Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH2:17][CH2:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCCc1ccccc1
Agent: Cl
Product: Nc1nc(CCc2cn(CCCc3ccccc3)nn2)c[nH]1
Yield: 36 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0735 g, 0.428 mmol) was reacted with (3-azido-propyl) benzene, which was synthesized using previously reported methods (Suenaga et al., Tetrahedron Letters 2003, 44, 5799-5801), (0.083 g, 0.514 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.051 g, 36%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.87 (s, 1H), δ 7.32-7.22 (m, 5H), δ 6.54 (s, 1H), δ 4.31 (t, 2H), δ 3.05 (t, 2H), δ 2.93 (t, 2H), δ 2.67 (t, 2H), δ 2.23 (m, 2H) ppm; 13C (75 MHz CD3OD) δ 153.3, 146.6, 140.4, 134.3, 128.8, 128.7, 128.6, 126.6, 121.5, 67.5, 53.9, 32.8, 32.9, 29.5 ppm; HRMS (ESI) calcd for C16H20N6 (M+) 296.1822. found 296.1828.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]1=[O:11]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 3-(1H-indol-2-ylmethylene)-4-methyl-1,3-dihydroindol-2-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:31])[N:19]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[CH2:20][C@H:13]12.C(N(CC)CC)C>C(Cl)Cl>[O:31]=[C:18]1[N:14]2[CH2:15][CH2:16][CH2:17][C:12](=[O:11])[C@H:13]2[CH2:20][N:19]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=1[CH3:30]
Reactant: Cc1c(N2C[C@@H]3[C@H](O)CCCN3C2=O)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2C[C@@H]3C(=O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
A mixture of oxalyl chloride (94 μL, 0.19 mmol) in DCM (50 μL) was cooled to −78° C. and a solution of DMSO (26 μL, 0.37 mmol) in DCM (0.7 mL) was added. The resulting mixture was stirred at −78° C. for 15 min. A solution of 4-[(8R,8aR)-8-hydroxy-3-oxohexahydroimidazo[1,5-a]pyridin-2-yl]-2-chloro-3-methylbenzonitrile (77J) (16 mg, 0.052 mmol) in DCM (0.5 mL) was followed by DCM (0.5 mL) and stirred at −78° C. for 30 min. Triethylamine (120 μL, 0.86 mmol) was added and gradually warmed to rt over 1 h. The solvent was removed and the residue was purified by flash chromatography (silica gel, 30-50% EtOAc/hexane) to give the title compound 78A (12.9 mg) as a white solid: Chiral analytical HPLC (ChiralPak AD OD 4.6×250 mm, 35% IPA/hexane isocratic) retention time 13.8 min (100% ee); MS (ES) m/z 304.1 [M+1]+; HRMS calcd for C15H13ClN3O2 302.0696, Found 302.0681.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])[CH:8]=O.[CH3:19][C:20]([CH3:22])=[O:21].Cl>C(OCC)(=O)C.CCCCCC.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:8]=[CH:19]/[C:20](=[O:21])[CH3:22])[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][C:15]#[CH:16]
Reactant: CC(C)=O
Reactant: C#CCOc1c(OC)cc(C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: C#CCOc1c(OC)cc(/C=C/C(C)=O)cc1OC
Yield: 54.1 %

Procedure:
To an aqueous 10% sodium hydroxide solution (4.3 mL, 1.0 M) was added slowly dropwise a mixture of an ethanol (4.3 mL, 1.0 M) solution of 3,5-dimethoxy-4-prop-2-ynyloxybenzaldehyde (0.95 g, 4.3 mmol) and acetone (1.27 mL, 17.3 mmol), and the resultant mixture was stirred for 1 hour at room temperature, followed by addition of 10% hydrochloric acid. The mixture was then extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure to give a residue which was subjected to silica gel chromatography. A white solid (605 mg, 54%) was obtained from an ethyl acetate/hexane eluent (1:1 v/v).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[ClH:24].CCOCC>[Pt].C(O)(=O)C.CO>[OH2:16].[ClH:24].[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:18][CH:19]=1
Reactant: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: Fc1ccc(C(CC2CCNCC2)c2ccc(F)cc2)cc1
Product: O
Reaction time: 16 h

Procedure:
A mixture of 10.0 g (0.3 mole) α,α-bis(4-fluoropheny)-4-pyridineethanol and 1.2 g of 5% platinum on carbon catalyst in 200 ml of acetic acid was shaken under an atmosphere of hydrogen (49 psi) for 16 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. This was dissolved in methanol, an excess of ethereal hydrogen chloride was added and ether was added. A precipitate was collected to give 7.58 g (72%) as a white crystalline solid, mp 171°-173° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[NH:20]1[CH:24]=[N:23][N:22]=[N:21]1>>[N:20]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: c1nnn[nH]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2cnnn2)cc1)c1ccccc1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and tetrazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.57 (s, 2H), 7.17 (br s, 2H), 7.26–7.42 (m, 7H), 8.52 (s, 1H); HPLC-MS: m/z=332.0 (M+23); Rt=3.24 min.
Reaction SMILES: [C:1]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([O:26][CH2:27][C:28]#[N:29])[CH:20]=[CH:19]2)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:30]1[C:28]([CH2:27][O:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:8]2[O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=2[C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:25]=[CH:24]3)=[N:29][N:32]=[N:31]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 6 of Example 1, the title compound was prepared from 2-{[6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.350 g, 0.913 mmol), sodium azide (0.297 g, 4.56 mmol), and ammonium chloride (0.246 g, 4.60) mmol) in DMF (6 mL). Crystallization from acetonitrile (also using charcoal), and drying of the product for 16 hours at 84° C. yielded a light yellow solid (0.0978 g), mp 150-151° C. Mass spectrum (+APCl, [M+H]+) m/z427; 1HNMR (400 MHz, DMSO-d6): δ16.8-17.1 (br, 1H), 8.4 (d, 1H, J=1.2 Hz), 8.0-8.05 (m, 3H), 7.85 (dd, 1H, J=8.5 Hz and 1.7 Hz), 7.7 (d, 1H, J=7.5 Hz), 7.65 (d, 1H, J=2.4 Hz) 7.45 (m, 3H), 5.65 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2(m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C25H22N4O3: Calculated: C, 70.41;H, 5.20; N, 13.14. Found: C, 70.21;H, 5.14; N, 13.23.
Reaction SMILES: [CH3:1][CH:2]([CH:9]([CH:21]([CH:23]([CH2:25][OH:26])[OH:24])[OH:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C1COCC1.C(#N)C>[CH3:1][CH:2]([CH:9]([C@@H:21]([CH:23]([CH2:25][O:26][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:24])[OH:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCC(C(C)CCCCCC)C(O)C(O)CO
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(C(C)CCCCCC)[C@H](O)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
17 grams of 1-(2-octyl)dodecyl-glycerol (dried by azeotropic distillation with benzene) was dissolved in a mixture of dry THF (400 ml) and dry acetonitrile (160 ml). Triphenylchloromethane (15.8 grams) and dry triethylamine (14 ml) were added, and the reaction mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, poured on ice (1 kilogram), transferred to a separatory funnel and extracted with diethyl ether (3×200 ml). The combined organic phase was washed consecutively with water (200 ml), dilute (1.5%) sulfuric acid (2×100 ml), water (200 ml), concentrated aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the obtained crude product was purified by chromatography on a silica gel (350 grams) column. 26 grams of pure (S)-1-(2-octyl)dodecyl-3-trityl-glycerol was eluted by hexane followed by a mixtures of hexane and chloroform (50-100%) as a yellow oil. The yield was 92.7%.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:19]2[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH:20]=2)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1>C(Cl)Cl.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C:19]2[CH2:20][CH2:21][CH2:22][N:23]=2)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)cc2c1OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1cc2c(c(C3=NCCC3)c1)OCCO2
Reaction time: 3 h

Procedure:
TFA (0.09 mL, 1.18 mmol) was added to a solution of tert-butyl 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (0.04 g, 0.117 mmol) in DCM (5 mL) at 0° C. and stirring was continued at 25° C. for 3 h. Reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with ethyl acetate, washed with saturated NaHCO3 solution, dried over anhydrous sodium sulphate to afford 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,4-dihydro-2H-pyrrole (Int-55). MS (ESI) m/z 222 (M+H)
Reaction SMILES: C1(=O)[N:5]([C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H](CCC(OC)OC)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](N)CCC(OC)OC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(S)-2-Phthalimido-5,5-dimethoxypentanoic acid, methyl ester [prepared as described in Example 4 (f), 3.35 g., 10.43 mmol.) in methanol (70 ml.) was treated with hydrazine monohydrate (531 μl., 10.95 mmol., 1.05 eq.) and the solution was stirred at room temperature for 6 days. The mixture was filtered and the solid was washed with methanol. The filtrate was concentrated, triturated with methylene chloride, filtered again, concentrated, and dried in vacuo to yield 1.89 g. of title product as a cloudy oil. TLC (10% methanol in methylene chloride) Rf =0.39.
Reaction SMILES: [F:1][C:2]([F:59])([F:58])[C:3]([NH:5][C:6]1[N:10]([C:11]2[C:12]([F:53])=[CH:13][C:14]([CH3:52])=[C:15]([CH:17]([S:22][CH:23]([C:28]3[CH:33]=[C:32]([N:34]4[C:38]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[N:37][C:36]([C:46]([F:49])([F:48])[F:47])=[N:35]4)[C:31]([F:50])=[CH:30][C:29]=3[CH3:51])[C:24]([F:27])([F:26])[F:25])[C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:9]=[C:8]([C:54]([F:57])([F:56])[F:55])[N:7]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:68])C=1>C(Cl)(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:40]([NH:39][C:38]1[N:34]([C:32]2[C:31]([F:50])=[CH:30][C:29]([CH3:51])=[C:28]([CH:23]([S:22]([CH:17]([C:15]3[CH:16]=[C:11]([N:10]4[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:58])[F:59])=[N:7][C:8]([C:54]([F:55])([F:56])[F:57])=[N:9]4)[C:12]([F:53])=[CH:13][C:14]=3[CH3:52])[C:18]([F:21])([F:20])[F:19])=[O:68])[C:24]([F:27])([F:26])[F:25])[CH:33]=2)[N:35]=[C:36]([C:46]([F:47])([F:48])[F:49])[N:37]=1)=[O:45]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2NC(=O)C(F)(F)F)cc1C(SC(c1cc(-n2nc(C(F)(F)F)nc2NC(=O)C(F)(F)F)c(F)cc1C)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2NC(=O)C(F)(F)F)cc1C(S(=O)C(c1cc(-n2nc(C(F)(F)F)nc2NC(=O)C(F)(F)F)c(F)cc1C)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
0.8 g of [5-(5-trifluoroacetylamino-3-trifluoromethyl-1,2,4-triazolyl)-4-fluoro-2-methylphenyl]2,2,2-trifluoroethyl sulfide was dissolved in 50 ml of chloroform, and 0.3 g of m-chloroperbenzoic acid was added at 0° C., followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained solid was purified by column chromatography (eluent ethyl acetate:hexane=1:1) to obtain 0.6 g of [5-(5-trifluoroacetylamino-3-trifluoromethyl-1,2,4-triazolyl)-4-fluoro-2-methylphenyl]2,2,2-trifluoroethyl sulfoxide as a pale yellow powder (melting point 233 to 237° C.).
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:18]#[N:19])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N>C(O)C.O.[Ni]>[ClH:26].[ClH:1].[NH2:19][CH2:18][CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: NCC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
14.5 g of 4-(4-benzylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyronitrile hydrochloride are dissolved in 400 ml of 95° ethanol. A solution of 20 ml of concentrated ammonia in 40 ml of water and Raney nickel (10% by weight of the amount of amine) are added to the mixture, which is then placed under a hydrogen atmosphere, with vigorous stirring, for 4 hours, after which 1.67 l of hydrogen have been consumed. After filtration of the catalyst, the filtrate is concentrated under vacuum and the residue is taken up in ethyl acetate, washed with water, dried and concentrated under vacuum. The residue is taken up in a solution of hydrogen chloride in methanol, filtered off and recrystallized from a 3/7 acetone/ether mixture.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:7][C@H:4]([CH2:3][CH:2]([CH3:1])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:5][CH3:6])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCCC(C)C[C@@H](O)CC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCC(C)C[C@H](CC)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of (S)-5-methylnon-8-en-3-ol (9.5 g, 61 mmol) in DCM (100 mL) was added pyridine (20 mL) followed by DMAP (0.74 g, 6.08 mmole) and the solution was stirred for 10 min. p-toluenesulfonyl chloride (17.39 g, 91 mmole) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred overnight. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (100 mL). The organic solution was washed with aqueous 1.5 N HCl solution; saturated bicarbonate solution; brine solution; dried over anhydrous Na2SO4; filtered; and evaporated under reduced pressure to get crude compound (15 g, 79%). The crude compound was taken to the next step without further purification. MS: MS m/z 328.4 (M++18).
Reaction SMILES: [CH3:1][OH:2].C(OC([N:13]1[CH2:27][CH2:26][C:16]2([C:20](=[O:21])[N:19](CC#N)[C:18](=[O:25])[CH2:17]2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1.C[N:29]([CH3:32])C=O>[Pd]>[C:32]([CH2:1][O:2][N:19]1[C:18](=[O:25])[CH2:17][C:16]2([CH2:15][CH2:14][NH:13][CH2:27][CH2:26]2)[C:20]1=[O:21])#[N:29]
Reactant: CO
Reactant: N#CCN1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: CN(C)C=O
Agent: [Pd]
Product: N#CCON1C(=O)CC2(CCNCC2)C1=O
Reaction time: 5 h

Procedure:
In a mixture solvent consisting of methanol (10 ml) and dimethylformamide (10 ml) was dissolved 8-benzyloxycarbonyl-2-cyanomethyl-2,8-diazaspiro[4,5]decane-1,3-dione (0.6 g). The solution was subjected to catalytic hydrogenation for 5 hours at room temperature and under atmospheric pressure, using palladium as the catalyst. The catalyst was removed, and the solvent was evaporated off, then, the residual solid was recrystallized from ethanol to obtain 0.38 g of a coloress solid, m.p. 273° to 278° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][CH:19]=2)[C:13]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:12]1.[F-:42].[K+].Cl[C:45]([F:51])([F:50])C(OC)=O>CN(C=O)C.O>[CH2:38]([C:13]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:36])(=[O:37])[NH:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:20][CH:19]=2)[C:15](=[O:16])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[C:45]([F:51])([F:42])[F:50])[N:12]=1)[CH2:39][CH2:40][CH3:41]
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
To a solution of 600 mg (0.935 mmol) of 2-(2-bromo-5-nitrophenyl)-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step B) in 1.87 mL of DMF were added 65 mg (1.12 mmol) of potassium fluoride, 179 mg (0.935 mmol) of cuprous iodide, and 197 μL (270 mg, 1.87 mmol) of methyl chlorodifluoroacetate. The mixture was stirred in a sealed tube at 120° C. for 12 hours. The cooled mixture was diluted with H2O and extracted 3× with ethyl acetate. The combined organic extracts were washed with H2O, then brine, and dried over Na2SO4. The residue obtained upon evaporation of the filtered solution was flash chromatographed on silica gel (gradient elution with 8.5:1 to 5:1 hexane-EtOAc) to give 216 mg (37%) of the title compound as a solid, mp 135°-137° C. [Subsequently eluted was 187 mg (32%) of the corresponding 2-chloro-5-nitrophenyl analog, obtained as a byproduct.] The desired product was homogeneous by TLC (98:2 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 638 (M+Li)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([CH3:13])[C:9]2=[O:12])=[CH:5][C:4]=1[N+:14]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)Cl.[OH-].[Na+]>C(O)C.O>[NH2:14][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[O:2][CH3:1])[C:9](=[O:12])[N:8]([CH3:13])[CH2:7]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C)C2=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1N)CN(C)C2=O
Temperature: 65 °C
Yield: 70.8 %

Procedure:
To 6-methoxy-2-methyl-5-nitroisoindolin-1-one (111 mg, 0.5 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (451 mg, 2 mmol) and the mixture was heated to 65° C. for 5 h. DCM (20 mL) and 2M NaOH(aq) (10 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-amino-6-methoxy-2-methylisoindolin-1-one (68 mg, 71%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=193 at 2.32 min. 1H NMR (400 MHz, DMSO): δ 7.01 (s, 1H), 6.74 (s, 1H), 5.44 (br s, 2H), 4.24 (s, 2H), 3.85 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([CH2:11][C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].Cl[C@@H:26]1[N:29](C(=O)C(OCOC(=O)C(C)(C)C)=O)[C:28](=[O:43])[C@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45].C(O)(=O)C>ClCCl>[C:4]([O:8][C:9]([CH:11]([C@H:26]1[NH:29][C:28](=[O:43])[C@@H:27]1[C:44]([OH:47])([CH3:46])[CH3:45])[C:12](=[O:24])[C:13](=[N+:22]=[N-:23])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)CC(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)N1C(=O)[C@@H](C(C)(C)O)[C@@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C(=O)C(=[N+]=[N-])C(=O)OCC(Cl)(Cl)Cl)[C@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: -78 °C

Procedure:
To 50 ml of 0.2 M methanolic sodium methoxide solution stirred and cooled at -78° C., are successively added 3.43 g of 2,2,2-trichloroethyl 4-t-butyloxycarbonyl-2-diazo-3-oxobutyrate in 30 ml of dichloromethane and 10 mMol equivalent of pivaloyloxymethyl [3R,4S]-2-[4-chloro-3-(1-hydroxyisopropyl)-2-oxoazetidin-1-yl]-2-oxoacetate, which is prepared according to the procedure of Example 1, in 30 ml of dichloromethane. After a few minutes, 0.6 ml of acetic acid is added to the solution and the solution is evaporated to dryness under reduced pressure. The residue is taken into 50 ml of ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to give the crude product. The product is subjected to silica-gel column chromatography by use of n-hexane-ethyl acetate=1:2 for elution. The fractions containing the desired compound are combined and concentrated to give 2.6 g of the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][O:1][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[O:32])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Product: COc1ccc(NC(=O)OCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.