Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N+:12]([O-])=O.[H][H]>C1C=CC=CC=1.[Pd]>[CH3:11][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:12]2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: Cc1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: c1ccccc1
Product: Cc1ccc2cc[nH]c2c1
Reaction time: 5 h
Yield: 83 %

Procedure:
A glass-lined rocking autoclave was charged with a solution of 300 g (1.45 moles) of trans-β-dimethylamino-4-methyl-2-nitrostyrene in 3 l of benzene and 15 g of 5% palladium on carbon. Th autoclave was pressurized with 20 psi of hydrogen and rocked for 5 hours. The mixture was filtered through a bed of Celite, which was washed thoroughly with benzene. The filtrate was concentrated to half its volume and washed with 1 l of 0.25N hydrochloric acid, 500 ml of saturated sodium bicarbonate and 500 ml of brine. The aqueous phases were backwashed with 500 ml of benzene and the combined organic phases were dried over sodium sulfate and concentrated. The residual dark brown oil was distilled at vacuo to afford 157.9 g (83%) of product as a light yellow oil, b.p. 80-85°/0.05 mmHg, which solidified after seeding to a light yellow solid. m.p. 29-30.5°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 12.9 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.75 g, 0.19 mmol), isopropyl sulphonyl chloride (0.042 g, 0.29 mmol), TEA (0.059 g, 0.58 mmol), and DCM (10 mL) to afford 0.012 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.32 (s, 3H), 1.35 (s, 3H), 3.15 (m, 1H), 4.36 (s, 2H), 7.26-7.66 (m, 3H), 8.08-8.11 (m, 3H), 8.65 (s, 1H); MS (m/z): 492.08 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[O:22]=[C:23]1[CH:28]([N:29]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][CH2:8][C:6]3[O:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[C:13]2=[O:15])[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cccc(NCc2ccc(CO)o2)c1C(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccc(CO)o4)c3C2=O)C(=O)N1

Procedure:
3-[(5-Hydroxymethyl-furan-2-ylmethyl)-amino]-phthalic acid (3.04 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-Dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by chromatography (SiO2, 60% ethyl acetate/hexanes) to give 0.40 g of solid which was dissolved in methylene chloride (70 ml) and washed with saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated leaving 0.32 g (27%) of product as a yellow solid: mp 172–174° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 6.99 (t, J=6.0 Hz, 1H), 6.27 (d, J=2.9 Hz, 1H), 6.20 (d, J=2.9 Hz, 1H), 5.18 (t, J=5.7 Hz, 1H), 5.07 (dd, J=5.2 and 12.5 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 4.33 (d, J=5.7 Hz, 2H), 2.96–2.82 (m, 1H), 2.63–2.46 (m, 2H), 2.06–1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.80, 170.07, 168.80, 167.24, 155.00, 151.10, 145.79, 136.08, 132.12, 117.57, 111.04, 109.71, 108.06, 107.60, 55.63, 48.60, 39.05, 30.98, 22.13; Anal. Calcd. For C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.30; H, 4.54; N, 10.70.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:5]=[C:4]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:36]1([CH2:35][O:34][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:27]=2[C:4]2[CH:5]=[C:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[C:7]3[CH2:8][N:9]([S:10]([CH3:13])(=[O:11])=[O:12])[C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNS(C)(=O)=O)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(S(C)(=O)=O)C(=O)N3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(methylsulfonyl)amino]methyl}-4-pyridinyl)-1-piperidinecarboxylate (0.050 g, 0.091 mmol) and triethylamine (0.077 mL, 0.549 mmol) in tetrahydrofuran (15 mL) was added to a solution of triphosgene (0.027 g, 0.091 mmol) in tetrahydrofuran (5 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs under an argon atmosphere. After quenched by water, the mixture was extracted with ethy acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was triturated with diisopropyl ether and collected by filtration to give tert-butyl 3-[7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(methylsulfonyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]-1-piperidinecarboxylate as a yellow solid (0.028 g, yield; 55%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[CH:10]1[N:9]=[CH:8][N:7]2[CH2:2][CH2:3][C:4](=[O:5])[C:6]=12
Reactant: O=C(CCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCn2cncc21
Temperature: 0 °C
Yield: 45.7 %

Procedure:
3-Hydroxy-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (129 g) was dissolved in ethyl acetate (2 L). While stirring under ice-cooling (ice-salt), triethylamine (65.8 ml) was added and then a solution of methanesulfonyl chloride (34.2 ml) in ethyl acetate (50 ml) was added. The mixture was stirred at the same temperature for 1 h and ice water (0.8 L) was added to the reaction mixture, which was followed by partitioning. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (2.36 L) and the mixture was stirred at 70° C. for 3 h. The reaction mixture was allowed to assume room temperature. Methanol (0.8 L) and triethylamine (61 ml) were added and the mixture was stirred again at 70° C. for 1.5 h. The solvent was evaporated under reduced pressure and ethyl acetate (200 ml) was added to the resulting residue. The insoluble material was filtered off. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent; methanol/ethyl acetate; 1/24–1/9). The eluate was recrystallized from methanol/ethyl acetate to give the title compound (18.84 g) as pale brown crystals.
Reaction SMILES: [C:1]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:29][OH:30]>CCO>[C:1]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[C:24](=[N:29]/[OH:30])/[NH2:25])=[CH:20][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: COC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(/C(N)=N/O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 85 °C
Yield: 95.5 %

Procedure:
Prepared using General Procedure 2: To a stirring solution (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate (1.0 g, 2.74 mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (572.2 mg, 8.22 mmol) and TEA (1.38 g, 13.7 mmol). The reaction was heated to 85° C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with water (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude material was crystallized from isopropanol (20 mL) to afford 1.04 g (95%) of (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl)propanoate (INT-2) as a white solid. LCMS-ESI (m/z): calcd for: C22H27N3O4, 397.2. found 398.1 [M+H]+, tR=2.26 min (Method 1). 1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.57 (s, 1H), 8.78 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.79-4.49 (m, 1H), 3.65 (s, 3H), 3.15 (dt, J=13.6, 6.0 Hz, 2H), 1.75 (d, J=13.6 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][C:9]([OH:11])=O)[N:7]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:6]1[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1nc(CC(=O)O)c[nH]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: Cc1nc(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)c[nH]1
Yield: 7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methyl-1H-imidazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 162, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-4-yl)acetamido)propanamide (52 mg, 7%). 1H-NMR (400 MHz, DMSO-D6): σ 10.19 (s, 1H), 8.40-8.36 (m, 2H), 7.61 (d, 2H), 7.32-7.18 (m, 6H), 7.04-6.97 (m, 3H), 6.74 (br s, 1H), 4.69-4.64 (m, 1H), 4.52 (s, 2H), 3.67-3.54 (m, 4H), 2.20 (s, 3H). MS (EI) for C28H27FN4O4. found 503.2 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:31])[CH:26]=[CH:27][O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25](=[O:31])[CH:26]=[CH:27][O:28]4)=[CH:23][CH:22]=3)[O:9][C:8]=2[CH:15]=1
Reactant: O=c1ccoc2cc(OCCCBr)ccc12
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3c(=O)ccoc3c1)CO2
Temperature: 80 °C
Yield: 4.4 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (4.0 g, 17 mmole), 7-(3-bromopropoxy)chromen-4-one (4.9 g, 17 mmole) and diisopropylethylamine (15.1 ml, 87 mmole) were combined in 150 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed on a silica gel column using first dichloromethane and then 5% methanolic dichloromethane as eluents. The fractions containing material with Rf=0.59 on silica gel tlc (chloroform/methanol/ammonia=95/5/1) were combined, concentrated, and the residue was dissolved in 50% methanol/dichloromethane. The mixture was then treated with 4N isopropanolic HCl until the solution was 3 in pH and crystallized by triturating with ether. Two further recrystallizations gave 0.3 g of title compound as a yellow solid hydrochloride, quarter hydrate, m.p. 155°-157° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][OH:11])([O-:3])=[O:2].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>ClCCl>[Si:25]([O:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[N+:1]([O-:3])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccccc1CNCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCNCc1ccccc1[N+](=O)[O-])(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 3-[(2-nitrobenzyl)amino]propan-1-ol (1.1 g, 5.0 mmol) in dichloromethane (50 mL) was treated with imidazole (0.68 g, 10 mmol) and tert-butylchlorodiphenylsilane (1.4 mL, 5.5 mmol) and stirred at 23° C. for 2 hours. The reaction mixture was quenched by the addition of H2O (50 mL) and 2 M aqueous NaOH (10 mL), and extracted with dichloromethane (2×50 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 5-50% ethyl acetate/hexanes) provided 3-{[tert-butyl(diphenyl)silyl]oxy}-N-(2-nitrobenzyl) propan-1-amine (1.8 g, 80%) as a yellow oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([O-:26])=[O:25]>C1COCC1>[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[CH2:13][CH2:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: COc1ccc(C2=NNC(=O)CC2)cc1OC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=NN(Cc3ccc([N+](=O)[O-])cc3)C(=O)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
A suspension of 4.70 g of 6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one (“A”) in 150 ml of THF is treated with 2.24 g of potassium tertbutoxide and stirred for 30 minutes. 4.32 g of 4-nitrobenzyl chloride are added thereto and the mixture is stirred at room temperature for 10 hours. The solvent is removed. and the residue is worked up in the customary manner. 2-(4-Nitrobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, m.p. 126°, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19](SC)SC)[CH:15]=[N:14]1.BrN1C(=O)CCC1=O.O.[NH2:33]/[C:34](/[C:39]#[N:40])=[C:35](\[NH2:38])/[C:36]#[N:37]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19]=[N:33][C:34]([C:39]#[N:40])=[C:35]([NH2:38])[C:36]#[N:37])[CH:15]=[N:14]1
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CSC(Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)SC
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: N#CC(N)=C(C#N)N=CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-[2,2-di(methylthio)ethyl]-2H-1,2,3-triazole was treated with N-bromosuccinimide in aqueous acetonitrile., After 10 minutes the mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-acetaldehyde. This was then treated with diaminomaleonitrile in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[2-(2-amino-1,2-dicyanoethenylimino)ethyl]-2H-1,2,3-triazole, which was cyclised in a similar manner to Example 1a, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[(4,5-dicyano-1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole (Compound 30).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O.C1OC2C=CC(C[Cl:21])=CC=2O1>CCOCC>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Cl:21]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1ccccc1CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1ccccc1CCl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
16.8 ml of thionyl chloride are added dropwise, over the space of approximately 30 min, to 10 ml of 2-methoxybenzyl alcohol (Fluka, Buchs, Switzerland) and 53.76 g of diisopropylaminomethylpolystyrene (polyhunig base, see Ex. 44a)) in 200 ml of abs. ether. After the mixture has been stirred at 0° C. for a further 1.5 h, it is filtered with suction and the filtrate is concentrated on a RE and under HV. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 6:1). TLC Rf (hexane:ethyl acetate=4:1)=0.5. 1H-NMR (200 MHz, CDCl3): 7.42-7.24 (m, 2H); 7.0-6.84 (m, 2H); 4.68 (s, 2H); 3.9 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][CH:48]1[CH:53]2[CH2:54][CH2:55][N:50]([CH2:51][CH2:52]2)[CH2:49]1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:47][CH:48]2[CH:53]3[CH2:54][CH2:55][N:50]([CH2:51][CH2:52]3)[CH2:49]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1
Reactant: Nc1cc(OCc2cccc(I)c2)c(C(=O)O)cc1Cl
Reactant: NC1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A mixture of 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzoic acid (3.23 g, 8 mmol) and 1-hydroxybenzotriazole hydrate (1.23 g, 8 mmol) in anhydrous N, N-dimethylformamide (6 mL) under nitrogen was stirred for 30 minutes, treated with 1,3-dicyclohexylcarbodiimide (1.71 g, 8.3 mmol) in anhydrous N,N-dimethylformamide (2 mL), and stirred for 2 hours. A solution of 3-aminoquinuclidine (1.52 g, 12 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added, and the mixture was stirred for 18 hours, filtered, and the filtrate concentrated in vacuo. The residue was dissolved in 20% methanol/tetrahydrofuran and filtered through a short column of alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo and the residue was triturated from acetonitrile and recrystallized (2 crops) from 95% ethanol to afford 1.25 g (31%) of colorless solid; mp 196°-197° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH:19]([CH3:32])[C:20]([O:22]CC1C=CC(OC)=CC=1)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH:19]([CH3:32])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)C(C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxybenzyl 2-(N-CBZ-L-valyloxy)-propionate (7.8 g, 17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml) and the solution was stirred for one hour at room temperature. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 5.0 g
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=2)[CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3]1.[H-].[Na+].C(OCC)C.[Cl:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=O>CN(C)C=O>[Cl:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:10]/[C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc([P+](Cc2cccc(-c3ccsc3)c2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CCCCCCl
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCCC/C=C/c1cccc(-c2ccsc2)c1
Reaction time: 0.25 h

Procedure:
400 mg of 3-(3-thienyl)benzyl(triphenyl)phosphonium bromide was dissolved in 2 ml of dimethylformamide, and under ice cooling, 37 mg of 60% oily sodium hydride was added. The mixture was stirred for 15 minutes, and to this solution was added an ethyl ether solution (0.6 ml) of the foregoing aldehyde compound. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=19/1] to give 123 mg of the captioned compound (a mixture of E:Z=1:1) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22]>C(O)C>[C:1]1([C:7]2[C:15]([CH:16]=[N:19][NH:20][C:21]([NH2:23])=[O:22])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(N)=O
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Solvent: CCO
Product: NC(=O)NN=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 41.5 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) and semicarbazide hydrochloride (0.25 g) in ethanol (7ml) was refluxed for 1 hour and then cooled. The resulting precipitates were filtered and recrystallized from a mixture of water and ethanol to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde semicarbazone (0.26 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
While 30 mL solution of 2.72 g 4-hydroxyacetophenone and 5.2 mL diisopropyl ethylamine in dichloromethane was stirred under ice-cooling in a stream of nitrogen, 4.2 mL 2-(trimethylsilyl)ethoxymethyl chloride was added thereto. Then, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was evaporated, then ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 5.22 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].Cl[C:7]1[C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[NH:12][C:11]=2[C:10]([N+]([O-])=O)=[CH:9][CH:8]=1>CO.C1COCC1>[CH3:23][O:22][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:20]4=[C:7]([N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:19]4[C:18]=2[CH:17]=1)[CH:8]=[CH:9][CH:10]=3
Reactant: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Reactant: NNCCO
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1nn(CCO)c3cccc(c13)N2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.6 g of 2-hydroxyethyl hydrazine in 5 ml of methanol and 20 ml of THF was added over 1.5 hours to a mixture of 6.09 g of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone in 75 ml of methanol and 55 ml of THF, and the resulting suspension was stirred 20 hours at room temperature. The precipitate was collected and recrystallized from DMSO-methanol, Providing 9-methoxypyrazolo[3,4,5-kl]acridine-2(6H)ethanol, mp 275°-276° C.