Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30].C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(=O)N(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), dimethylcarbamoyl chloride (72.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent is was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow powder (42.8 mg).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[NH:3][N:2]=1)=[O:19])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCC=C(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCC=C(C)C)[nH]n1

Procedure:
Hydrazine hydrate (0.41 mL, 8.48 mmol) was added to a stirring room temperature solution of 49 (0.1.9190 g, 8.48 mmol) in EtOH (8.5 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (½ h): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes: 2N NH3 in EtOH): 1H (CDCl3, 400 MHz): δ 12.73 (1H, broad s), 6.57 (1H, s), 5.09 (1H, t, J=6.8 Hz), 4.32 (2H, q, J=7.1 Hz), 2.70 (2H, t, J=7.5 Hz), 2.29 (2H, q, J=7.5 Hz), 1.63 (3H, s), 1.52 (3H, s), 1.30 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.27, 106.11, 60.65, 31.49, 27.53, 25.52, 17.51, 13.10 ppm. HPLC: 9.986 min.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=C[C:30]2[C:31]3[N:32]=[C:33]([C:39](N)=O)SC=3CCOC=2C=1.N1C=CC(CNN)=CC=1>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:39]=[CH:33][N:32]=[CH:31][CH:30]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCc1ccncc1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccncc3)nc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with pyridin-4-ylmethyl-hydrazine to give 8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[CH2:7][CH:8]3[CH2:13][N:9]3[S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>O1CCCC1>[OH:19][CH2:18][CH2:20][NH:21][CH2:13][CH:8]1[CH2:7][C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[NH:9]1
Reactant: NCCO
Reactant: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CN21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S1(=O)NC(CNCCO)Cc2ccc(C(F)(F)F)cc21
Yield: 147.1 %

Procedure:
A solution of 8,8a-dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine 3,3-dioxide (685 mg, 0.260 mmol), ethanolamine (0.785 mL, 13.0 mmol) and triethylamine (0.33 mL, 2.6 mmol) in tetrahydrofuran (25 mL) was heated in a sealed tube at 100° C. for 3 h. The cooled reaction was concentrated in vacuo. The residue was chromatographed (silica, 2%–20% methanol/dichloromethane gradient) to provide 3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine 1,1-dioxide as a white solid (124 mg) and additional impure material: LCMS (neg. ion spectrum) m/z 323.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S-:10])=[N:2]1.[K+].[OH-].[K+].Cl[CH:15]([F:17])[F:16]>O1CCOCC1.O>[F:16][CH:15]([F:17])[S:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: [S-]c1nsc2ccccc12
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Sc1nsc2ccccc12
Temperature: 0 °C

Procedure:
4.1 g (0.02 mol) Potassium 1,2-benzoisothiazole-3-thiolate was suspended in 25 ml dioxane and treated with a solution of 5.6 g (0.10 mol) potassium hydroxide in 9 ml water. At a temperature of 60°-70° C., a slow stream of chlorodifluoromethane was passed through over 30 minutes. The mixture was added to 500 ml ice/water and extracted several times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residual oil was purified by silica gel column chromatography (eluent: hexane/diethyl ether 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.ClC1C=CC=CC=1Cl.Cl>[N+](C)([O-])=O>[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1cccc2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
p-Methoxybenzenesulfonyl chloride, 2.0 mol, anhydrous stannic chloride, 2.25 mol, 1-methoxynaphthalene, 2.25 mol, and 3 l of o-dichlorobenzene were mixed at room temperature under nitrogen. The mixture was stirred at room temperature overnight (ca 7 hours needed) and decomposed with 3N hydrochloric acid. The organic layer was diluted with 1250 ml of nitromethane and washed with 2 portions of 1N hydrochloric acid followed by pure water. The organic layer was treated with magnesium sulfate, filtered, evaporated, extracted with hot toluene and dried at 120° c. for two hours to give 577 g, 88% yield, m.p. 160°-162° C.
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26]CC)=[O:25].[O-]CC.[Na+:35]>C(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:22]([CH2:29][CH2:30][CH3:31])=[C:23]([C:24]([O-:26])=[O:25])[N:3]=[N:2]3)=[CH:20][CH:19]=2)=[O:9])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[Na+:35]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)[O-])nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Azido-N-(2-morpholin-4-ylethyl)benzamide obtained in Example 61a) and ethyl 3-oxohexanoate (1.07 ml, 6.35 mmol, 1.25 eq.) were dissolved in ethanol (23 ml), sodium ethoxide (480 mg, 6.35 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 20 min, and then at 60° C. for 13 hr. The resulting solid was suspended in ethyl acetate, and the insoluble material was collected by filtration, washed with ethyl acetate and dried to give the title compound as a grayish white powder (2.44 g, 5.09 mmol, quant.).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][C:40]([F:43])([F:42])[F:41])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][C:40]([F:43])([F:41])[F:42])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 65 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide, gave Compound 139, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide (170 mg, 65%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.50-7.25 (m, 7H), 7.15-6.90 (m, 6H), 5.00 (s, 2H), 4.79-4.60 (m, 3H), 4.00 (m, 1H), 3.70-3.60 (m, 1H). MS (EI) for C27H23F4N5O5 found 574 (MH+).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[CH:14][CH:13]=1>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:17]([N:16]1[C:12]([NH:11][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]1)([CH3:19])[CH3:18]
Reactant: CC(C)n1nccc1N
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nccc1Nc1ccccc1C(=O)O
Yield: 97.3 %

Procedure:
To 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) was added K2 CO3 (33.4 g, 0.242 mol), then 5-amino-1-isopropylpyrazole (27.3 g, 0.218 mol) and finally copper (II) acetate monohydrate (0.9 g, 4.5 mmol). The reaction mixture was refluxed overnight and then the DMF was evaporated. The residue was poured into ice/water and then the mixture was acidified with acetic acid and concentrated HCl to a pH of about 4. A precipitate formed which was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to afford 52 g (97.2%) of N-(1-isopropylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][OH:13])=[CH:6][CH:5]=1>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#CCO)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCO)cc1
Reaction time: 24 h
Yield: 92.7 %

Procedure:
A solution of 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g) in EtOAc (75 mL) and MeOH (75 mL) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (2 g) for 24 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The reaction was repeated by adding 10% palladium on carbon (2 g) and hydrogenating on a Parr shaker for 24 h. After filtering through Celite®, the solution was concentrated in vacuo to provide 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 1-acetyl-4-(4-aminophenyl)piperazine (1.0 g; 4.6 mmol) (from Step B above) in N,N-dimethylformamide (10 mL) was added dropwise to a cooled (−15° C.) solution of thiocarbonyldiimidazole (855 mg, 4.8 mmol) in N,N-dimethylformamide (10 mL). After the addition was complete, the mixture was stirred at −15° C. for 30 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether (4×50 mL). The combined ether layers were washed with brine, dried (MgSO4), filtered, and evaporated to give 1-(acetyl)-4-(4-isothiocyanatophenyl)piperazine (1.0 g, 84%).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]1=[O:25].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:3]1=[O:25])(=[O:35])=[O:34]
Reactant: COc1ccc(CCN2C(=O)N(N)C[C@H]2c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)C[C@H]2c2ccc(OC)cc2)cc1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(R)-(4-methoxyphenyl)-2-imidazolidinone (247 g, 0.72 mol) in dichloromethane (2.35 L) and pyridine (174 mL, 2.15 mol) is cooled in an ice bath to 18° C. Methanesulfonyl chloride (73 mL, 0.94 mol) is added dropwise. The reaction is stirred cold for 2.5 hours then washed with 0.5 N HCl (2×1.5 L), brine (2×1.5 L) and dried (Na2SO4). The solvent is then removed in vacuo to afford a mixture of the desired product (75%) and unreacted starting material (25%) which is separated by liquid chromatography. [α]20D −39.83 (c 0.89, CHCl3) 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.81, 2H, ArH), 7.02 (d, J=8.51, 2H, ArH), 6.91 (d, J=8.81, 2H, ArH), 6.80 (d, J=8.81, 2H, ArH), 4.41 (m, 1H), 3.92 (m, 1H), 3.82 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.60-3.72 (m, 1H), 3.30 (m, 1H), 3.03 (s, 3H, CH3), 2.87-2.98 (m, 1H), 2.53-2.79 (m, 3H). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S¼H2O: C, 59.77, H, 6.57; N, 9.96. Found: C, 59.82, H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([Mg]Br)#[CH:15]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]#[CH:15])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. In a solution of 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 16.2 mmol) in tetrahydrofuran (40 mL) was dropped in ethynyl magnesium bromide (70 mL, 35 mmol) at −78° C. Then the solution was stirred overnight at room temperature. Then the reaction mixture was quenched with saturated NH4Cl and extracted with dichloromethane, dried with anhydrous sodium sulfate to afford 3-Ethynyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 44%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][NH:5]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CC2CC1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Yield: 65.9 %

Procedure:
A solution of 2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (0.4402 g, 1.6 mmol), p-fluoro-nitrobenzene (0.56 mL, 5.4 mmol), N,N-diisopropylethylamine (0.84 mL, 4.82 mmol) in 5 mL of acetonitrile is heated at 100° C. overnight. After the solvent is removed, the residue is treated with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane to yield 0.246 g (65% yield) of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19](I)[N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:40]=2)O1>O1CCOCC1.O.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>[CH2:1]([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([C:35]3[CH2:40][CH2:39][O:38][CH2:37][CH:36]=3)[N:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(COCc2ccccc2)nn2c(I)ncc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(COCc2ccccc2)nn2c(C3=CCOCC3)ncc12
Temperature: 125 °C
Yield: 77 %

Procedure:
To a solution of compound 5 (1.0 g, 2.61 mmol) in dioxane (12 mL) at room temperature was added dropwise a solution of Cs2CO3 (2.5 g, 7.66 mmol) in water (3 mL), followed by addition of Pd(PPh3)4 (300 mg, 0.26 mmol) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (636 mg, 3.0 mmol). The reaction mixture was degassed by purging with N2 for 15 min. Then the mixture was heated to 125° C. under microwave irradiation for 40 min. After removal the solvent, the residue was purified by chromatography on silica gel column eluted with PE/EtOAc=10:1 to 1:5) to afford compound 6 (680 mg, 76% yield) as a white solid. LC-MS: m/z 339.1 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([O:25]CC)=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O>[C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:18]([C:23]([OH:25])=[O:24])=[N:17]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(CCl)n(-c2sc(C)c(C)c2C(=O)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(-n2nc(C(=O)O)nc2CCl)c(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.3 g. of ethyl 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate in 5 ml. of methanol is added 1 ml. of 2N-sodium hydroxide. After the mixture is stirred for 1 hour at room temperature, the resulting solution is neutralized with 2N-hydrochloric acid, then diluted with water and extracted with chloroform. After the chloroform layer is washed with water and dried over sodium sulfate, the solvent is evaporated. Recrystallization of the residue from methanol yields 1-(3-benzoyl-4,5-dimethyl-2-thienyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid as crystals melting at 162° to 163° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OCCCCCCBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
10 g of [4-(6-bromo-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone are dissolved in 200 ml of DMF and, after the addition of 14.7 g of sodium azide, the mixture is stirred at 90° C. for 24 hours, filtered and the filtrates are concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution. The organic phase is dried and concentrated. There are obtained 9.2 g of [4-(6-azido-hexyloxy)-phenyl]-(4-bromo-phenyl)-methanone, MS: m/e 401 (M+H+, 1Br).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[C:13]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].C[N+](C)(C)C.C(O)(=O)C>C(O)(C)C>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH2:23])=[CH:24][CH:25]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=Cc1ccc(OC(C)(C)C)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: C=Cc1ccc(O)cc1

Procedure:
A mixture of 46.3 g of poly(p-acetyloxystyrene/p-tert-butoxystyrene) obtained according to (1) above and 100 ml of a 16% aqueous solution of tetramethylammonium hydroxide was refluxed with stirring in 300 ml of isopropanol for 4 hours. The reaction solution was neutralized with acetic acid and concentrated under reduced pressure, and the residue was dissolved in 150 ml of acetone and poured into 5,000 ml of water to cause crystallization. Precipitated crystals were filtered out, washed with water and dried in vacuo to give 33.8 g of poly(p-hydroxystyrene/p-tert-butoxystyrene). P-hydroxystyrene unit/p-tert-butoxystyrene unit molar ratio in the polymer≈3:1 (1HNMR). Mw≈8,540; Mw/Mn=1.30 (GPC with polystyrene calibration).
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:16])[CH:12]=2)[C:7]1=[O:17].[O-][CH2:20][CH2:21][CH2:22]C.[Na+].Cl>C(O)CCC>[CH2:2]([O:3][C:4]([C:5]1[NH:6][C:14](=[O:15])[C:13]2[C:8]([C:7]=1[OH:17])=[CH:9][CH:10]=[C:11]([I:16])[CH:12]=2)=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)CN1C(=O)c2ccc(I)cc2C1=O
Reactant: CCCC[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)c1[nH]c(=O)c2cc(I)ccc2c1O
Temperature: 80 °C

Procedure:
Freshly cut sodium metal, 0.40 g, was dissolved in 22 ml of n-butanol at 65° C. under a nitrogen atmosphere. A mixture of 3.0 g of (5-iodo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid methyl ester in 22 ml of n-butanol was added to the sodium butoxide solution and the reaction mixture was heated to 80° C. for 2 h. The cooled reaction mixture was acidified with 100 ml of 1 M hydrochloric acid to give a solid precipitate. The solid was collected by filtration and separated by silica gel chromatography (eluant; 19:1 dichloromethane:ethyl acetate) to give 0.219 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(−)-ion, M−1=386.0 amu, and 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(−) ion, M−1=386.0 amu.