Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:20]/[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(/C=C/[N+](=O)[O-])c(F)c1

Procedure:
A solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 33 mmol) and ammonium acetate (1.0 g, 13 mmol) in nitromethane (40 mL) was heated on a steam bath for 2.5 h. The reaction mixture was concentrated under reduced pressure, and the sticky residue was partitioned between dichloromethane and water. The organic layer was washed with half-saturated brine, dried (MgSO4), filtered, and concentrated. The residue was triturated in hexane and the solid was filtered and washed with hexane and dried to give 5.57 g of crude product 2-fluoro-4-methoxy-1-((E)-2-nitrovinyl)benzene as an orange solid, M.P. 80-82° C. 1H NMR (CDCl3): δ 8.02 (d, J=13.5 Hz, 1H), 7.66 (d, J=13.5 Hz, 1H), 7.43 (m, 1H), 6.68-6.80 (m, 2H), 3.87 (s, 3H). GC/MS: 197 [M]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.Cl.[CH3:12][NH:13][O:14][CH3:15].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:15][O:14][N:13]([CH3:12])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: CNOC
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCOCC1
Yield: 57.7 %

Procedure:
Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto, then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at −30° C., and the mixture was stirred at −5° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58%). Boiling point: 125-129° C./8.0 hPa, 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J=2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J=2.4, 11.9, 11.9 Hz, 2H). Step 2: 2-(Benzoimidazol-2-yl)-4-(2-furyl)thiazole (167 mg, 0.625 mmol) obtained in Reference Example 562 was dissolved in THF (5 mL). To the solution was added n-hexane solution of n-butyl lithium (1.58 mol/L; 1.01 mL, 1.56 mmol) at −78° C. under an argon atmosphere, and the mixture was stirred at −78° C. for 10 minutes. The THF solution (1 mL) of N-methoxy-N-methyltetrahydropyran-4-carboxamide (270 mg, 1.56 mmol) obtained in Step 1 was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a title compound (191 mg, 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CO>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-fluoro-2-nitrophenol (4.05 g, 25.8 mmol) in MeOH (200 mL) was added tin(II) chloride dihydrate (17.47 g, 77.4 mmol). The reaction mixture was heated at reflux and monitored by LC/MS. When significant reduction was complete, the reaction mixture was cooled to rt, poured over ice, and made basic (pH 9) with 50% saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined extracts washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-amino-4-fluorophenol as a grayish green solid. 1H NMR (CDCl3, 300 MHz) δ 6.64 (dd, 1H), 6.47 (dd, 1H), 6.33 (dt, 1H), 4.48 (br s, 1H), 3.78 (br s, 2H).
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C@H:28]([CH3:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.[OH-].[Na+]>CO>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[C@@H:28]2[CH3:29]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from ethyl 4-{[(R)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenyl carbonate (0.05 g, 0.11 mmol), a 2.5 N aqueous sodium hydroxide solution (2 mL, 5 mmol), and methanol (2 mL), according to the procedure and in the same manner as described in Example 32, Method A, Step e to yield 4-{[(R)-8-fluoro-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol* as a solid (0.04 g, 100%), m.p. 193° C.;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:17][C:18](=O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:18]([CH3:19])[CH2:17][C:16]([CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:15])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(C)(C)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CC(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-methyl-4-phenyl-pentan-2-one.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A solution of methanesulfonyl chloride (28 ml, 0.36 mole) in dichloromethane (50 ml) was added dropwise to a solution of piperidine-4-carboxylic acid ethyl ester (50 grams, 0.32 mole) and triethylamine (53 ml, 0.38 mole) in dichloromethane (350 ml) at 0° C. The reaction mixture was stirred at 0-5° C. for 3 hours. The solution was washed with 2×100 ml water, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The solid residue was triturated with 100 ml ethyl ether, collected by filtration and dried to give 1-methanesulfonylpiperidine-4-carboxylic acid ethyl ester (68 grams, 90%), m.p. 91-92° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl>ClC(Cl)C>[CH2:8]1[C:9]2([CH2:14][CH2:13][N:12]([C:1]([Cl:4])=[O:2])[CH2:11][CH2:10]2)[CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: C1CCC2(C1)CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(Cl)N1CCC2(CCCC2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1.57 ml of phosgene (20% solution in toluene, 2.96 mmol) were initially charged in 5 ml of dichloroethane and cooled to −20° C., then a mixture of 8-azaspiro-[4,5]decane (750 mg, 2.96 mmol) and triethylamine (1.28 ml, 9.2 mmol, 3.1 eq.) was added slowly. After 30 min, the mixture was allowed to come to RT; after 1 h, according to LC-MS, a little starting material was still present but also three new peaks. Subsequently, the mixture was added to 2 N aqueous HCl, the aqueous phase was extracted with dichloromethane, and the organic phase was washed with saturated NaHCO3 solution and dried over sodium sulfate; subsequently, the mixture was concentrated by rotary evaporation under reduced pressure. Crude yield: 592 mg
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:4]=[N:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cncnc2)N1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncnc4)c32)c1CCCN1CCN(C)CC1

Procedure:
4-Pyrimidin-5-yl-1,3-dihydroindol-2-one (53 mg, 0.25 mmol) was condensed with 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (88 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: O[CH:2]([C:4]1[N:5]=[C:6]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:7]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=1)[CH3:3].P(=O)(O)(O)O>CO.[OH-].[OH-].[Pd+2]>[CH2:2]([C:4]1[N:5]=[C:6]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[N:7]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=1)[CH3:3]
Reactant: CC(O)c1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Pd+2]
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CO
Product: CCc1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 60 °C
Reaction time: 144 h

Procedure:
Add palladium hydroxide on carbon (4.20 g, 60% wet, 0.15 g/g limiting reagent) to a solution of tert-butyl 4-(4-(1-hydroxyethyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate; phosphoric acid (28.00 g, 57.08 mmol) in methanol (10 mL). Stir under a hydrogen atmosphere in a Parr system (150 psi, 60° C.) for six days. Stir further under a hydrogen atmosphere in a Parr system (300 psi, 80° C.) for seven days. Filter over Celite®. Concentrate the filtrate in vacuo and dilute with acetone (280 mL). Stir overnight at room temperature. Filter and dry the resulting white solid under vacuum to give tert-butyl 4-(4-ethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate; phosphoric acid (23.00 g, 85%). MS (ES) m/z=377 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[N:9]2[CH3:18])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc2c(c1)NC(=O)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−5°-0° C.) of 6-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (600 mg, 3.14 mmol) in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and the mixture stirred for 15 min. Add dropwise to the reaction mixture iodomethane (215 μL, 3.45 mmol), the cold bath is removed and stirred for 2 hrs. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.C([Li])(C)(C)C.[CH3:36][C:37]([CH3:39])=[O:38].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:37]([OH:38])([CH3:39])[CH3:36])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC(C)=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 200 mg, 0.501 mmol) in 8 mL of THF at −78° C. under Ar was added isopropylmagnesium chloride (275 μL, 0.551 mmol, 2.0 M in THF). The resulting mixture was warmed to RT and stirred for 5 min, cooled to −78° C. again. To the mixture was added tert-butyllithium (884 μL, 1.50 mmol, 1.7 M in pentane) and the resulting mixture was stirred at −78° C. for 10 min. Acetone (736 μL, 10.0 mmol) was then added, and the reaction was warmed to RT and stirred for 0.5 h under Ar. The mixture was treated with 5 mL of saturated NH4Cl followed by 40 mL of EtOAc, washed with brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-4% MeOH/DCM) gave 101 mg (53%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.52 (s, 1H), 9.68 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.72 (d, 1H, J=2.3 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.35 (d, 1H, J=2.3 Hz), 5.78 (m, 1H), 2.64 (s, 1H, OH), 2.30 (m, 2H), 2.11 (m, 2H), 1.62 (s, 6H), 1.59 (t, 2H, J=6.5 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H26N4O2, 379.2 (M+H). found 379.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31](NC)=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>>[CH:3]([O:2][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=1[NH:28][C:26]1[C:25]([Cl:39])=[CH:24][N:23]=[C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])[N:27]=1)([CH3:8])[CH3:4]
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3C(=O)OC(C)C)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide (60 mg, 0.2 mmol) in an analogous manner to Example 946 to afford a yellow foam (45 mg, 40%). Mp: 117-20° C. LCMS (m/e) 566 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.14 (s, 1H), 8.85 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.07 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 2H), 7.45 (s, 1H), 7.12 (t, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 5.38 (m, 1H), 3.75 (m, 7H), 3.25 (m, 1H), 2.90 (m, 2H), 2.70 (m, 2H), 2.60 (m, 2H), 2.41 (m, 2H), 2.12 (m, 2H), 1.81 (m, 1H), 1.65 (m, 1H), 1.42 (d, J=6 Hz, 6H).
Reaction SMILES: [N:1]1C=CC=CC=1.[C:7](Cl)([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8]>C(Cl)Cl>[C:7](=[O:8])([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[NH2:1]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: c1ccncc1
Solvent: ClCCl
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
To a stirring solution of amine (2 mmol, 1.00 eq) and pyridine (4 mmol, 2.00 eq) in CH2Cl2 (18 ml) at RT was added Troc-Cl (1.87 mmol, 1.05 eq). After 4 hours the reaction was washed with 3M HCl (1×), satd. NaHCO3 (1×), dried (Na2SO4), filtered and evaporated to afford the target 2,2,2-trichloroethyl carbamate. The material was used as is in the next reaction.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH2:10]Br)=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CC(C)=O.O>[C:1]([C:5]1[O:9][C:8]([CH2:10][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(C(C)(C)C)oc1CBr
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)(C)C)oc1CN1CCCCC1
Yield: 14.7 %

Procedure:
A solution of methyl 5-tert-butyl-2-(bromomethyl)furan-3-carboxylate (0.28 g, 1.0 mmol) and piperidine (99 μL, 1 mmol) in acetone (5 mL) was stirred at room temperature 3 days. The mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-50% EtOAc-hexanes) to obtain methyl 5-tert-butyl-2-((piperidin-1-yl)methyl)furan-3-carboxylate (41 mg, 15% yield). LC/MS: m/z 280.3 (M+H)+ at 2.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])(O)=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1[N:19]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][C:2]=1[CH3:10]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccccc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 95 °C
Yield: 34.9 %

Procedure:
To a solution of 140 g (0.67 mol) of methyl 4-bromo-3-oxo-pentanoate in 300 mL of anhydrous toluene was added 210 g (1.73 mol) of benzamide, 132 g (0.93 mol) of sodium hydrogen phosphate, and ˜20 mL of EtOH. The suspension was stirred with heating to 95° C. for 24 h, then cooled to 0° C., filtered, and the solids washed with cyclohexane (2×100 mL) followed by 20% EtOAc in hexanes (200 mL). The combined filtrates were washed with 2×100 mL 10% KOH solution and brine (100 mL). The organics were dried (MgSO4), concentrated to a thin oil, and purified by chromatography on 1 kg of silica gel (230-400 mesh). Gradient elution of the column with 10% to 50% EtOAc in Hexanes gave 54 grams (35% yield) of the title compound as a pale yellow oil; 1H NMR (CDCl3, 400 MHz) δ8.0-7.98 (m, 2H), 7.43-7.40 (m, 3H), 3.73 (s, 3H), 3.59 (s, 2H), 2.37 (s, 3H); low resolution MS (ES+)m/e 232.4 (MH+); TLC Rf=0.64 (4/1 hexanes/EtOAc).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]([CH3:32])[C@H:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26].Cl.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@@H:2]([C:10]([N:23]([CH3:32])[C@H:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CN[C@H](C(=O)OC)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 16.1 g of Z-DPhe-OH, 10 g of H-NMeVal-OMe hydrochloride and 10.1 ml of diisopropyl-ethylamine in 100 ml of dichloromethane is cooled to 0-5° and 11.35 g of EDCI are added. The mixture is first stirred-for one hour at 0-5°, then overnight at room temperature. The solvent is removed and the residue is taken up in MTBE and washed with Na2CO3 (5%), 1N HCl and water and dried. After removal of the solvent, Z-DPhe-NMeVal-OMe is obtained in a yield of 84.5%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].S(Cl)([Cl:15])=O>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([Cl:15])=[O:9]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. A 100-mL, three-necked, round-bottomed flask equipped with an addition funnel, reflux condenser, and a nitrogen sweep to an HCl gas scrubber was charged with 5-chloro-2-methylbenzoic acid (10.00 g, 58.62 mmol). The apparatus was cooled in an ice bath, and thionyl chloride (40 mL, 550 mmol) was added in one portion. The ice bath was removed and the reaction mixture was warmed to about 50° for about 45 minutes in order to completely dissolve the 5-chloro-2-methylbenzoic acid. The reaction mixture was allowed to gradually cool with stirring to room temperature overnight. The excess thionyl chloride and the HCl and SO2 reaction side-products were removed by vacuum distillation. The residue was distilled under vacuum to afford 5-chloro-2-methylbenzoyl chloride as an oil: bp 65° (0.2 torr). This material was transferred immediately into an addition funnel and added dropwise with stirring to a commerical 40% dimethylamine solution (50 mL, 445 mmol) in water (150 mL). After complete addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ether, washed with water, dried, and concentrated. The resulting oil was distilled under vacuum to afford 5-chloro-N,N-2-trimethylbenzamide (10.40 g, 52.65 mmol, 90% yield) as an oil: bp 95°-101° (0.15 torr); IR(neat) 1650 cm-1 ; 1H NMR(CDCl3) δ 7.07-7.53(m,3H), 3.12(s,3H), 2.84(s,3H). Anal. Calcd for C9H12ClNO: C,60.76; N,6.12; Cl,17.94; N,7.12. Found: C,60.57; N,6.06; Cl,17.84; N,6.86.
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:10])(=[NH:9])[CH2:7][CH3:8].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16](OCC)=[O:17])[CH3:12].Cl>>[CH2:11]([O:13][C:14]([C:15]1[C:16](=[O:17])[NH:10][C:6]([CH2:7][CH3:8])=[N:9][CH:21]=1)=[O:25])[CH3:12]
Reactant: CCC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cnc(CC)[nH]c1=O
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a cold (0° C.) solution of NaOEt (0.2 mol) in absolute alcohol (150 mL) was added propionamidine hydrochloride (10.9 g, 0.1 mol) in one portion. A solution of 2-ethoxymethylene-malonic acid diethyl ester (21.6 g, 0.1 mol) in absolute alcohol (60 mL) was added dropwise to the above mixture during 20 minutes. After the addition was completed, the whole mixture was heated to reflux for 2.5 hours, then cooled and poured to ice water. The aqueous solution was acidified to pH 5 with HCl (6 M), extracted with ethyl acetate (4 100 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was re-crystallized with acetonitrile to afford 2-ethyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester as white crystals (17 g, 86%). 1H NMR(CDCl3) δ 8.71 (s, 1H), 4.37-4.32 (q, 2H), 2.84-2.78 (q, 2H), 1.38-1.34 (m, 6H). MS (ESI) m/e (M+1)+197.2.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:10]1[C:9]2[C:4](=[C:5]([N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c([N+](=O)[O-])cccc2c(=O)[nH]1
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Yield: 55 %

Procedure:
To a solution of 2-methyl-8-nitroquinazolin-4(3H)-one (250 mg, 1.22 mmol) in toluene (1 mL) was added POCl3 (374 mg, 2.44 mmol) and the reaction mixture was heated at reflux for 10 h. Then the reaction mixture was concentrated and triturated with Et2O. The precipitate obtained was filtered and dried to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.60-8.58 (d, J=7.8 Hz, 1H), 8.52-8.49 (d, J=9.0 Hz, 1H), 7.95-7.89 (t, J=7.8 Hz, 1H), 2.75 (s, 3H).