Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[C:12]1([C:22]([C:24]2[C:31]([Cl:32])=[CH:30][C:27]([CH2:28]Br)=[CH:26][C:25]=2[Cl:33])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([CH2:28][C:27]2[CH:26]=[C:25]([Cl:33])[C:24]([C:22]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[O:23])=[C:31]([Cl:32])[CH:30]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: O=C(c1c(Cl)cc(CBr)cc1Cl)c1cccc2ccccc12
Reactant: NC(=O)c1nn[nH]c1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3cccc4ccccc34)c(Cl)c2)c1N
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 33.3 %

Procedure:
A solution of 5-amino-l,2,3-triazole-4-carboxamide (364 mg, 2.86 mmol) in 5 ml of dry dimethylformamide was treated with 50 % sodium hydride dispersion in mineral oil (137 mg, 2.86 mmol). The reaction mixture was warmed to 45° C. and then stirred for 45 minutes. A solution of 4-(1-naphthoyl)-3,5-dichlorobenzyl bromide (0.98 g, 2.49 mmol) in 5 ml of dry dimethylformamide was added. The reaction mixture was heated at 45° C. for an additional 20 minutes and then stirred at ambient temperatures for 1 hour. The mixture was slowly added to 100 ml of water containing two drops of glacial acetic acid. The precipitate was collected by filtration and thoroughly washed with water. The solid was dissolved in methylene chloride and washed with brine and dried with anhydrous sodium sulfate. Evaporation of the solvent afforded 1.11 g of crude product which was purified by column chromatography on silica gel (3g methanol in methylene chloride) to give 0.365 g of 5-Amino-1-[4-(l-naphthoyl)-3,5-dichlorobenzyl]1,2,3-triazole-4-carboxamide and 0.46 g of an isomer of undefined regiochemistry.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:33]4[O:37][C:36]([C:38]5[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=5)=[N:35][N:34]=4)[CH:17]=[C:18]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:45]([O:50][CH2:51][CH2:52]Br)(=[O:49])[C:46]([CH3:48])=[CH2:47].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:45]([O:50][CH2:51][CH2:52][O:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:36]2[O:37][C:33]([C:16]3[CH:15]=[C:14]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)[CH:19]=[C:18]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:17]=3)=[N:34][N:35]=2)[CH:39]=1)(=[O:49])[C:46]([CH3:48])=[CH2:47]
Reactant: C=C(C)C(=O)OCCBr
Reactant: Oc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 21 h

Procedure:
To a solution of 3-(5-(3,5-dicarbazol-9-ylphenyl)-1,3,4-oxadiazol-2-yl)phenol (0.7 g, 1.23 mmol) and 2-bromoethyl methacrylate (0.25 g, 1.30 mmol) in DMF (20.0 ml) was added K2CO3 (2.0 g, 14.47 mmol) at room temperature under stirring. The reaction was carried out at room temperature for 21 h. Water (100.0 ml) was added. Brown solid product was obtained by filtration and washed with methanol. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After removal of solvent, white glass-like solid product was dissolved in THF (10.0 ml). Methanol (120.0 ml) was added into THF solution. White solid product was obtained and collected by filtration. After vacuum dry, the product as white solid in 0.7 g (83.3%) was obtained. 1H NMR (400 MHz, CDCl3, δ): 8.47 (d, 5=1.6 Hz, 2H), 8.16 (d, J=8.0 Hz, 4 Hz), 8.01 (d, J=1.6 Hz, 1H), 7.71 (dt, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.67 (m, 1H), 7.57 (d, J=8.4 Hz, 4H), 7.49-7.40 (m, 5H), 7.34 (m, 4H), 7.10 (m, 1H), 6.11 (t, 5=1.2 Hz, 1H), 5.55 (m, 1H), 4.49 (t, J=4.4 Hz, 2H, OCH2), 4.29 (t, J=4.4 Hz, 2H, OCH2), 1.92 (t, J=1.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 167.24, 165.05, 163.35, 159.01, 140.51, 140.32, 135.85, 130.43, 128.12, 127.36, 126.43, 126.16, 124.60, 123.84, 123.77, 120.82, 120.61, 119.95, 119.09, 112.50, 109.52, 66.24, 62.81, 18.26. [M]+ calcd for C44H32N4O4, 680.2.2. found 680.2. Anal. Calcd for C44H32N4O4: C, 77.63; H, 4.74; N, 8.23. Found: C, 77.49; H, 4.69; N, 8.21.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN(CC)CC.[Na+].[Cl-]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][N:6]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCOCC2)cn1
Temperature: 45 °C
Yield: 90.4 %

Procedure:
A mixture of 4.9 g (28 mmol) 5-chloro-pyrazine-2-carboxylic acid methyl ester (commercially available), 3.2 g (37 mmol) morpholine and 7.37 g (73 mmol) NEt3 in 50 mL dioxane was heated to 45° C. for 16 h. Water and NaCl aq. was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with NaCl aq., dried with MgSO4, filtered and evaporated. The residue was recrystallized from ethyl acetate to yield 5.65 g (89%) of the title compound as white solid. m/z (ES+): 224.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1.C([Li])CCC.[S:22](=[O:24])=[O:23].ClN1C(=O)CCC1=O.[C:33]([NH2:37])([CH3:36])([CH3:35])[CH3:34]>O1CCCC1>[CH3:34][C:33]([NH:37][S:22]([C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1)(=[O:24])=[O:23])([CH3:36])[CH3:35]
Reactant: O=S=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reactant: CC(C)(C)N
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.55 g (0.0151 mol) of 3-bromo-N-triisopropylsilylpyrrole in 100 mL anhydrous tetrahydrofuran (THF) under nitrogen atmosphere was cooled to -60° C. then treated with 10.4 mL of 1.6M butyllithium in hexanes (0.0166 mol) dropwise at such a rate as to keep the temperature below -60° C. After ca. 30 minutes at this temperature, liquified sulfur dioxide was added (3.9 mL, 0.090 mol). The brown solution was then warmed to room temperature, and the THF was removed under reduced pressure. The resulting light brown solid was dissolved in 100 mL acetic acid and then treated with 2.0 g (0.015 mol) N-chlorosuccinimide with cooling to keep the temperature less than 25° C. After 2 hours, the acetic acid was evaporated under reduced pressure and the residue taken up in ethyl acetate. This solution was washed successively with water, NaHCO3 solution, 5% NaHSO3 solution, NaHCO3 solution, brine, then dried with MgSO4 and evaporated in vacuo. The resulting dark brown oil residue was dissolved in methylene chloride (200 mL) and treated with 8 mL (0.075 mol) t-butylamine and then stirred for 3 days at ambient temperature. The solution was then washed with 1N HCl, dried (MgSO4), and evaporated to a dark oil. Chromatography on silica gel (10% ethyl acetate/hexanes) afforded 4.0 g of the title compound as an amber oil that solidified on standing.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[OH:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[Si:8]([O:16][CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1nc2ccccc2[nH]1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
At room temperature, triethylamine (2.27 ml, 16.3 mmol) and TBDMS chloride (1.65 g, 10.95 mmol) were added to a solution of 2-hydroxymethylbenzimidazole (1.48 g, 9.95 mmol) in DMF-(30 ml). After 3.5 h, the reaction-was terminated by addition of water, the mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate. Chromatography (silica gel, cyclohexane:ethyl acetate 2:1, Rf=0.35) gave 2.52 g of 2-tert-butyldimethylsilyloxymethyl-benzimidazole (97% of theory) as a brownish powder. MS (DCI, NH3)=263 (M+H+). 1H-NMR (DMSO-d6): 0.00 (6H, s); 0.80 (9H, s); 4.75 (2H, s); 7.0-7.1 (2H, m); 7.4-7.5 (2H, m); 12.15 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:4]2[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[CH:6][N:5]=2)[CH2:13][CH2:14]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1nc(C)cnc1NCC1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Product: COc1nc(C)cnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine using N-(benzyloxycarbonyloxy)succinimide (Sigma-Aldrich). M.S. (M+1): 371.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].BrCC.[Mg].O=C1[O:14][C:13](=O)[C:12]2([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:11]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[O:14]=[C:13]([C:12]1([NH:11][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:1][CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)OC(=O)N2c1ccccc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)CC)CC1
Reaction time: 1 h

Procedure:
A Grignard-complex, ethyl magnesium bromide, is prepared in the conventional manner, starting from 10.57 parts of 1-bromoethane and 2.14 parts of magnesium in 27 parts of dry tetrahydrofuran. This complex is added dropwise to a warm suspension of 25.7 parts of ethyl 2,4-dioxo-1-phenyl-3-oxa-1,8-diazaspiro[4,5]decane-8-carboxylate in 213 parts of dry tetrahydrofuran: exothermic reaction. Upon completion, stirring is continued for 1 hour at room temperature. After cooling, the reaction mixture is decomposed by dropwise addition of an ammonium chloride solution. The layers are separated and the aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding ethyl 4-(1-oxopropyl)-4-(phenylamino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]#[C:16][Si](C)(C)C)[C:3]=1[C:21]([F:24])([F:23])[F:22].[C:25]([Cu])#[N:26].[OH-].[NH4+]>CN1C(=O)CCC1>[F:24][C:21]([F:22])([F:23])[C:3]1[C:2]([C:25]#[N:26])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:15]=[CH:16][NH:8]2
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1C#C[Si](C)(C)C
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Temperature: 250 °C

Procedure:
An NMP solution (15 mL) of N-{4-chloro-3-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]phenyl}-2,2-dimethylpropanamide (1.04 g, 2.77 mmol) was treated with CuCN (1.04 g, 11.01 mmol) and the resulting mixture was heated at 250° C. in a microwave for 5.5 h. The dark brown reaction mixture was poured into crushed ice (250 mL) containing conc. ammonium hydroxide (30 mL). The resulting slurry was filtered and rinsed with Et2O. The filtrate was diluted with Et2O (50 mL) and partitioned. The aqueous portion was extracted with Et2O (2×25 mL). The combined organic portions were washed with H2O (25 mL) and brine (25 mL). Drying (Na2SO4) and filtration were followed by concentration to a brown/yellow solid (0.723 g) that was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1>>[CH:8]1([C:2]2[CH:3]=[C:4]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:5]=[C:6]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:1]=2[OH:7])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Oc1ccccc1
Reactant: C1=CCCC1
Product: Oc1c(C2CCCC2)cc(C2CCCC2)cc1C1CCCC1
Reaction time: 15 h
Yield: 11.6 %

Procedure:
To 470 g of phenol and 100 g of an acid-activated fuller's earth 1020 g of cyclopentene are added dropwise at 140° C whereupon the mixture is stirred at the same temperature for 15 h. After elimination of the catalyst by filtration the reaction mixture is distilled by fractionation. Besides 2,4,6-tricyclopentylphenol 173 g of a fraction are obtained having a boiling range of 205° to 212° C at 1.4 mm Hg which are recrystallised from ligroin. Yield: 143 g of 2,4,5-tricyclopentylphenol. Melting point: 104° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:20])([C:13]#[C:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:29][CH2:30][C:31](Br)=[O:32]>CCOCC>[Cl:21][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:31](=[O:32])[C@H:30]([CH3:29])[O:20][C@:8]([C:13]#[C:14][C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: O=C(Br)CCBr
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H]1O[C@](C#Cc2ccco2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 265 mg of 6-amino-3-chloro-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.150 mL of dry pyridine and 0.100 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF at 0°, 25 mg of 100% sodium hydride was added, and the resulting mixture was stirred for 15 min at 0° and at room temperature for 30 min. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to a residue which was purified by column chromatography on silica gel (elution with 17-33% ethyl acetate in hexanes) affording after crystallization from ethyl acetate/hexanes 5 mg of the title compound: HRMS: Calcd. for C17H12NO3C1F3 (M+H)+: 369.037956. Found: 369.036835.
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)=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27].[H-].[Na+].C([Li])CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:11][CH:12]([OH:13])[CH2:28][C:26](=[O:27])[CH2:25][C:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of 5,5-bis(4-fluorophenyl)-4-(1-methyl-ethyl)-2,4-pentadienal (0.5 g, 1.6 mmol) in 20 mL tetrahydrafuran at -70° C., was added the dianion of t-butyl acetoacetate (2.1 mL of 1M solution in THF, 2.1 mmol) which was prepared by adding t-butyl acetoacetate (4.0 g, 25 mmol) in 4 mL tetrahydrofuran to a suspension of sodium hydride (1.0 g of 50% in oil, 25 mmol) in 6 mL tetrahydrofuran at -10° C., butyl lithium (11.4 mL of 2.2M solution) 25 mL was added and stirred for 0.5 hrs. After stirring for 2.5 hrs. the reaction was quenched with 2N hydrochloric acid. The mixture was extracted with diethyl ether. The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 1% methanol in methylene chloride to give 0.5 g of the title compound as a clear oil. MS(CI): m/e =370 for M3 ;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1>[Ni].CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc([N+](=O)[O-])cn3)CC2)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCN(Cc3ccc(N)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A suspension of 1-(4-methoxy-benzyl)-4-(5-nitro-pyridin-2-ylmethyl)-piperazine (Step 111.2) (0.635 g, 1.85 mmol) and Raney Nickel (0.150 g) in MeOH/THF (1:1, v/v; 50 mL) was stirred for 24 h at rt, under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1) to afford 439 mg of the title compound as a white solid. Title compound: ESI-MS: 313.3 [M+H]+; tR=1.40 min (System 1); TLC: Rf=0.18 (DCM/MeOH, 9:1).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:28].C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH2:27]([C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[CH3:28]
Reactant: CCc1ccc(C(=O)c2ccccc2)cc1CC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CCc1ccc(C(=CC#N)c2ccccc2)cc1CC

Procedure:
3-(3,4-Diethylphenyl)-3-phenylacrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-diethylbenzophenone (0.95 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 2 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 8% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried and then dried in vacuo to afford 0.6 g (57%) of a mixture of the E and Z isomers as a white solid: mp 63-64° C.; 1H NMR (CDCl3) δ7.51-6.99 (m, 16 H), 5.72 (s, 2 H), 2.76 -2.55 (m, 8 H), 1.32-1.14 (m, 12 H); 13C NMR (CDCl3) δ163.3, 144.7, 142.2, 137.3, 136.5, 130.2, 129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127.2, 126.2, 118.2, 93.9, 93.7, 25.5, 25.3, 15.2, 15.0.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCCCC(=O)Cl
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: CCCCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and valeryl chloride. m.p.: 124-126° C. 1H-NMR (CDCl3) δ: 10.02 (1H, br s), 8.40-8.18 (2H, m), 7.62-7.54 (2H, m), 7.47-7.42 (2H, m), 7.28 (1H, s), 7.09 (1H, d, J=8.8 Hz), 2.55-2.45 (5H, m), 1.82-1.68 (2H, m), 1.52-1.38 (2H, m), 0.98 (3H, t, J=7.0 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:6]1[C@@H:9]([CH2:10][CH:11]=[O:12])[NH:8][C:7]1=[O:13])([CH3:5])[CH3:4].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:1][O:2][C:3]([C@H:6]1[C:7](=[O:13])[NH:8][C@@H:9]1[CH2:10][C:11]([OH:16])=[O:12])([CH3:5])[CH3:4]
Reactant: CC(C)=O
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S, 4R)-3-(1-methoxy-1-methylethyl)-4-(2-oxoethyl)azetidin-2-one (760 mg) in acetone (60 ml) was added dropwise 2N Jones Reagent (4.10 ml) at 0° C. After stirring for 30 minutes at 0° C., isopropyl alcohol (8 ml) was added to the resultant mixture, and then evaporated in vacuo. The residue was dissolved in a saturated aqueous sodium chloride (40 ml) and extracted with chloroform (80 ml×5). After drying over magnesium sulfate, the chloroform extracts were filtered and evaporated in vacuo. The residue was chromatographed on silica gel (30 g) eluting with a mixture of methylene chloride and methanol (10:1 to 1:2), and then a mixture of acetic acid and ethyl acetate (1:50) to give 2-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (545.1 mg) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:6]([NH2:8])[N:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16])(=[O:19])[CH3:18]
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(N)nnc1-c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A solution of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (2 gm, 8 mM) and acetic anhydride (10 mls) in acetic acid (20 mls) was stirred and heated to reflux for 2 hours. The solution was then cooled and evaporated down in vacuo. The residue was treated with aqueous 0.880 ammonia (100 mls) and the resultant mixture was stirred for 2 hours. The solid was separated by filtration, dried then recrystallized from isopropanol to give 5-acetamido-3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine. Yield 1.0 gms (42%), m.p. 250°-252° C. (uncorrected).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10](SC)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].OO.[S:16]([O-:19])([O-])=[O:17].[Na+].[Na+].Cl.[C:23](O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:16]([CH3:23])(=[O:19])=[O:17])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(SC)ccc1C(=O)O
Reactant: CC(=O)O
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
2-methoxy-4-(methylthio)benzoic acid (10.8 g, 54 mmol) is dissolved in acetic acid and the solution was cooled to 10° C. Sodium tungstate 2-hydrate (1.2 g, 3.7 mmol) was added until percipitation. After the precipitation had dissolved and the solution was cooled H2O2 (4.1 ml, 135 mmol) was added dropwise. 10 minutes later the reaction mixture was heated to 50° C. for 1 h. Sodium sulphite (3.4 g, 27 mmol) in water (80 ml) was added and the resulting mixture was stirred for 30 min. Water and aqueous HCl (10%) were added. The aqueous phase was extracted with EtOAc and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a white powder (5.7 g). No further purification was made of this intermediate. 1H-NMR (400 MHz, MeOH): δ 7.92 (1H, d, J 8 Hz), δ 7.61 (1H, s), δ 7.56 (1H, d, J 8 Hz), δ 3.95 (3H, s), δ 3.18 (3H, s).