentrated in vacuo. Flash chromatography (SiO2, 1.5×15 cm, 0-12% EtOAc/hexane gradient) provided 28 (52 mg, 90%) as a white solid: mp 99-101° C.; 1H NMR (CDCl3, 250 MHz) δ8.03 (br s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.37 (m, 2H), 5.24 (d, J=6.1 Hz, 1H), 5.15 (d, J=6.1 Hz, 1H), 4.06 (m, 4H), 3.65 (s, 3H), 3.51 (app t, J=10.1 Hz, 1H), 1.59 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ152.3, 150.5, 141.1, 136.2, 127.9, 126.6, 124.6, 124.1, 122.4, 121.4, 107.7, 100.0, 81.2, 57.5, 52.1, 45.9, 40.8, 28.4; IR (film) νmax 2976, 1704, 1634, 1449, 1336, 1147, 1055, 983 cm−1; FABHRMS (NBA) m/z 378.1463 (C20H24ClNO4+H+ requires 378.1472).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:32]([O:31][C:29]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([O:18][CH2:17][CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[CH:20][CH:21]=2)[CH2:26]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCC3CCNCC3)cc2C1
Yield: 87 %

Procedure:
4-(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-piperidine-1-carboxylic acid benzyl ester (1.3 g) was hydrogenated using 7.5% palladium carbon (300 mg) in a mixture of tetrahydrofuran (10 ml) and methanol (20 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (815 mg).
Reaction SMILES: CS(O[CH2:6][C@:7]1([CH3:19])[CH2:11][C:10]2[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1)(=O)=O.[C:20]1([CH:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:19][C@@:7]1([CH2:6][N:31]2[CH2:32][CH2:33][CH:28]([NH:27][CH:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:29][CH2:30]2)[CH2:11][C:10]2[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1
Reactant: Cc1cc(C)c2c(c1C)O[C@](C)(COS(C)(=O)=O)C2
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C)c2c(c1C)O[C@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 177 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A suspension of (S)-(2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl methanesulfonate (0.34 g), N-(diphenylmethyl)-4-piperidinamine (0.73 g), and potassium carbonate (0.38 g) in N,N-dimethylacetamide (2 mL) was stirred under argon gas at 177° C. for 6 hours. This reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and extracted with 1N-hydrochloric acid. The aqueous layer was made basic with 2N-sodium hydroxide/water and extracted with diisopropyl ether. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to provide the title compound (0.49 g). Yield 79%.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:24])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[C:15]([Cl:23])[CH:14]=2)=CC=1)([O-])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH:30][C:11](=[O:24])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[CH2:22])=[C:15]([Cl:23])[CH:14]=1
Reactant: COC(=O)CN
Reactant: C=CCOc1ccc(CC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid p-nitrophenyl ester (3.69 g) was dissolved in chloroform (30 ml). To the solution was added glycine methyl ester hydrochloride (1.5 g) in dry chloroform (30 ml) containing dry triethylamine (1.4 ml), and the solution was stirred at 40° C. for 4 hrs.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([CH3:19])[CH:11]=2)=[N:8][N:9]=1)([CH3:4])[CH3:3]>[Zn].CN(C)C=O.O>[CH3:4][C:2]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:19])[CH:11]=2)=[N:8][N:9]=1)([CH3:1])[CH3:3]
Reactant: Cc1cc(-c2nnc(C(C)(C)C)o2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc(C(C)(C)C)o2)ccc1N
Temperature: 100 °C

Procedure:
A mixture of 2-(1,1-dimethylethyl)-5-(3-methyl-4-nitrophenyl)-1,3,4-oxadiazole (1.6 g), FeCl3.6H2O (5 g) and zinc powder (4 g) in a dimethylformamide/water mixture (1/1, 25 ml) is heated at 100° C. for 30 minutes and then filtered through Celite. After dilution with saturated aqueous sodium carbonate solution, the reaction mixture is extracted with diethyl ether. Drying over magnesium sulphate and evaporation of the organic phase gives the title aniline.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=CC=CC=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:14][C:1](=[O:8])[CH:2]=[CH2:7])(=[O:13])[CH:11]=[CH2:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)O
Product: C=CC(=O)OC(=O)C=C

Procedure:
Moreover, in the case of benzoyl chloride, the resulting mixed anhydride is more reactive than benzoyl chloride. Thus, the carboxylate ion of acrylic acid preferentially reacts with the mixed anhydride to give acrylic anhydride and the benzoate ion, which subsequently reacts with unreacted benzoyl chloride to give benzoic anhydride, according to reaction scheme I.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[CH:11]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1cc(Cl)c2ccccc2n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of 2,4-dichloroquinoline (0.2 g, 1 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.282 ml, 2.2 mmol) in toluene (2 ml) was refluxed during 18 hours then cooled to room temperature. The reaction mixture was diluted with CH2Cl2 and quenched with a saturated solution of NaHCO3. Aqueous phase was extracted with CH2Cl2 (2×). Combined organic phases were washed with H2O, dried over NaSO4, and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 97:3) to provide 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.235 g, 79%) as a yellow oil, MS: m/e=295.3 (M+H+).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-fluorobenzyl chloride to form 1-(4-fluorobenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 242° C. (dec).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Cl:7][CH2:8][C:9]([OH:11])=O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:7][CH2:8][C:9]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:9](=[O:11])[CH2:8][Cl:7])=[O:11]
Reactant: O=C(O)CCl
Reactant: OCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCl)OCCCCOC(=O)CCl
Temperature: 25 °C

Procedure:
In a 2 liter, 4 neck round bottom flask equipped with a mechanical stirrer, a solution of 75 grams of 1,4-butanediol, 240 grams of chloroacetic acid and 3 grams of para-toluenesulphonic acid 750 ml toluene was refluxed for 6 hours using a Dean-Stark apparatus. The solution was then cooled to room temperature. The toluene layer was washed with water (2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml), dried over sodium sulfate, and distilled to get crude 21, which was purified by recrystallization in chloroform:hexane (1:7) to get 92 grams of pure 21 as a white fluffy powder. m.p: 74-76.5° C., IH NMR (CDCl3) δ1.78 (t, 2H, CH2), 4.05 (s, 2H, CH2), 4.25 (t, 2H, CH2)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17]Br)=[N:13][NH:12][C:11]=1[NH2:19].[CH3:20][NH2:21]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][NH:21][CH3:20])=[N:13][NH:12][C:11]=1[NH2:19]
Reactant: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCc1n[nH]c(N)c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 32 %

Procedure:
A mixture of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine (130 mg, 0.39 mmol) and methylamine (5 mL of a 2 M solution in THF, 10 mmol) was stirred at room temperature for 60 hrs. The resulting solid was isolated by filtration, washed with THF, and then with water. The product was air dried to yield 38 mg (32%) of the title compound as an off white solid. MS (m/z, ES+): 288.2 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=1[O:26][CH3:27])=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=2[O:26][CH3:27])=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: COc1ccc(C(C)=O)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2ccc(OC)c(OC)c2OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (0.781 g, 4.8 mmol) and 2,3,4-trimethoxyacetophenone (1.0 g, 4.8 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (7.60 ml, 0.096 mol). The reaction mixture was stirred at room temperature for 24 h. A pale yellow precipitate was isolated and dried under vacuum over night. 1.693 g (86%) of a pale yellow powder was isolated. 1H-NMR (CDCl3) δ 7.60 (d, 1H), 7.5 (m, 1H), 4.4 (d, 1H), 7.3 (d, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 3.9 (t, 2H), 3.9 (s, 3H), 3.9 (s, 3H), 3.9 (s, 3H), 1.75 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 191.0. Mass Spectrum m/e (M+1) 357. Anal. Calcd. for C21H24O5.H2O: C, 67.44; H, 7.01. Found: C, 67.49; H, 6.93.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18]Br)[C:12]=2[F:20])[CH:9]=1)[C:5]#[N:6].[N-:21]=[N+:22]=[N-:23].[Na+]>CS(C)=O.CCOC(C)=O>[N:21]([CH2:18][C:13]1[C:12]([F:20])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=2)[C:5]#[N:6])[C:16]([Cl:17])=[CH:15][CH:14]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
3-bromo-5-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile (2.25 g, 5.36 mmol) and sodium azide (0.349 g, 5.36 mmol) were combined in DMSO (10 mL) and stirred overnight at 25° C. The reaction mixture was diluted with EtOAc, washed 4× with water, dried over MgSO4, filtered and concentrated to dryness to give 3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (2.04 g, 5.35 mmol, 100% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (t, 1H), 7.48-7.63 (m, 4H), 4.60 (s, 2H).