Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][C@H:13]2[NH:16][C@:10]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:15][CH2:14][C@H:13]2[N:16]([CH2:25][CH:24]=[CH2:23])[C@:10]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H]2CC[C@@]1(c1ccccc1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCN1[C@@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of (1S,2S,5S)-2-(tert-butyldimethylsilyloxy)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 55; 237 mg), allyl bromide (0.4 ml), potassium carbonate (230 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was treated with diethyl ether, washed with water and brine, then dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-25%) to give the title compound (230 mg, 98% two steps).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O>CS(C)=O>[O:13]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ncccc1-c1ccc(F)nc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A mixture of potassium carbonate (3287 mg), phenol (821 mg) and 6′-fluoro-3,3′-bipyridin-2-amine (1500 mg) in DMSO (15 mL) was stirred for 1 hr at 150° C. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (1750 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[C:4](=[O:17])[N:3]1[CH3:18].[Cl:19]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[Cl:19][C:5]1([C:8]2[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])[C:6](=[O:7])[N:2]([CH3:1])[N:3]([CH3:18])[C:4]1=[O:17]
Reactant: Cc1cc(C)c(C2C(=O)N(C)N(C)C2=O)c(C)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C)c(C2(Cl)C(=O)N(C)N(C)C2=O)c(C)c1
Yield: 78.4 %

Procedure:
There was refluxed with heating a mixture of 0.50 g (2.0 mmols) of 1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3, 5-dione, 0.32 g (2.4 mmols) of N-chlorosuccinic acid imide, 19 mg (0.08 mmol) of benzoyl peroxide and 20 ml of carbon tetrachloride for 30 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with an aqueous solution of saturated sodium hydrogencarbonate and a saturated solution of sodium chloride and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was washed with hexane, thereby obtaining 0.44 g (yield 78%) of 4-chloro-1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in the form of yellowish white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15](OC)=[O:16])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Intermediate 18 (0.662 g, 2.1 mmol) dissolved in a mixture of THF (5 ml) and MeOH (5 ml) and added sodium borohydride (79 mg, 2.1 mmol). Colour of the reaction mixture changed to pink and then two drops of water added to it. Reaction mixture allowed to stir at rt for 1 h and at this stage colour changed to pink to pale yellow. Reaction mixture was allowed to stir further overnight. Work up (AcOEt/H2O) and evaporation of organic layer on vacuum afforded the title compound (558 mg) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.42 (d, J 8.9, 2H), 8.01 (d, J 8.9, 2H), 7.01 (s, 1H), 5.77 (t, J 5.4, 1H), 4.63 (d, J 5.4, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13]C)=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)[CH3:2].F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.O.OC1C2N=NNC=2C=CC=1.[C:46]([O:50][C:51](=[O:58])[NH:52][CH2:53][C:54]([NH:56][NH2:57])=[O:55])([CH3:49])([CH3:48])[CH3:47].C(N(C(C)C)C(C)C)C>ClCCl.O>[C:46]([O:50][C:51](=[O:58])[NH:52][CH2:53][C:54]([NH:56][NH:57][C:8]([C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4](=[O:13])[NH:5][C:6]=1[CH3:12])=[O:10])=[O:55])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCc1cc(C(=O)O)c(C)nc1OC
Reactant: CC(C)(C)OC(=O)NCC(=O)NN
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)NNC(=O)CNC(=O)OC(C)(C)C)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) of Step 2, Example 14 is dissolved in dichloromethane (60 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (838 mg, 2.82 mmol) is added, followed by hydroxybenzotriazole hydrate (392 mg, 2.56 mmol). The resulting mixture is stirred at rt for 30 min to give a suspension, which is treated with hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (509 mg, 2.69 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 135 hr, LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with five portions of dichloromethane, the combined extract is washed with saturated aqueous sodium bicarbonate (30 mL), then dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1). Fractions containing the product are combined and evaporated and repurified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1 increasing to 1:1) to obtain {2-[N′-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hydrazino]-2-oxo-ethyl}-carbamic acid tert-butyl ester (686 mg, 73% yield) as a white solid. MS: m/e 755 (100%) (2M+Na), 367 (70%) (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.97 (1H, br.s), 8.22 (1H, br.s), 7.44 (1H, s), 5.21 (1H, br.t), 3.96 (5H, m), 2.59 (3H, s), 2.53 (2H, q), 1.48 (9H, s), 1.18 (3H, t).
Reaction SMILES: C[N:2]([CH3:16])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[O:17]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1CN)[CH3:18]>CN1C(=O)N(C)CCC1>[CH3:18][O:17][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:16][N:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=2)[C:7]1=[NH:8]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CN(C)/C=C/c1cc([N+](=O)[O-])ccc1C#N
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(Cn2ccc3cc([N+](=O)[O-])ccc3c2=N)c(OC)c1

Procedure:
(E)-2-(2-(Dimethylamino)vinyl)-4-nitrobenzonitrile (4.6 g, 21.2 mmol) and 2,4-dimethoxylbenzylamine (4.0 mL, 1.25 eq) in DMPU (10 mL) were heated at 140° C. for 3 h. The solvent was removed by vacuum distillation and residue was treated with hexanes/ethyl acetate (1:1). The solid was collected by filtration and washed with hexane to give 2-(2,4-dimethoxybenzyl)-6-nitroisoquinolin-1(2H)-imine (4.6 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 3.81 (s, 3H) 4.96 (s, 1H) 6.28 (d, J=6.59 Hz, 1H) 6.46 (d, J=7.47 Hz, 1H) 6.58 (d, J=1.76 Hz, 1H) 7.03 (d, J=8.79 Hz, 1H) 7.27 (d, J=6.15 Hz, 1H) 8.02 (dd, J=9.01, 2.42 Hz, 1H) 8.31 (d, J=2.20 Hz, 1H) 8.43 (d, J=8.35 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](=[O:31])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)[C:11]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:31])[CH2:7][CH2:8][NH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:32][CH:33]=1
Reactant: COC(=O)c1c(NCCC(=O)c2ccc(F)cc2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccc(F)cc1
Yield: 62 %

Procedure:
Dissolve 3-[(p-fluorophenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL) and stir for 4 hours at room temperture. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate inuacuo. Purify the residue by flash chromatography (30% ethyl acetate/hexane) and recrystallize from ethyl acetate/hexane to yield the title compound (1.0 g, 62%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1.[CH3:28][N:29]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([CH:38]=1)[NH2:37])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(O)CCC.C(OCC)(=O)C>[CH3:30][N:29]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:39])=[C:36]([NH:37][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:27][CH:26]=2)[CH:38]=1)[CH3:28]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Clc1nc(-c2ccccn2)c2ccccc2n1
Reactant: Cc1ccc(CN(C)C)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(CN(C)C)cc1NC(=O)c1ccc(Nc2nc(-c3ccccn3)c3ccccc3n2)cc1
Temperature: 70 °C
Yield: 31.9 %

Procedure:
To a solution of 2-chloro-4-(pyridin-2-yl)quinazoline (60 mg, 0.25 mmol) in butanol was added 4-aminobenzoic acid (36 mg, 0.26 mmol) and the stirred mixture was heated to reflux for 20 min, after which time the reaction mixture was cooled and the solvent removed on a rotary evaporator. The residue was redissolved in dimethylformamide (20 mL) and 5-((dimethyl-amino)methyl)-2-methylaniline (50 mg, 0.30 mmol), HATU (170 mg, 0.45 mmol) and Hunig's base (150 μL, 0.87 mmol) were added to the solution. The stirred mixture was heated to 70° C. for 18 h, then diluted with ethyl acetate and the solution was extracted with 10% aqueous lithium chloride and 1 N hydrochloric acid. The combined acidic washes were made basic with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The product was purified by preparative reverse phase HPLC to give N-{5-[(dimethylamino)methyl]-2-methylphenyl}-4-[(4-pyridin-2-ylquinazolin-2-yl)amino]benzamide as a yellow solid (39 mg, 16% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 10.30 (s, 1H), 9.68 (s, 1H), 8.84-8.83 (m, 1H), 8.49-8.47 (d, 1H), 8.16-8.09 (m, 3H), 8.16-8.09 (m, 2H), 7.99-7.97 (m, 2H), 7.43-7.39 (m, 1H), 7.37 (s, 1H), 7.21 (d, 2H), 7.07 (d, 1H), 3.43 (br s, 2H), 2.22 (s, 6H), 2.20 (s, 3H). MS (EI) for C30H28N6O: 489.3 (MH+).
Reaction SMILES: [OH-].[K+].[C:3]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>CN(C)C=O>[CH2:6]([O:5][C:3]([C:8]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:4])[CH3:7]
Reactant: CCOC(=O)C(C)c1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CC2(C(=O)OCC)CCCC2=O)cc1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To 200 ml of dimethyl formamide containing 6.0 g of potassium hydroxide was added 15.6 g of 2-carboethoxycyclopentanone with stirring at room temperature to give a homogeneous solution. Under ice-cooling, 25 g of ethyl 2-(p-chloromethylphenyl)propionate was added dropwise thereto, and the mixture was heated at 80° C. with stirring for 2 hours. After completion of the reaction, the reaction mixture was poured into an ice-water, extracted with ether, the extract washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 28 g of an oily substance, which was subjected to a vacuum distillation affording 21 g of the desired compound, b.p. 175°-178° C. at 0.5 mm Hg.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>C(O)(=O)C.O>[I:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: [I-]
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a stirred clear solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (15 g, 93 mmol) in acetic acid (150 mL) and water (150 mL) was added sulfuric acid (5.5 mL, 101 mmol) dropwise at 0° C. A solution of sodium nitrite (12.90 g, 187 mmol) in water (100 mL) was then added dropwise over 40 min at the same temperature. The mixture was stirred at 0° C. for 10 min before being added to a stirred solution of sodium iodide (55.8 g, 372 mmol) in water (600 mL) slowly over 2 h at 0° C. The resulting brown suspension was stirred at 0° C. for 30 min and at room temperature for 1 h. The mixture was extracted with ethyl acetate (400 mL, 2×100 mL). The combined ethyl acetate extracts were washed with water (60 mL), saturated aqueous Na2S2O3 solution until the brown color disappeared, and saturated aqueous K3PO4 (60 mL) solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 5 to 15% ethyl acetate in hexanes) afforded 6-iodo-3,4-dihydronaphthalen-1(2H)-one (17.3 g, 63.6 mmol) as a solid. LC/MS M+1=273.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH2:10]=O.CNC.[CH2:15]=[CH:16][CH:17]=[CH2:18]>C(O)(C)C>[CH3:8][C:4]1[C:3](=[O:9])[C:2]([CH3:1])=[CH:7][C:6]2([CH2:10][CH2:18][CH:17]=[CH:16][CH2:15]2)[CH:5]=1
Reactant: C=O
Reactant: C=CC=C
Reactant: Cc1cccc(C)c1O
Agent: CNC
Solvent: CC(C)O
Product: CC1=CC2(C=C(C)C1=O)CC=CCC2

Procedure:
Following the same general procedure as in Example I, 50 mmols of 2,6-dimethylphenol were reacted with 55 mmols of paraformaldehyde, 12.5 mmols of aqueous dimethylamine, and 100 mmols of 1,3-butadiene in 54 g of isopropyl alcohol at about 190° C. for 9-10 hours. The process resulted in the formation of 2,4-dimethylspiro[5.5]undeca-1,4,8-trien-3-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.24 (s, 3H), 2.41–2.47 (m, 4H), 2.63–2.69 (m, 2H), 3.46–3.53 (m, 8H), 3.69–3.72 (m, 4H), 7.0 (s, 1H) 7.04–7.12 (m, 2H), 7.19 (d, 1H), 7.25 (s, 1H), 7.57 (d, 1H), 7.88 (s, 1H), 8.04 (d, 1H), 8.26 (d, 1H), 9.83 (s, 1H), 10.33 (s, 1H); Mass Spectrum: M+H+ 560.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20]C(OC(C)(C)C)=O)=[CH:18][CH:19]=1)[CH:6]([S:9]C(=O)C)[CH2:7][CH3:8])C>Cl>[NH2:20][C:17]1[N:16]=[CH:15][C:14]([CH2:13][CH:5]([CH:6]([SH:9])[CH2:7][CH3:8])[C:4]([OH:28])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(CC)SC(C)=O
Agent: Cl
Product: CCC(S)C(Cc1ccc(N)nc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-pentanoic acid ethyl ester/C (4.3 mg; 0.01 mmol) in concentrated HCl (2 mL) was refluxed under argon for 1.5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford 2.9 mg of the title compound as the hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CC1(C)CCCC(C)(C)N1[Li].Cl([F:27])(=O)(=O)=O>C1COCC1>[F:27][C:9]1[S:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: COc1cccc2ccsc12
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: COc1cccc2cc(F)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 1-benzothien-7-yl methyl ether (230 mg, 1.40 mmol) in dry THF (5 ML) was added dropwise to a freshly prepared solution of 2,2,6,6 tetramethyl-lithio-piperidine (1.68 mmol) in THF (10 mL) at −78° C. The resulting solution was stirred at this temperature for 30 mins before perchloryl fluoride gas was condensed into the reaction. After the strong exotherm had stopped the mixture was allowed to stir at −78° C. for a further 30 mins. After this time the reaction was quenched with NH4Cl (sat, 20 mL) and diluted with diethyl ether. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane to yield a colourless oil (128 mg, 50%); δH (300 MHz, CDCl3) 7.32-7.20 (2H, m, Ar), 6.80-6.62 (2H, m, Ar), 3.95 (3H, s, OCH3).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:16]CN(C(C)C)C(C)C.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)=[C:31]([CH:34]=1)[C:32]#[N:33].CI>C(Cl)Cl.[Zn+2].[Br-].[Br-].CN1C(=O)CCC1>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][S:14][C:11]3[N:12]([CH3:16])[CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:34][C:31]=2[C:32]#[N:33])=[CH:37][C:38]=1[C:43]([F:46])([F:45])[F:44]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1SCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a solution of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (70 mg, 0.318 mmol) and DIPEA (0.083 ml, 0.477 mmol) in DCM (2 ml), was added 5-(chloromethyl)-2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (110 mg, 0.318 mmol). The mixture was stirred at 60° C. overnight. After removing the solvent by nitrogen, the residue was dissolved in MeCN (4 ml), and NMP (1.5 ml), and ZnBr2 (107 mg, 0.477 mmol) and DIPEA (0.083 ml, 0.477 mmol) were added. The mixture was then heated at 60° C. for 10 min. And MeI (0.020 ml, 0.318 mmol) was added dropwise, then stirred at 60° C. for 1.5 h. Purification via MDAP then afforded the title compound (24 mg, 11.49% yield). LCMS: rt=3.20 min, [M+H+]=544
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:11][N:12]=1.O>O1CCCC1>[CH3:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:11][N:12]=1
Reactant: COC(=O)CCc1cnc(C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(CCCO)s1
Temperature: 10 °C
Yield: 69.2 %

Procedure:
A mixture of 125 ml of tetrahydrofuran and 3.42 g of lithium aluminum hydride was cooled to about 10° C. and a mixture of 10.9 g of methyl 2-methyl-5-thiazolepropanoate in 70 ml of tetrahydrofuran was slowly added thereto with stirring while keeping the temperature between 10-15° C. The mixture was then stirred for about 30 minutes and tetrahydrofuran containing 20% of water was slowly added. The mixture was filtered and the filter was washed with ethyl acetate. The filtrate was dried over magnesium sulfate and concentrated to dryness under reduced pressure to obtain 8.4 g of a raw product which was rectified under reduced pressure to obtain 6.4 g of 2-methyl-5-thiazole-propanol with a boiling point of 106° C. at 0.05 mm Hg.
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]4=[O:36])=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Under inert conditions, 5 ml of DMSO are admixed with 30 mg of NaH (60% in paraffin oil), and the mixture is heated at 75° C. for 30 min, until the evolution of gas has ceased. A solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride is then added dropwise, and the mixture is stirred at room temperature overnight. The reaction is terminated and the mixture is poured into 100 ml of water and extracted with ethyl acetate. The evaporated organic phase is chromatographed on an RP-8 column and the product is eluted with acetonitrile/water. This gives 20 mg (7.5% of theory) of the target compound.