Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.N>C(Cl)Cl.[Rh]>[C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCCCC1
Agent: [Rh]
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: NCC1(c2ccccc2)CCCCC1

Procedure:
A mixture containing 1-phenyl-1-cyclohexane-carbonitrile (5.0 g, 27.0 mmol), 150 ml of EtOH, 35 ml of ammonia and 5% rhodium on alumina (1.0 g) was reacted for 12 hours at 80° C. and 500 psi. The mixture was filtered and the filtrate was concentrated in vacuo to provide an oil. This oil was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(N1CCC[C@H]1C(O)=O)=[O:4].C1C([N+]([O-])=O)=CC=C(O)C=1.[CH2:30]1[CH2:35][CH2:34][CH:33]([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:32][CH2:31]1>C(Cl)Cl>[C:37]([NH:36][CH:33]1[CH2:32][CH2:31][CH2:30][CH2:35][CH2:34]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Boc-Gly-Pro-OH (2.8 g, 0.01 mol.) and p-nitrophenol (1.7 g, 0.012 mol.) were dissolved in DCM (100 ml) and DCC (2.1 g, 0.01 mol.) was added to the solution by portions while stirring the solution. A precipitate (dicyclohexylurea, DCU) soon formed. After stirring the solution at room temperature for 3.5 hours, TLC analysis (developing solvents:ethyl acetate/hexane, 3:1) showed that all the starting material Boc-Gly-Pro-OH was consumed. The Rf for the product Boc-Gly-Pro-ONp is 0.45 in this solvent system. DCU was removed by filtration and DCM was removed under reduced pressure. Ethyl acetate was added to the remaining oil and the resulting solution was chilled to 0° C. More precipitate formed and was removed by filtration. The above procedures were repeated and a brownish oil was obtained. The product was directly used in the synthesis of Boc-Gly-Pro-Hyp(OBz)-OH without further purification and characterization.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 90.3 %

Procedure:
A solution of Example 39H (2.76 g, 5.80 mmol), mesyl chloride (1.79 mL, 23.2 mmol), and pyridine (3.75 mL, 46.4 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.71 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1 H) 0.74 (m, 7 H) 1.34 (m, 1 H) 1.57 (m, 3 H) 2.15 (m, 2 H) 3.08 (m, 3 H) 7.56 (m, 3 H) 7.75 (m, 3 H) 8.16 (m, 1 H) 10.26 (m, 1 H) 13.76 (m, 1 H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](Cl)=[O:22].[Na+].C([O-])(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:22]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: O=C([O-])CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 2.75 h

Procedure:
A solution of 46.0 g of (R)-4-phenyl-2-oxazolidinone in 300 g (338 mL) of peroxide-free tetrahydrofuran is cooled to −5 to 0° C. (bath temperature −10 to −5° C.) over a period of 15 minutes. 145.2 g (166.8 mL) of 25% w/w potassium t-amylate/toluene solution is added over a period of 25 minutes while maintaining an internal temperature below 0° C. The reaction mixture is warmed to 20±5° C. within 1 hour and stirred at this temperature for 2.5-3 hours. The mixture is cooled to −15 to −5° C. over a period of 30 minutes, and crude 2-fluorobenzenacetyl chloride (obtained above) is added over a period of 45 minutes while maintaining an internal temperature below −5° C. (bath temperature −15 to −10° C.). After the addition is completed, the mixture is warmed to 20±5° C. over a period of 1 hour, and diluted with 100 mL of toluene. This is added to 500 mL of saturated citric acid monosodium salt solution (100 g in 450 g of water) and the mixture is stirred for 5 minutes. The organic layer is separated, and washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each. The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 450 mL of t-butyl methyl ether and the mixture is heated to reflux (53-58° C.) to obtain a solution; 225 mL of t-butyl methyl ether is then distilled off at atmospheric pressure (bath temperature 60-65° C.). The resulting mixture is cooled to 20-25° C., and stirred at this temperature for 16 hours, then cooled to −5 to 0° C. and stirred at this temperature for additional 2 hours and filtered. The resulting solid is dried under vacuum (66-76 mm Hg) at 45-50° C. for 12 hours to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a white crystalline solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C([O-])(=O)C.[Na+].[Br:19]Br.O>C(O)(=O)C>[Br:19][C:8]1[CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: COC(=O)c1n[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VI) (0.177 g, 1 mmol), sodium acetate (0.492 g, 6 mmol) and bromine (0.308 mL, 6 mmol) in glacial acetic acid (5 mL) was heated overnight at 120° C. in a sealed tube. The solution was cooled and poured into water. The solids formed were filtered, washed with water and dried at room temperature under vacuum. The crude product was purified on a flash silica gel column (100% DCM→100:2 DCM:MeOH) to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) as a white solid (78 mg, 0.31 mmol, 30% yield). 1H NMR (CDCl3) δ ppm 3.95 (s, 3 H), 8.62 (d, J=3.01 Hz, 1 H), 8.73 (d, J=3.01 Hz, 1 H); ESIMS found for C8H6BrN3O2 m/z 256.3 (M+H).
Reaction SMILES: [Br:1][C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.C(OCC)(=O)C.[CH3:17][NH:18][CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[OH:7][C@@H:8]1[C@@H:2]([Br:1])[CH2:3][CH2:4][C@H:5]([C:6]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:9]1
Reactant: CNC
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Temperature: 5 °C
Reaction time: 14 h

Procedure:
(1S,4S,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (200 g) was added to ethyl acetate (1000 ml), and the obtained solution was then cooled to 5° C. Thereafter, a 50% dimethylamine aqueous solution (305.7 ml) was added to the reaction solution, and the obtained mixture was then stirred for 14 hours. Thereafter, a mixed solution of citric acid (131.17 g), common salt (92.00 g) and water (324 ml) was added to the reaction solution, and the obtained mixture was then heated to 30° C. The reaction solution was stirred for 30 minutes, and thereafter, it was left at rest, so that the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (800 ml) again. The organic layers were gathered, and the gathered organic layer was then concentrated to 1000 ml. Water (400 ml) was added to the concentrated solution, and the thus mixed solution was concentrated again to obtain an aqueous solution (500 ml) of (1S,3S,4S)-3-hydroxy-4-bromo-N,N-dimethylcyclohexanecarboxamide. To this aqueous solution (500 ml), a 28% ammonia aqueous solution (1247 ml) and a 25% sodium hydroxide aqueous solution (123 ml) were added, and the obtained solution was then heated to 40° C., followed by stirring the reaction solution for 6 hours. Thereafter, the reaction solution was concentrated to 1000 ml to obtain an aqueous solution containing the title compound (147.52 g, yield: 81%).
Reaction SMILES: C(OC(=O)C)C.Cl.C(OCC)(=O)C.C(OC(=O)[NH:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(C)(C)C>CO>[NH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2)[CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1
Reactant: Cn1c(=O)ccc2cc(OCCCN(CCNC(=O)OC(C)(C)C)Cc3ccncc3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCCN(CCN)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A 4N-hydrogen chloride ethyl acetate solution(0.22 ml) was added to an ethyl acetate solution (3 ml) of (2-{[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (137 mg), and the mixture was stirred at room temperature overnight. 5N-Ammoia methanol solution(1 ml) was added to the reaction mixture, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound(85.7 mg) as an colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:11]=[CH2:10]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Into a 1 L round-bottomed flask containing 500 ml of acetonitrile was added 4-fluorophenol (30.0 g, 267.6 mmol), 3-bromoprop-1-ene (41.7 g, 344.7 mmol, 1.3 eq), and potassium carbonate (55 g, 398 mmol, 1.5 eq). The mixture was stirred for 3.5 hours at 60° C. (oil bath).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 336.3 parts of 4-fluorophenol, 417.5 parts of allyl bromide, 420 parts of potassium carbonate and 480 parts of acetone is stirred and refluxed for 8 hours. After cooling to room temperature, 2250 parts of water are added. The aqueous layer is separated and extracted twice with ether. The combined extracts are washed successively twice with sodium hydroxide solution 10% and twice with sodium chloride solution, dried over potassium carbonate, filtered and evaporated. The oily residue is distilled in vacuo, yielding 381.8 parts of 4-allyloxy-fluorobenzene; bp. 93° C at 23 mm. pressure; nD20 : 1.4950; d2020 : 1.070.
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:17]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:15]4[C:4]([CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12]2)=[CH:5][CH:6]=[C:7]3[CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)Cl
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A mixed solution of 4.1 g of pyrene, 2 g of t-butyl chloride and 33 ml of dichloromethane was cooled to 0° C. under a nitrogen stream, and 2.7 g of aluminum chloride was added. After this mixed solution was stirred at room temperature for 3 hours, 30 ml of water was added, and this was extracted with 30 ml of dichloromethane. The organic layer was washed with 20 ml of water two times, dried with magnesium sulfate, and evaporated. This was purified by silica gel column chromatography, and vacuum-dried to obtain 3 g (content 65%) of 2-t-butylpyrene.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].C[N+](C)(C)C.[C:19]([O:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(OC(C)(C)C)=O.OC1C=CC(C=C)=CC=1>>[C:30]([O:29][C:27]([O:26][C:19]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=Cc1ccc(O)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
10.00 gs (6.17×10-2 moles) of 4-acetoxystyrene was added to a 25 wt % solution of tetramethylammonium hydroxide (52 mL, 15% mole excess). After stirring for 15 minutes, a clear yellowish solution was obtained. To this solution was added with stirring to mix the phases 13.46 gs (6.17×10-2 moles) of di-tert-butyl dicarbonate. Slow formation of product was observed during 1 to 2 hours and the reaction essentially reached completion after 5 hours. A slight amount of residual 4-hydroxystyrene was detected by thin layer chromotography. The reaction mixture was extracted with two (15 mL) portion of ethyl ether. The ethyl ether extract was washed with 10 mL of 25% tetramethylammonium hydroxide(TMAH) and distilled water to remove base. The organic layer was dried over MgSO4 filtered and the solvent removed under vacuum yielding 11.87 gs (87% yield) of pure 4-tert-butyloxycarbonyloxystyrene. Analysis of the product indicated: IR(cm-1): 2950, 1755, 1275, 1150; 1H NMR(CDCl3, ppm): 1.54(s, 9H), 5.20(d(11 Hz), 1H), 5.67(d(18 Hz), 1H), 6.67(d of d(11, 18 Hz), 1H), 7.11(d(8 Hz), 2H); 7.38(d(8Hz), 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: CSc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.6 g, 9.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]yridine, 7a, (2.5 g, 6.0 mmol) and Na2CO3 (1.9 g, 18.0 mmol) were dissolved in DME (37.5 mL) and water (7.5 mL). The mixture was purged with nitrogen for 20 minutes, treated with Pd(PPh3)4, purged with nitrogen for another 20 minutes and heated to reflux overnight. After cooling to room temperature, water (35 mL) was added and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and acetonitrile and dried overnight at 50° C., affording 2.3 g (88.5%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.70-8.57 (m, 2H), 8.55-8.42 (m, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:74][CH:75]1[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH:75]5[CH2:80][CH2:79][N:78]([CH3:81])[CH2:77][CH2:76]5)=[O:27])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To a suspension of 0.0293 g (0.000072 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-50a) in 3 mL of dimethylformamide was added 0.0156 g (0.00012 mole) of 1-hydroxybenzotriazole, 0.043 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.08 mL (0.0005 mole) of ethyldiisopropylamine. The mixture was stirred for 15 minutes and then 0.0129 g (0.00011 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-85:15) to give 0.0181 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-50).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[OH:19][C@@H:20]1[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:19][C@@H:20]2[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CO1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Temperature: 60 °C

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step ii) (0.25 g) and 1,1-dimethylethyl (S)-4-hydroxyisoxazolidine-2-carboxylate (0.16 g) in dry THF (5 mL) was added 60% Sodium hydride (0.034 g) over 5 min. The reaction mixture was stirred and heated at 60° C. for 7 days, 1120 was added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (1:9) to give the subtitle compound as a gum. Yield: 0.15 g.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].S(=O)(=O)(O)O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([F:27])[C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].BrCC#N>C1COCC1>[C:1]([CH2:2][NH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([F:27])[C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20])#[N:4]
Reactant: COC(=O)c1cc(N)c(C)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(C)c(NCC#N)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of N,N-diisopropylethylamine (187 mL, 1073.6 mmol) in THF (240 mL) at 60-65° C. was added a solution of methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt (80.0 g, 268.8 mmol) in THF (720 mL), maintaining the temperature in the range 45-65° C. Bromoacetonitrile (56.2 mL, 806.8 mmol) was charged and the solution heated to reflux for 3 d before concentration to 8 rel. vols. by distillation at atmospheric pressure. The solution was cooled to ambient temperature and water (1000 mL) added, maintaining the temperature in the range 18-23° C. The pH was adjusted to 1.2-1.5 with aq. hydrochloric acid (4 M, ˜80 mL) and the resulting slurry stirred at ambient temperature for 2 h before being filtered through 100 μm filter cloth under nitrogen. The filter cake was washed with mixed heptanes (2×320 mL) and dried under nitrogen at up to 45° C. to afford methyl 3-(cyanomethylamino)-5-fluoro-4-methylbenzoate (54.9 g, 99.1% w/w).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:14][S:15]([CH2:18][CH2:19]COS(C)(=O)=O)(=[O:17])=[O:16].[ClH:26].Cl.COCC(NC(=O)CN1CCNCC1)C>>[ClH:26].[ClH:26].[CH3:14][S:15]([CH2:18][CH2:19][CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)CCCOS(C)(=O)=O
Agent: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CS(=O)(=O)CCCN1CCNCC1

Procedure:
1-(3-Methanesulfonyl-propyl)-piperazine dihydrochloride was prepared from 1-tert-butyloxycarbonyl-piperazine and methanesulfonic acid 3-methanesulfonyl-propyl ester (prepared according to Baerlocher, F. J. et al. Aust. J. Chem. 1999, 52, 167-172) in an analogous manner as described for the preparation of N-(2-methoxy-1-methyl-ethyl)-2-piperazin-1-yl-acetamide dihydrochloride (example 40).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11]O.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(CO)nc2ccccc21
Solvent: ClCCl
Product: Cn1c(CCl)nc2ccccc21

Procedure:
A solution of (1-methyl-1H-benzoimidazol-2-yl)-methanol (500 mg, 3.08 mmol) and SOCl2 (1.1 mL) in DCM (2 mL) was stirred at room temperature for 3 hours. After evaporation of the solvents, 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) was obtained and was used without any purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>O>[CH3:19][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCC(=O)N2

Procedure:
To a solution, prepared by mixing 8.2 g. 6-hydroxy-3,4-dihydrocarbostyril with 50 ml. water containing 2 g. sodium hydroxide, was added dropwise with stirring 8.5 ml. dimethyl sulfate (sp. gr. 1.332). During the course of the addition the resulting mixture was maintained at about pH10 by periodic additions of 10% sodium hydroxide solution. The mixture was stirred for 21/2 hours at room temperature, filtered and the collected solids were washed thoroughly with water to give after recrystallization from methyl alcohol 6.3 g. 6-methoxy-3,4-dihydrocarbostyril; m.p. 142.5°-143.5°C.