Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2(O[CH:11]2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[CH3:9][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: CC(=O)C1(c2ccccc2)OC1c1ccncc1
Solvent: CCO
Product: Cc1n[nH]c(-c2ccncc2)c1-c1ccccc1

Procedure:
A solution of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (350 mg, 1.46 mmol) and anhydrous hydrazine (0.7 ml, 20 mmol) in ethanol (3 ml) was heated at reflux for 4 hours. The reaction was cooled, and the solvent was evaporated to dryness. The resulting residue was purified by chromatography (silica gel, 1:1 acetone/hexane) to give the desired product as a crystalline solid, which was recrystallized from ethyl acetate and hexane to give pure 4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine (145 mg, 42%): m.p. 164–165° C. Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.45; N, 17.70.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+]>CO>[CH:24]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:7]=2[O:6][CH3:5])[CH2:11][CH2:12]1)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
To a solution of 10% acetic acid in methanol was added 4-(2-methoxy-4-nitrophenoxy)piperidine (148 mg, 0.59 mmol, 1 eq), anhydrous acetone (5 eq), and sodium cyanoborohydride (1.5 eq). The solution was stirred at room temperature for 24 h. Reaction is 85% complete. Charged additional anhydrous acetone (5 eq) and sodium cyanoborohydride (1.5 eq) and stirred for 24 h. The solvent was evaporated, the residue brought to pH=10 with sodium carbonate and extracted with EtOAc. The organic layer was washed with water, brine, dried with magnesium sulfate and evaporated to afford 1-isopropyl-4-(2-methoxy-4-nitrophenoxy)piperidine as a yellow oil (163 mg, 97%). LC/MS (m/z): 295.2 (MH+), Rt 1.96 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]2.C1C(=O)N([Br:21])C(=O)C1.OS(O)(=O)=O>O>[Br:21][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc2c(c1)CCC2(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1Br)C(C)(C)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
To a suspension of 5-methoxy-1,1-dimethyl-indan (2.16 g, 12.25 mmol) (prepared following the procedures described in U.S. Pat. Appl. Publ., 2006100460) in water (120 ml), NBS (2.2 g, 12.3 mmol) was added. The reaction mixture was heated to 60° C. while stirring. Concentrated H2SO4 (1.3 ml, 40% aq. solution) was then added and stirring was continued for 5 hours. The reaction mixture was cooled to rt. The mixture was extracted with diethyl ether three times. The combined organic extract was washed with brine and dried (Na2SO4). Silica gel chromatography (ethyl acetate/heptane) provided 2.78 g (89%) of the title compound.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][CH:6]([Cl:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Cl:12])[F:5])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)C(F)Cl
Solvent: CCO
Solvent: OCCO
Product: CC(C)NC(=O)C(F)Cl
Reaction time: 2 h

Procedure:
A solution of 11.8 grams (0.2 mole) isopropyl amine in 20 milliliters ethyl alcohol were added dropwise at 10°-15° C. with stirring to a solution of ethyl fluorochloroacetate and 5 drops of ethylene glycol in 80 milliliters ethyl alcohol. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time, the solution was evaporated to leave a liquid, 25.2 grams, nD30 1.4395, identified as the title compound by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH3:13])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([OH:11])[CH2:12][S:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[CH:4][CH:3]=1
Reactant: Sc1ccccc1Cl
Reactant: CC1(CCc2ccc(Cl)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(O)(CCc1ccc(Cl)cc1)CSc1ccccc1Cl

Procedure:
A mixture of 4 g. of 2-[2-(4-chlorophenyl)ethyl]-2-methyloxirane, 3.6 g. of 2-chlorothiophenol and 500 mg. of anhydrous potassium carbonate in 50 ml. of acetone is stirred at reflux for approximately 3 hours. The solvent is then evaporated and 200 ml. of ether is added to the residue. The resulting mixture is washed with water (3 × 40 ml.), dried (MgSO4) and evaporated to afford 4-(4-chlorophenyl)-1-(2-chlorophenylthio)-2-methyl-2-butanol which is used directly as described later in the procedure.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:44]/[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=4)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2ccccn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), [(2-pyridyl)methyl]triphenylphosphonium chloride (0.94 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)pyridine as colorless crystals (0.68 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nn1cnc2ccccc2c1=O
Solvent: ClCCCl
Product: O=c1c2ccccc2ncn1NC(=S)Nc1ccc(Br)cc1

Procedure:
4-Bromophenyl isothiocyanate (2.51 g, 11.72 mmol) is added to a mixture of 3-amino-4(3H)quinazolinone (1.72 g, 10.66 mmol) in a 1,2-dichloroethane at reflux under a nitrogen atmosphere. The reaction mixture is heated at reflux for 2 days, cooled, washed with ether and filtered. The filter cake is dried to give the title product as a white solid, 2.44 g, mp 189°-190° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 0.75 h

Procedure:
A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (Evans, U.S. Pat. No. 4,665,171) and 1.3 equivalent of oxalyl chloride in 200 mL dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 mL/milliequivalent of acetic acid derivative) resulting in vigorous gas evolution. After 45 minutes all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h under vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].CCOC(C)=O>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A stirred mixture of 4-ethoxybenzoic acid (0.33 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.67 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 18 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated. The residue was triturated in Et2O, then EtOAc and isolated by filtration followed by drying in vacuo to give 4-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.27 g, 30% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.73 min (97.04%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 1.34 (t, J=7.0 Hz, 3H), 1.81-1.95 (m, 3H), 1.97-2.12 (m, 1H), 2.53-2.61 (m, 2H), 2.61-2.78 (m, 1H), 4.09 (q, J=6.9 Hz, 3H), 4.60 (d, J=5.9 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 7.44-8.44 (m, 5H), 9.06 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.53, 21.02, 28.57, 29.11, 42.52, 58.76, 63.31, 113.99, 121.56, 123.16, 125.97, 129.09, 129.55, 131.37, 133.35, 147.73, 161.02, 165.89, 167.75, 167.89, 172.13, 172.19; LCMS: MH=450; Anal Calcd for C24H23N3O6+0.75H2O: C, 62.26; H, 5.33; N, 9.08. Found: C, 62.25; H, 5.13; N, 9.17.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH2:25]([O:32][CH2:33][C:34](O)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][CH2:33][C:34]([NH:18][C:15]1[CH:16]=[N:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([O:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:2]([F:1])([F:23])[F:24])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Reactant: O=C(O)COCc1ccccc1
Product: O=C(COCc1ccccc1)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1

Procedure:
The title compound was prepared in the same manner as described for Example 25, step 2 from 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridin-3-amine and benzyloxyacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[Br:1][C:2]1[C:7]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
5-Bromo-6-chloro-3-pyridinecarboxylic acid (68.0 g, 0.288 mol, CAN 29241-62-1) was dissolved in DMSO (1000 mL). To this solution was added with stirring potassium hydroxide (48.25 g, 0.86 mol) and after 10 minutes of stirring at room temperature 2,2,2-trifluoroethanol (26.9 mL, 0.374 mol) was added. The mixture was stirred at room temperature for 24 h. Water (1000 mL) and concentrated hydrochloric acid (107 mL, 1280 mmol, 37%) was added and the suspension was stirred vigorously for 4 hours. The precipitate was filtered, washed with water (4×100 mL) and vacuum dried over night to give the title compound (80.4 g) as an off white solid; MS (EI) 299, 301 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1)[CH3:4].[C:15]([OH:22])(=[O:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20]>>[OH:1][CH2:2][CH:3]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][C:15]([OH:22])=[O:21])[CH:10]=[CH:11][CH:12]=1)=[O:14])[CH3:4]
Reactant: CC(CO)NC(=O)c1cccc(I)c1
Reactant: C#CCCCC(=O)O
Product: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Yield: 99 %

Procedure:
The iodobenzamide (1)(2.00 g, 6.5 mmol) was coupled with 5-hexynoic acid using method B yielding (4)(1.87 g, 6.42 mmol; 99% yield).
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]C.Cl.[CH3:12][CH:13]([CH3:17])[C:14](=[NH:16])[NH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:12][CH:13]([C:14]1[NH:16][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:15]=1)[CH3:17]
Reactant: CC(C)C(=N)N
Reactant: COC1=C(Br)C(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a stirred solution of 2-bromo-3-(methyloxy)-2-cyclohexen-1-one (1.88 g) in anhydrous N,N-dimethylformamide (35 mL) at ambient temperature was added solid 2-methylpropanimidamide hydrochloride (1.349 g) and potassium carbonate (3.17 g). The reaction was then heated to 100° C. under an atmosphere of nitrogen for 3 hr. The reaction was diluted with dichloromethane (100 mL) the resultant solid was removed by filtration. The filtrate was concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (867 mg). LC/MS MH+ 179, Rt 0.34 min (2 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: OCCNCCO
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Br)c1)N(CCO)CCO
Temperature: 20 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a solution of 3-bromobenzene sulfonyl chloride (0.25 mL, 1.73 mmol) in dioxane (2.0 mL) was added dropwise a solution of diethanolamine (0.547 g, 5.20 mmol) in dioxane (1.0 mL) over 1 min. The reaction mixture was stirred at room temperature (20° C.) for 16 h. After this time the mixture was poured onto brine (30 mL) and extracted with ethyl acetate (25 mL). The organic liquor was concentrated in vacuo to afford the title compound, (0.495 g, 88%). No further purification was required.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:24].O>CC(C)=O>[Br:12][C:4]1[C:3]2[O:13][CH2:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)([OH:24])[NH:1][C:2]=2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[CH:5]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: Nc1c(O)c(Br)cc(F)c1[N+](=O)[O-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(Br)c2c1NC(O)(c1cccnc1)CO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Amino-6-bromo-4-fluoro-3-nitrophenol (500 mg, 1.9 mmol) and potassium carbonate (780 mg, 5.7 mmol) were stirred in acetone (8 mL) for 5 minutes and 2-bromo-1-pyridin-3-ylethanone hydrobromide (530 mg, 1.9 mmol) was added as a solid over 5 minutes. The mixture was stirred at rt for 5 minutes and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes gave the desired compound, 0.69 g, 99%. LCMS calculated for C13H10BrFN3O4 (M+H)+: m/z=370.1, 372.1. found: 370.0, 372.0.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO.C1COCC1>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Methyl 4-(1H-indol-1-ylmethyl)benzoate (9.05 g; 34 mmol) was dissolved in MeOH/THF (1:1), treated with sodium hydroxide (1.36 g, 34 mmol) stirred at room temperature overnight and concentrated under reduced pressure. The resultant concentrate was diluted with 1N sodium hydroxide (50 mL), washed with EtOAc, acidified with concentrated HCl and extracted with EtOAc. The combined extracts were dried over MgSO4 and concentrated to dryness to give the title product in 77% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 250 (MH+).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([NH:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][O:9][C:8]([CH3:23])([CH3:22])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:24]([C@@H:6]1[CH2:7][C:8]([CH3:23])([CH3:22])[O:9][CH2:10][C@@H:11]1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)C[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Yield: 118.1 %

Procedure:
To a solution of (4S,5S)-2,2-dimethyl-5-((2-(trimethylsilyl)ethoxy)carbonylamino)-tetrahydro-2H-pyran-4-yl methanesulfonate (1.6 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (2.3 g, 35 mmol) and sodium acetate (2.8 g, 35 mmol) at room temperature. The resultant mixture was stirred at 95° C. for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed by water (100 mL×8) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.3 g, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C)C=O>[CH2:23]([O:22][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2)=[O:21])[CH3:24]
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc2oc(=O)ccc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6-Hydroxycoumarin (405 mg; prepared in reference example 25) was dissolved in dry dimethylformamide (6 ml). Sodium hydride (60 mg) was added to the solution. The mixture was reacted for 15 min. Ethyl 5-bromopentanoate (0.48 ml) was added dropwise to the reaction solution. The mixture was stirred for 1 hr at 60° C. Ice-water was added to the reaction solution. The mixture was acidified with 1N hydrochloric acid. The mixture was extracted with ether. The extract was washed with water, dried anhydrous magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1→2:1) to give the title compound (398 mg) having the following physical data.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[C:17]([Cl:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[C@H:3]1[CH3:23].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[Cl:21])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][CH2:8][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[C@@H:3]1[CH3:23])=[O:22]
Reactant: C[C@H]1[C@H](N)CCN1C(=O)CNc1ncnc2cc(Cl)c(Cl)cc12
Reactant: O=C1CCOCC1
Product: C[C@H]1[C@H](NC2CCOCC2)CCN1C(=O)CNc1ncnc2cc(Cl)c(Cl)cc12

Procedure:
2-(6,7-Dichloroquinazolin-4-ylamino)-1-((2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-4-ylamino)pyrrolidin-1-yl)ethanone was synthesized from 1-((2S,3R)-3-Amino-2-methylpyrrolidin-1-yl)-2-(6,7-dichloroquinazolin-4-ylamino)ethanone and dihydro-2H-pyran-4(3H)-one using general procedure E. RP-HPLC (Table 1, Method a) Rt 1.52; m/z: (M+H)+ 438.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]#[N:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([CH3:14])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1cc(C#N)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(C)(C)C)cc1CN

Procedure:
3-tert.-butyl-1H-pyrazol-5-carbonitrile (J-IV) (10 mmol) was added to a suspension of NaH (60%) (12.5 mmol) in DMF (20 ml) at room temperature while stirring. After stirring for 15 minutes, methyl iodide (37.5 mmol) was added dropwise to this reaction mixture at room temperature. After stirring for 30 min at 100° C., the reaction mixture was mixed with water (150 ml) and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (100 ml) and sat. NaCl solution (100 ml) and dried over magnesium sulphate. After removal of the solvent under vacuum, the residue was purified by column chromatography (SiO2, various mixtures of EE and cyclohexane as the mobile solvent) and the product J-V was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:15][CH:16]=[CH2:17])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].B1C2CCCC1CCC2.[OH-:28].[Na+].OO>O>[OH:28][CH2:17][CH2:16][CH2:15][C:2]([CH3:18])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: [OH-]
Reactant: C=CCC(C)(C)C(=O)OCc1ccc(OC)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(COC(=O)C(C)(C)CCCO)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate (9.50 g, 38 mmol) and 9-BBN (115 mL, 57 mmol, 0.5 M in THF) was stirred at 60° C. for 60 min, whereupon the reaction mixture was cooled to −5° C. H2O (35 mL) was added, the reaction mixture was stirred for 5 min at −5° C., an aqueous solution of NaOH (35 mL, 3M) was added and the reaction mixture was stirred for a further 10 min at −5° C. An aqueous solution of H2O2 (35 mL, 30%) was added dropwise and the temperature of the reaction mixture was allowed to assume room temperature, whereupon the reaction mixture was stirred for 30 min at room temperature. After evaporation, water (200 mL) was added and the resulting mixture was extracted with CH2Cl2 (5×200 mL). The combined organic layers were dried (Na2SO2) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1→8% MeOH in CH2Cl2), to give 6.32 g of 4-methoxybenzyl 5-hydroxy-2,2-dimethylvalerate.