Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:58])([CH3:57])[C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]4)=[O:49])([CH3:58])[CH3:57])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN1CCN(C(=O)C(C)(C)N)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxy-ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [H-].[Na+].[CH3:3][Si:4]([C:7]#[CH:8])([CH3:6])[CH3:5].CS(O[CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)(=O)=O>O1CCCC1>[CH3:3][Si:4]([C:7]#[C:8][CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: C#C[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 3.2 grams (0.08 mole) of sodium hydride (60% in mineral oil) in 25 mL of tetrahydrofuran is stirred, and a solution of 7.9 grams (0.08 mole) of trimethylsilylacetylene in 15 mL of tetrahydrofuran is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about one hour. The reaction mixture is then cooled to 0° C., and a solution of 18.9 grams (0.08 mole) of 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane in 25 mL of tetrahydrofuran is added dropwise. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred during about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is stirred in water, and the mixture is extracted with three 50 mL portions of diethyl ether. The combined extracts are washed with water and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure, yielding 8-trimethylsilylethynyl-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[N:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1ccc(-c2nnco2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nnco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4(a) from 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[O:12]=[CH:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of the methyl ester from Example 11, Step A (2.0 mmol, 594 mg) in 20 mL of dry DCM cooled to −78° C under nitrogen was added dropwise over 20 min. Diisobutylaluminum hydride (4 mmol, 4 mL of a 4 M solution in toluene). The reaction was stirred for 2 h at −78° C. after which time MeOH (4 mL) cooled to −78° C. was canulated into the reaction mixture. After 10 min. the solution was allowed to reach room temperature. DCM (30 mL) was added to the reaction, and the solution was poured into 60 mL of 2N HCl. The organic phase was collected and the aqueous phase was extracted with DCM (2×20 mL). The combined organic phase was dried with MgSO4 and concentrated under reduced pressure. The aldehyde was further purified by flash chromatography on silica gel (40 g) using a step gradient of 0% to 16% EtOAc/hexanes, increasing in 4% increments. The aldehyde eluted in 12-16% EtOAc/hexanes, affording a white waxy solid. 1H NMR (500 MHz, CDCl3): δ 9.76 (s, 1H), 7.28-7.4 (m, 1H); 7.11 (d, 1H, J=7.7 Hz); 7.04 (dd, 1H, J=9.8 Hz, 2.0 Hz), 6.96-7.02 (m, 1H), 5.25 (br s, 1H), 2.92-3.1 (2H, m), 1.45 (s, 9H). MS (ESI): m/z 250 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[O:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1>C1COCC1>[O:29]1[CH2:34][CH2:33][CH:32]([CH:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[OH:36])[CH2:31][CH2:30]1
Reactant: O=CC1CCOCC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A round bottom flask at −78° C. was charged with 4-bromo-4′-(trifluoromethyl)-1,1′-biphenyl (192 mg, 0.638 mmol) and THF (2.1 mL). nBuLi 2.5M in Hexane (281 μL, 702 mmol) was then added dropwise. The mixture stirred for one hour at −78° C. after which time, tetrahydro-2H-pyran-4-carbaldehyde (86 μL, 0.83 mmol) was added in one portion and mixture stirred for 30 minutes. Reaction mixture warmed up to 0° C. and stirred for an additional hour. Reaction quenched with ammonium chloride solution (aq. sat.) and extracted twice with ethyl acetate. Combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated to provide the crude oil. Purification by silica gel flash chromatography (MeOH/DCM) to give the title compound as a colorless oil (118 mg, 55.0%). MS (M): 336.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9](=O)[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:8][C:3]1[C:2]([NH:1][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1CNc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.8 %

Procedure:
To a 5 L 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 1.6 L of acetic acid and 80.0 grams (0.62 moles) of 3-amino-2-chloropyridine. The mixture was agitated for approx. 10 minutes at 25° C. for dissolution. To the resulting solution was charged 105.9 grams (119.3 mL/0.78 moles/1.25 equivalents) of o-anisaldehyde (2-methoxybenzaldehyde), upon which was obtained a yellow solution after stirring 10 minutes at 25° C. Over a 30 minute period in portions were added 263.7 grams (1.24 moles, 2.0 equivalents) sodium triacetoxyborohydride, while maintaining a temperature of 20° C. The mixture was stirred for 12-18 hours and concentrated to a semi-solid, which was partitioned between methylene chloride and water (800 mL each). The pH was adjusted to 9.5 with 700 mL 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. by cooling. The layers were separated, the aqueous layer was washed with methylene chloride (3×300 mL each), and the methylene chloride layers were combined. The organic layer was washed with 300 mL of saturated sodium chloride solution, and then dried with magnesium sulfate for 30 minutes. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, leaving an off white tacky material (174 grams). The product was reslurried in 120 mL of fresh ethyl acetate at 0°-5° C. for 1.5 hours, filtered, washed with cold ethyl acetate and dried, giving 133.2 grams (86.1%) of the title compound. M.P. 121° -125° C. 1H NMR (CDCl3) δ 7.70 (dd, 1H, J=1Hz, 2Hz), 7.25 (m, 2H), 7.05 (m, 1H), 6.90 (m, 3H), 4.95 (t, 1H), 4.40 (d, 2H, J=6), 3.85 (s, 3H).
Reaction SMILES: ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:40][C:41]1[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][N:42]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(Cl)C2N(C(C(NC3C=CN=C(Cl)C=3)=O)=CN=2)N=1>ClCCCl>[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([NH:47][C:45]3[CH:44]=[CH:43][N:42]=[C:41]([Cl:40])[CH:46]=3)=[O:28])=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccnc(Cl)c1)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(O)c1cnc2c(Cl)cc(Cl)nn12
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(Cl)c1)c1cnc2c(Br)cc(Cl)nn12
Temperature: 65 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A ˜1:1 mixture 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (6.57 g, 28.3) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (5.52 g, 42.5 mmol) followed by N,N-dimethylformamide (0.207 g, 2.83 mmol). The reaction mixture was heated at 65° C. for 5 hours, concentrated and dried under high vacuum for 1 hr and taken into the next step without further purification. The crude mixture of acid chloride was suspended in DCE (100 mL) and treated with 2-chloropyridin-4-amine (4.37 g, 34.0 mmol) and N,N-diisopropylethylamine (5.49 g, 42.5 mmol) and stirred at room temperature for 2 hours. The reaction mixture was filtered through a Buchner funnel, and washed with DCE (2×25 mL) to isolate a 1:1 mixture of 6,8-dichloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (7.7 g, 22.5 mmol, 79% yield) as a light brown solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.51 minutes. [M+H[=343.84, and [M+H[=387.8.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:25]([C:26]3[N:31]=[C:30](S(C)=O)[C:29]([F:35])=[CH:28][N:27]=3)=[CH:24][N:23]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]2=[N:21][CH:22]=1>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:25]([C:26]3[N:31]=[C:30]([NH:1][C@H:2]4[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]4)[C:29]([F:35])=[CH:28][N:27]=3)=[CH:24][N:23]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]2=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](N)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
tert-Butyl N-[(1R,3S)-3-aminocyclohexyl]carbamate, 20a, (0.15 g, 0.70 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.49 g, 1.05 mmol) were dissolved in THF (30 mL) and allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by two rounds of silica gel chromatography—first with (0%-10% MeOH/CH2Cl2) second with (10%-50% EtOAc/hexanes) to provide tert-butyl N-[(1R,3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate (20b) (330 mg, 38%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].Cl>[OH-].[Na+].C(OCC)C>[C:8]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)N[C@@H](CO)C(=O)O
Reaction time: 2.5 h

Procedure:
5.25 g (50.0 mmol) of L-serine was dissolved in 1 N aqueous sodium hydroxide solution. 50 ml of 1 N aqueous sodium hydroxide solution and a solution of 5 ml (40.6 mmol) of pivaloyl chloride in 12 ml of diethyl ether were simultaneously added dropwise to the obtained solution in ice bath. After stirring for 2.5 hours, 70 ml of 1 N hydrochloric acid was added to the reaction mixture to make it acidic. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Br:16][C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@@H:21]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:21]2[C:22]3[C:18](=[C:17]([Br:16])[CH:25]=[CH:24][C:23]=3[F:26])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Br)ccc(F)c32)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
(1S,2S)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 6.51 g, 31.57 mmol), (S)-4-Bromo-7-fluoro-indan-1-ol (Intermediate 8, 7.29 g, 31.57 mmol) and triphenyl phosphine (9.11 g, 34.72 mmol) are dissolved in dry tetrahydrofuran (50 mL) and cooled to −20° C. under nitrogen atmosphere. Di-tert-butyl azodicarboxylate (8.00 g, 34.72 mmol) is added and the mixture stirred for 30 minutes at −20° C. then allowed to warm to room temperature and stirred overnight. The solvent is removed under vacuum and the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (Yield 8.23 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[S:12][CH2:11][N:10]2[CH:3]1[CH2:4][CH:5]1[CH:9]2[CH2:8][N:7](C(OCC)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:18])[S:12][CH2:11][N:10]2[CH:3]1[CH2:4][CH:5]1[CH:9]2[CH2:8][NH:7][CH2:6]1
Reactant: CCOC(=O)N1CC2CC3N(CSC3(C)C)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)SCN2C3CNCC3CC21

Procedure:
6 g (22.2 mmol) of ethyl 9,9-dimethyl-10-thia-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 12 g of Ba(OH)2.8H2O in 100 ml of water. Potassium carbonate is added, barium carbonate is filtered off with suction and the filtrate is extracted ten times using 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=O)[CH:9]=1)(=[O:3])[CH3:2].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ClCCl>CS(C)=O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22](=[O:24])[N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)N2CCN(c3ccccc3)CC2)nc(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a well of a 96 well microtitre plate were added methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (30μl of a 0.3M solution in anhydrous DMSO) and 4-phenylpiperazine (30w1 of a 1.5M solution). This solution was left to shake on a plate shaker for 16 hrs. After this time 800 μl of dichloromethane were added, then 100 mg of PS-NCO. The plate was sealed, then mixed for 48 hrs. The slurry was filtered and the solvents removed in vacuo, to furnish the title compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([NH2:9])[C:7]#[N:8])[CH:2]=[CH2:3].[OH:10][N:11]=[C:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13](O)=[O:14].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=O)CCCCC1>O1CCOCC1>[CH2:1]([O:4][CH2:5][CH:6]([NH:9][C:13](=[O:14])[C:12](=[N:11][OH:10])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: C=CCOCC(N)C#N
Reactant: CC(C)CC(=NO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: C1COCCO1
Product: C=CCOCC(C#N)NC(=O)C(CC(C)C)=NO
Yield: 96 %

Procedure:
In 750 ml of dioxane were dissolved 52 g of 3-allyloxy-2-aminopropionitrile, 40 g of α-hydroxyiminoisocaproic acid and 34.9 g of N-hdyroxysuccinimide. Thereto was added 59.7 g of N,N'-dicyclohexylcarbodiimide. The mixture was subjected to a reaction for 16 hours at room temperature. After completion of the reaction, N,N'-dicyclohexylurea was removed by filtration. The filtrate was concentrated to remove dioxane. The resulting residue was mixed with 800 ml of ethyl acetate. The mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 40% by volume of ethyl acetate-n-hexane) to obtain 67 g of 3-allyloxy-2-(α-hydroxyiminoisocaproylamino)propionitrile (Compound B-2) as white crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(Cl)Cl>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH:16][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CCOC(C)(C)c1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h

Procedure:
In this example 1.45 g (1.03 ml) of chloroacetyl chloride was added dropwise to a solution containing 1.44 g (2 ml) of triethylamine and 0.0129 mole of 2-methyl-6-(1-ethoxy-1-methylethyl)aniline in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. Another 0.51 ml of chloroacetyl chloride and 1 ml of triethylamine was then added dropwise. The mixture was then again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with saturated aqueous sodium bicarbonate, dried and evaporated affording the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:8].[C:21](OC(=O)C)(=[O:23])[CH3:22].[O:28]1CC[CH2:30][CH2:29]1>>[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:29](=[O:28])[CH3:30])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=[O:8])(=[O:23])[CH3:22]
Reactant: Nc1ccc(O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(OC(C)=O)c(C(=O)Nc2cccc3[nH]ccc23)c1
Reaction time: 3 h

Procedure:
A suspension of 2.6 g of the product of Step A in 70 ml of tetrahydrofuran was cooled to 0° C. to 5° C. and then 4.7 ml of acetic anhydride were added. The mixture was held at room temperature for 3 hours and was then evaporated to dryness under reduced pressure at 50° C. The residue was taken up in a 1-1 mixture of chloroform-methanol and was filtered. The product was dried at 80° C. to obtain 2.7 g of 5-acetylamino-2-acetoxy-N-(1H-indol-4-yl)-benzamide melting at >263° C.
Reaction SMILES: [N+]([O-])(O)=[O:2].[Br:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][C:7]=1[CH3:14].[OH2:15]>>[Br:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][C:7]=1[C:14]([OH:2])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Br)c(C)cc1Br
Reactant: O
Product: Cc1cc(Br)c(C(=O)O)cc1Br
Temperature: 25 °C

Procedure:
To a mixed solution of nitric acid (45 ml, 70-71%) and water (55 ml) was added portionwise 2,5-dibromo-p-xylene 802 (13.2 g, 50 mmol). The resulting mixture was heated to reflux and continued to reflux for 6 days. The mixture was cooled to room temperature and the white solid was collected by filtration. The solid was placed into a mixture of ethyl acetate (100 ml) and water (100 ml), to which was added sodium carbonate portion wise (ca 10-12 g) over a 2 hour period until all the solid dissolved. The organic layer was separated and the aqueous layer was made strongly acidic by the addition of concentrated HCl to pH 2-3. A white solid was collected by filtration and dried in vacuum to give 2,5-dibromo-4-methylbenzoic acid: 9.6 g (65%).
Reaction SMILES: [CH2:1]1[O:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[O:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1.S1(CCCC1)(=O)=O>>[Cl-:19].[CH2:2]1[O:3][CH:4]([CH:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[O:11][CH2:1]1
Reactant: COc1ccc(CCl)cc1
Reactant: c1ccc(C2OCCO2)nc1
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(CN2C=CC=CC2C2OCCO2)cc1
Product: [Cl-]
Temperature: 95 °C
Reaction time: 4 h

Procedure:
A mixture of pyridine-2-carboxaldehyde ethylene acetal (20 g; 0.13 mol), 4-methoxybenzyl chloride (21.2 g; 0.13 mol), and sulfolane (5 ml) in a 250 ml reaction flask was heated under nitrogen to 95° C. with stirring for 4 hours and then the mixture was allowed to react at room temperature overnight. The organic solvent was decanted, the resulting gummy precipitate was triturated with ethyl acetate :hexane (2:8), refluxed with stirring, and cooled. The solvent was decanted to yield 1-(p-methoxybenzyl)pyridine-2-carboxaldehyde ethylene acetal chloride (Formula IX: R1 =R7 =H; R2 =4'--OCH3 ; Z- =Cl-).
Reaction SMILES: C(OC(=O)C[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([O-])=[O:22])[C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2)(C)(C)C.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH:34]=[CH:35][CH:36]=1.[C:48]([OH:54])([C:50](F)(F)F)=[O:49]>C(OC)(C)(C)C.CO>[C:48]([O:54][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH:32]=2)=[O:22])[C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2)(=[O:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)CC1c2ccccc2C(=O)N(CC(=O)[O-])c2ccccc21
Reactant: NCc1cccc(NC(=O)NCc2ccccc2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(=O)OC1c2ccccc2C(=O)N(CC(=O)NCc2cccc(NC(=O)NCc3ccccc3)c2)c2ccccc21

Procedure:
Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (66) with (3-{[(benzylamino)-carbonyl]amino}phenyl)methanamine (hydrochloride) (41), TFA cleavage and stirring of the resulting crude product with methyl tert-butyl ether/CH3OH 19:1 afforded 0.61 g of slightly brownish solids; ESI-MS [M+H+]=563.25.