Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([B:30]3[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1.O>[CH3:39][N:40]([CH3:44])[C:41]([N:15]1[C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]([C:24]3[CH:29]=[CH:28][C:27]([B:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]4)=[CH:26][CH:25]=3)=[N:10][C:11]=2[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16]1)=[O:42]
Reactant: CC1(C)OB(c2ccc(-c3nc4c(-c5ccccc5)n[nH]c4c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)C(=O)n1nc(-c2ccccc2)c2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)n(-c3ccc(Cl)cc3)c(=O)c21
Temperature: 80 °C

Procedure:
To a solution of 6-(4-chloro-phenyl)-3-phenyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (100.0 mg, 0.191 mmol) in anhydrous pyridine (1.0 mL) is added dimethylcarbamyl chloride (87.4 μL, 0.953 mmol). The reaction mixture is heated at 80° C. overnight before removal of the solvent. The residue is taken in water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with brine, concentrated, and purified by silica gel chromatography to provide 6-(4-chloro-phenyl)-7-oxo-3-phenyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-6,7-dihydro-pyrazolo[4,3-d]pyrimidine-1-carboxylic acid dimethylamide as a white solid product; HPLC-MS calculated for C32H31BClN5O4 (M+H+) 596.2, found 596.2.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C@@H:6]([CH2:8][C:9]([OH:11])=[O:10])[NH2:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O>[C:16]([NH:7][C@H:6]([CH2:8][C:9]([OH:11])=[O:10])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][CH:12]=1)(=[O:18])[CH3:17]
Reactant: N[C@H](CC(=O)O)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CC(=O)O)c1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
p-Bromo-β-phenylalanine (10.0 g, 41 mmol) was mixed with 40 ml of water and adjusted to pH 14 with 25% sodium hydroxide aqueous solution. After being cooled to 5° C., 8.5 ml of acetic anhydride (90 mmol) and 25% sodium hydroxide aqueous solution were simultaneously dropped into the mixture to keep it at a pH range of 11.5˜12 and the resulting mixture was stirred for 3 hours at a room temperature. After the mixture was adjusted to pH 2 with conc. HCl and stirred for one hour, the resulting precipitated crystal was filtered and dried under reduced pressure to give quantitatively 12.0 g of acetyl-p-bromo-β-phenylalanine.
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:27])(C1C=CC(C)=CC=1)(=O)=O.[I-:28].[Na+]>CC(C)=O>[I:28][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:27]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CI)O2)c(=O)[nH]c1=O
Yield: 90 %

Procedure:
To a stirred solution of the thymidine tosylate (10.65 g, 26.9 mmol) prepared according to the method of Example 23 in dry acetone (75 ml) was added sodium iodide (10 g, 66.7 mmol) and the mixture refluxed for 16 hours. The solvent was evaporated and diluted with ethyl acetate. The organic phase was washed with water (2×20 ml) and brine (10 ml) and dried with sodium sulfate. The title compound was crystallized from methanol as a white crystalline solid in 90-95% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[N-:11]=[N+:12]=[N-:13].[Na+].O>CN(C=O)C>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Methyl 6-azidohexanoate was synthesized via a modified literature procedure. A reaction mixture of methyl 6-bromohexanoate (6 g, 29 mmol) and NaN3 (9.4 g, 144 mmol) in 30 ml of DMF was stirred at 75° C. for 14 h under N2. After cooling down, the reaction mixture was poured into water. The product was extracted with hexane, washed with brine, and dried under MgSO4. Solvent was evaporated to give transparent liquid. Yield: 95%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2.[C:11](=O)=[O:12].C(=O)(O)N>ClC1C=CC=CC=1>[N:1]([CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=[C:11]=[O:12]
Reactant: O=C=O
Reactant: NCCC12CCC(CC1)C2
Agent: NC(=O)O
Solvent: Clc1ccccc1
Product: O=C=NCCC12CCC(CC1)C2

Procedure:
Following the procedure of Example 1 (Stage 3), 140 g (0.62 mol) 2-aminoethyl-2-(3-aminopropyl)5- (or 6) -aminoethyl-bicyclo-[2,2,1]-heptane in 1.5 liters of boiling chlorobenzene are initially converted with CO2 into the carbamic acid derivative which is thereafter phosgenated, first in the cold and then at boiling temperature. The 2-isocyanatomethyl-2-(3-isocyanatopropyl)-5- (or 6) -isocyanato ethyl-bicyclo-[2,2,1]-heptane is obtained from the clear reaction solution in the form of a pale yellow liquid by distillation at a boiling point of 186°-188° C./ 0.1 Torr. Yield 170 g (90%). Viscosity 80 cP/20° C.
Reaction SMILES: [CH2:1]([S:6][CH2:7][CH2:8][CH2:9][Cl:10])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(OCC)C>[ClH:10].[CH2:1]([S:6][CH2:7][CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCSCCCCl
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCOCC
Product: CC(C)CCSCCCN1CCCCC1
Temperature: 125 °C
Yield: 49.4 %

Procedure:
Mix 3-chloropropyl isopentyl sulfide (1.0 g, 5.5 mmol) and piperidine (3.3 mL, 33 mmol) and heat at 125° C. for 2 hours. Cool to room temperature and partition between 50% sodium hydroxide and ethyl ether. Separate the organic phase, wash the aqueous phase with ethyl ether (2×30 mL), combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 1.12 g (89%). Dissolve the product (1.0 g) in ethyl ether (100 mL) and treat with anhydrous hydrochloric acid. Collect the resulting yellow solid by vacuum filtration, recrystallize (ethyl acetate) and dry to yield 0.723 g of the title compound as white crystals; mp 155°-8° C. 438E-83
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:11](=[O:20])[NH:12]2.[Cl-].[NH4+]>O.CO.[Zn]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:11](=[O:20])[NH:12]2
Reactant: COC(=O)CCC#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)CCC#Cc1c(N)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Yield: 48 %

Procedure:
Using Method L above, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester (0.22 g, 0.57 mmol) (from Example 35 above) was reduced with zinc (0.33 g, 5.1 mmol) and ammonium chloride (67.1 mg, 1.25 mmol) in 10% water in methanol (20 mL) with heating at reflux for 4 h to give (Z)-5-[5-amino-2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester (Yield 0.1 g, 48%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:33])[F:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:35](N1C=CN=C1)([N:37]1C=CN=[CH:38]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:34])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]([F:32])[F:33])[CH:21]=1)[CH2:16][C:17]([N:37]([CH3:38])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OC(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid (350 mg, 0.72 mmol) in tetrahydrofurane was added carbonyldiimidazole (175 mg, 1.08 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added dimethylamine in THF (0.73 ml, 1.45 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile: water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3,4-bis-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (200 mg, 55%): mp, 83-85° C.; 1HNMR (CDCl3): 2.25 (s, 3H, CH3CO), 2.91 (s, 3H, NCH3), 3.06-3.13 (m, 4H, CHHCO+NCH3), 3.85 (dd, J=10, 15 Hz, 1H, CHHCO), 5.85-5.91 (m, 1H, CHN), 6.80 (t, JH-F=75 Hz, 1H, OCF2H), 6.84 (t, JH-F=75 Hz, 1H, OCF2H), 7.23 (d, J=7.5 Hz, 1H, Ar), 7.41-7.47 (m, 3H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=7.5 Hz, 1H, Ar), 9.51 (s, 1H, NHCO). 13C NMR (CDCl3): 24.8, 34.5, 35.4, 36.9, 50.5, 111.4, 111.5, 115.2, 115.6, 115.7, 117.9, 119.8, 119.9, 122.0, 122.4, 124.7, 126.1, 131.1, 135.8, 137.4, 138.2, 141.9, 142.2, 167.7, 168.8, 169.1, 169.7; Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.88; N, 8.13.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:26](Cl)=[O:27]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([F:22])[CH:31]=[C:30]([F:32])[CH:29]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: COc1ccc(-c2nc(NC(=O)c3cc(F)cc(F)c3)sc2Cc2ccccc2)cc1
Yield: 59.1 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 3,5-difluorobenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 59.1%, mp: 154-155└. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.23 (2H, s, CH2), 6.72 (2H, d, J=8.44 Hz, ArH), 6.82 (1H, t, 3JFH=8.40 Hz, ArH), 7.17˜7.37 (9H, m, ArH), 11.97 (1H, br, CONH); EI-MS m/e (%): 436.1 (M+, 100), 141.0 (36); HREI-MS Calcd. for C24H18F2N2O2S: 436.1057. found: 436.1053. Anal. Calcd. for C24H18F2N2O2S: C, 66.04; H, 4.16; N, 6.42. found: C, 66.02; H, 4.08; N, 6.44.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Ic1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 75.4 %

Procedure:
The title compound (3.5 g, 75.5%) was prepared from 1-iodo-4-phenoxy-benzene (3.9 g, 13.1 mmol) and 1-Boc-piperazine (2.5 g, 13.1 mmol) by the procedure described in step 1 of Example 4: MS (ESI) m/z 355 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 3.08 (t, J=4.8 Hz, 4H), 3.59 (t, J=4.8 Hz, 4H), 6.90-7.09 (m, 7H), 7.27-7.32 (m, 2H).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH2:16][C:15](=[O:18])[N:13]3[C:14]1=[C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=13)[CH2:5][CH2:4][CH2:3]2.[OH-:19].[Na+]>C(O)C>[CH3:1][C:2]1([CH2:17][CH2:16][C:15]([OH:19])=[O:18])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC12CCCc3c1n(c1ccccc31)C(=O)CC2
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC1(CCC(=O)O)CCCc2c1[nH]c1ccccc21

Procedure:
A solution of 1,2,3,3a,4,5-hexahydro-3a-methyl-6H-pyrido[3,2,1-jk]carbazol-6-one (0.5 g), described in Example 40, in ethanol (10 ml) and 10% sodium hydroxide solution (10 ml) is heated at reflux for 3 hr. The mixture is concentrated, diluted with water and washed with ether. The aqueous phase is rendered acidic with conc. HCl and extracted with chloroform. Concentration of the chloroform extract yields the title compound as a solid, mp 204°-206° C., identical to the product of Example 69.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[C:29]([F:32])[C:28]([OH:33])=[CH:27][CH:26]=2>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O.O>[F:32][C:29]1[C:28]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:27][CH:26]=[C:25]2[C:30]=1[CH:31]=[C:23]([CH3:22])[NH:24]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCc1ccccc1

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with DMAP (1.5 eq), 2-methyl-4-fluoro-5-hydroxyindole (WO0047212) (1 eq) in dioxane (20 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14](=O)[C:15]([F:18])([F:17])[F:16].Cl.[NH2:28][OH:29].Cl.O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]1[O:29][N:28]=[C:14]([C:15]([F:18])([F:17])[F:16])[CH:13]=1
Reactant: Cc1nc(-c2cc(C)c(OCCCC#CC(=O)C(F)(F)F)c(C)c2)no1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2cc(C)c(OCCCc3cc(C(F)(F)F)no3)c(C)c2)no1
Reaction time: 120 h
Yield: 18.5 %

Procedure:
To 479 mg of 3-{3,5-dimethyl-4-[3-(trifluoroacetylethinyl)propoxy]phenyl}-5-methyl-1,2,4-oxadiazole from part (a) above and 509 mg hydroxylamine hydrochloride in 10 mls of acetic acid at ambient room temperature was added with stirring 1 ml 1M hydrochloric acid. After twenty hours an additional 1 ml 1M aqueous hydrochloric acid and 1.00 g hydroxylamine hydrochloride were added and stirring was continued for five days. The reaction mixture was poured into 200 mls water and extracted with ethyl ether. The ethyl ether extracts were washed with water, dried (Na2SO4) and concentrated. A solution of the residue (470 mg) in benzene was heated at reflux overnight, cooled, diluted with methylene chloride, washed with aqueous 1.5M potassium bicarbonate and water, filtered through silica gel and concentrated. The oily residue was subjected to preparative TLC (silica gel; methylene dichloride) to yield 92 mg of the title compound, m.p. 62°-64.5° C.
Reaction SMILES: C(=S)=S.[CH2:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[CH3:5].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>O>[C:17]([C:10]1[C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[O:7][C:6]=1[CH2:4][CH3:5])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: CCc1cc2ccc(OC)cc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Solvent: O
Product: CCc1oc2cc(OC)ccc2c1C(=O)c1ccc(OC)cc1

Procedure:
Dried carbon disulfide solution (20 ml) of 2-ethyl-6-methoxy-benzofuran (2.76 g, 15.6 mmol) and p-anisoyl chloride (3.48 g, 20.3 mmol) was cooled on ice, to which tin chloride (IV) was dropped (5.25 g, 20.3 mmol) while stirring. The mixture was stirred at a temperature in a range of 5 to 10° C. for 3 hours and then poured into water. The organic layer was washed with diluted hydrochloric acid and water, dried over MgSO4, and concentrated under reduced pressure. Crude product thereof was purified by HPLC (silica gel, ethyl acetate: hexane=2:8) and a target product in pale yellow oily state (2.98 g, 9.60 mmol, 58%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)[CH2:5][CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[O:1][CH2:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)CCCCN(CCc1ccccc1O)Cc1ccc(C(=O)OC)cc1
Reactant: ClCc1ccc(C=Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(/C=C/c2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
1.0 g (2.50 mmol) of methyl 4-{[(2-hydroxyphenethyl)-(5-methoxy-5-oxopentyl)-amino]methyl}benzoate from Ex. 1, 0.687 g (3.00 mmol) of 4-(chloromethyl)stilbene and 0.520 g (3.75 mmol) of potassium carbonate in 10.0 ml of acetonitrile are heated at reflux for 18 hours. The solution is filtered and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography over silica gel using the mobile phase cyclohexane/ethyl acetate 4/1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]2[O:15][CH:16]=[N:22][N:23]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1)c1ccccc1-c1nnco1
Temperature: 90 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Methyl 2-[(4-bromophenyl)sulfonyl]benzoate (Example 144 Step 1; 150 mg, 0.46 mmol) and hydrazine hydrate (0.06 mL, 2.32 mmol) were stirred together at room temperature for 1.5 h then at 90° C. for 2 h. The excess hydrazine was removed in vacuo and the residue was dissolved in triethylorthoformate (4.6 mL) with catalytic camphorsulfonic acid and the mixture heated at 90° C. overnight. The cooled reaction mixture was partitioned between EtOAc and water and the organic layer was washed with brine and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant 50% EtOAc/isohexane) to yield 2-{2-[(4-bromophenyl)sulfonyl]phenyl}-1,3,4-oxadiazole (60 mg, 35%). δH (400 MHz, d6 DMSO): 9.42 (1H, s), 8.35-8.33 (1H, m), 7.97-7.91 (2H, m), 7.86-7.84 (3H, m), 7.80-7.78 (2H, m).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:13])[CH:8]=[N:9][C:10]=1Cl.[NH2:23][NH2:24]>O>[Cl:4][C:5]1[CH:6]=[C:7]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:13])[CH:8]=[N:9][C:10]=1[NH:23][NH2:24]
Reactant: NN
Reactant: O=S(=O)(Nc1cccc(O)c1)c1cnc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: NNc1ncc(S(=O)(=O)Nc2cccc(O)c2)cc1Cl
Yield: 80.3 %

Procedure:
To 500 ml ethanol was added 5,6-dichloro-3'-hydroxy-3-pyridinesulfonanilide (10.4 g, 42 mmol) and 95 percent hydrazine (60 mmol). The reaction mixture was refluxed overnight. The completely reacted mixture was chilled, and the precipitate was filtered off and washed with ethanol. The filtrate was concentrated so as to obtain a second crop, yielding a total of 16.5 g. The solid was stirred in 250 ml of water to remove any salts. The product was filtered, washed with water, and dried under vacuum at 50° C. to give 10.61 g (80 percent) of pure product.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[N:23]1([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][NH:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[NH:11][C:10](=[O:18])[C:9]4=[CH:19][S:20][C:21]([CH3:22])=[C:8]34)=[O:6])[CH2:35][CH2:34]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: C1CCN(CCCCC2CCNCC2)CC1
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 20 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[4-(piperidin-l-yl)butyl]piperidine in a yield of 20% of theory. Colourless crystals, m.p. 186°-187° C.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[C:4]([OH:15])(=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]>>[C:4]([O:15][CH2:1][CH2:2][OH:3])(=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: C1CO1
Reactant: CC(C)(C)CCCCCC(=O)O
Product: CC(C)(C)CCCCCC(=O)OCCO
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a one liter stainless steel autoclave, equipped with a mechanical stirrer, heater, cooling coils, automatic temperature controller, and a tared ethylene oxide cylinder, in a series of runs is added 500 grams neodecanoic acid and 2.0 g of the selected catalyst. The reactor is heated to approximately 100° C. and a gaseous N2 purge of the reactor is introduced to remove both oxygen and water. With continued N2 purging its temperature of the neo acid/catalyst solution is gradually raised to 150° C. Upon reaching temperature, the N2 purge is stopped and the reactor vents are sealed. Ethylene oxide is then slowly added to the reactor to maintain a reactor pressure of about 30 psig. The flow of ethylene oxide is then stopped. The reaction mixture is stirred for an additional 20 minutes, until the reactor pressure decreases to 15 psig. Total reaction time, from the start of ethylene oxide addition is about 55 minutes. The reactor is then vented, a gaseous nitrogen purge is introduced, and the reaction product is cooled to room temperature. The crude ethylene glycol mononeodecanoate product mixture thereby obtained was analyzed by gas chromatography. The data obtained are set forth in Table II below.