Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[CH:1]1[N:2]=[C:3]([CH:18]=[O:19])[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: CN(C)C=O
Reactant: c1ncn2c1CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc2n1CCCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine (prepared as described by Lattrell, R. et al. The J. of Antibiotics 1988, 41, 1395-1408) in THF (7 mL) at −78° C. was added a solution of n-BuLi (2.5 M in hexanes, 0.70 mL, 1.75 mmol) and the reaction stirred at −78° C. for 10 min. DMF (1.0 mL) was added to the mixture at −78° C. and the reaction warmed to room temperature and stirred for 2 h before quenching with saturated aqueous NH4Cl (5 mL). The mixture was diluted with EtOAc (30 mL) and brine and the organic phase washed with brine (1×30 mL), dried (Na2SO4) and concentrated in vacuo. The resultant brown oil (191 mg) was purified by column chromatography on silica gel (CH2Cl2/MeOH, 96:4) to afford the desired aldehyde (105 mg, 40%) as an orange oil. 1H NMR (CDCl3) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85 (t, 2H, J=6 Hz), 4.39 (t, 2H, J=6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](O)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.O>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([NH2:28])=[O:18])[CH2:15][N:16]=1)=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(C(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 11.1 %

Procedure:
To a solution of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (0.090 g) in N,N-dimethylformamide (6 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.034 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.049 g), and the mixture was stirred at 50° C. for 45 min. 28% Aqueous ammonia (2 ml) was added to the reaction, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography. (ethyl acetate:methanol=100:0-90:10), and recrystallized from hexane-ethyl acetate to give the title compound (0.010 g, yield 11%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[O:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 88.2 %

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic phases were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7](O)[C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1.[CH3:28][O:29][C:30]([O:34][Si](C)(C)C)=[C:31]([CH3:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[C:31]([CH3:33])([CH3:32])[C:30]([O:29][CH3:28])=[O:34])[S:5][CH:6]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(c1nc(Cl)cs1)c1[nH]c(-c2ccccc2)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Boron trifluoride THF complex (0.028 mL, 0.255 mmol) was added to a solution of 7-((4-chlorothiazol-2-yl) (hydroxy)methyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (114 mg, 0.283 mmol) and commercially available ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.143 mL, 0.707 mmol) in THF (5 mL). The mixture was stirred at room temperature for 5 minutes. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-80% EtOAc/hexane afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C>C(O)(=O)C>[OH:9][C:10]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1nc[nH]n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2ncnn2c1O

Procedure:
A mixture of 3-amino-1,2,4-triazole (8.4g, 100mM) and diethyl ethoxymethylenemalonate (24.0g, 110mM) in glacial acetic acid (150ml) was heated under reflux for six hours. The resulting precipitated product was filtered and dried in vacuo. Yield 8.20g (36.6%). δ (DMSO-d6), 12.85 (1H,s, --OH), 8.87 (1H,s, H2), 8.56 (1H,s, H5), 4.38 (2H,q,--CH2CH3), 1.34 (3H,t, --CH2CH3); νmax (KBr disc) 1730 (ester C=O)cm-1 ; (Found: C, 45.99; H, 3.94; N, 27.29%. C8H8N4O3 requires C, 46.16; H, 3.87; N, 26.91%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:11][C:4]1[N:3]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1CCN(c2nc(Br)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Yield: 65.6 %

Procedure:
A mixture of 2,6-dibromo-3-nitropyridine (Duffy, J., et al, J. Org. Chem. 56, (9), 3006, (1991)) (282 mg, 1.00 mmol), 4-methylpiperidine (118 μL, 1.00 mmol) and K2CO3 (138 mg, 1.00 mmol) in toluene (10 mL) was heated at 50° C. for 3 h. Toluene was removed in vacuo and the residue obtained was purified on silica (2% EtOAc/hexane) to obtain the title compound (197 mg, 66%). 1H-NMR (CDCl3; 400 MHz): δ 8.32 (d, 1H J=8.2 Hz), 7.94 (d, 1H J=8.2 Hz), 3.82 (m, 2H), 3.04 (m, 2H), 1.85 (m, 3H), 1.3 (m, 2H), 0.99 (d, 3H, J=6.4 Hz).
Reaction SMILES: OC(C1C=CC=CC=1)C([NH:5][CH:6]([CH2:16][CH3:17])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O>Cl>[CH2:16]([C@@H:6]([NH2:5])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:17]
Reactant: CCC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Agent: Cl
Product: CC[C@@H](N)CCCc1cccnc1

Procedure:
As in Example 16, a solution of 195 g of [R-(R*,R*)]-alphahydroxy-N-[1-ethyl-4-(3-pyridinyl)butyl]benzeneacetamide in 1.1L of 6N HCl was treated with 104 mL of conc. HCl and then was heated at reflux for 2 days. The crude amine, obtained by the normal work up, was distilled to give 109 g of (R)-alphaethyl-3-pyridinebutanamine, (bp 105° C./0.2 mm); [α]D25 -11.9° (c, 1.0, MeOH)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:17][CH3:18])[C:13]=1[CH2:14][CH2:15][CH3:16])[CH2:6]P(=O)([O-])[O-].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([O:17][CH3:18])[CH:11]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CCCc1c(OC)cc(CP(=O)([O-])[O-])cc1OC
Reactant: O=Cc1cc(F)cc(F)c1
Product: CCCc1c(OC)cc(C=Cc2cc(F)cc(F)c2)cc1OC
Yield: 27 %

Procedure:
This material was prepared from (3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 3,5-difluorobenzaldehyde in 27% yield in the same way as described in Example 21. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.66 (qint., J=7.0 Hz, 1H), 3.90 (s, 6H), 6.72 (s, 2H), 6.8-7.2 (m, 5H).
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([CH:14]([CH2:18][CH3:19])[C:15](O)=[O:16])[CH3:13]>>[CH:1]1([NH:8][C:9]2[S:10][C:14]([CH2:18][CH3:19])([CH2:12][CH3:13])[C:15](=[O:16])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: CCC(CC)C(=O)O
Product: CCC1(CC)SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cycloheptylthiourea and 2-ethylbutyric acid according to Method J and D.
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(-c2ccccc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)NCCCCCC(=O)O)cccc1-c1ccccc1
Yield: 90.5 %

Procedure:
The procedure of the step 2 in Example 80 was repeated except that the methyl 6-(2-methyl-3-phenyl-benzamido)hexanoate (61 mg, 0.18 mmol) instead of methyl 6-(3-bromo-2-methylbenzamido)hexanoate, and 15 mg of lithium hydroxide monohydrate (0.36 mmol) were dissolved in 3 mL of THF/H2O (2:1) to obtain the title compound (53 mg, 90%).
Reaction SMILES: [CH3:1][C:2](=[O:8])/[CH:3]=[CH:4]\[C:5](=[O:7])[CH3:6].[CH2:9]([SH:12])[CH2:10][CH3:11].N1CCCCC1>N1CCCCC1.CCOCC>[CH2:9]([S:12][CH:4]([CH2:3][C:2](=[O:8])[CH3:1])[C:5](=[O:7])[CH3:6])[CH2:10][CH3:11]
Reactant: CCCS
Reactant: CC(=O)/C=C\C(C)=O
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCSC(CC(C)=O)C(C)=O
Reaction time: 18 h
Yield: 86.6 %

Procedure:
In a 500 ml flask fitted with thermometer, addition funnel, reflux condenser and magnetic stirrer are placed 95 ml of ether, 35.4 g of cis-3-hexene-2,5-dione and one drop of piperidine. Addition of 24 g of n-propanethiol is started and as the addition progresses more piperidine is added (33 drops total) periodically. After standing 18 hours, the solution is washed successively with two 7.5 ml portions of 10% hydrochloric acid, saturated sodium chloride solution (10 ml), 5% sodium bicarbonate solution and two 10 ml portions of saturated sodium chloride solution. The ether solution is dried over sodium sulfate and concentrated to give 51.4 g of a dark yellow oil. Analysis by GLC shows the material to be essentially pure 3-thiopropyl-2,5-hexanedione. Mass spectral analysis shows molecular ion 188 then descending order 43, 103, 41, 145, 71, 114 and 61 m/e units.
Reaction SMILES: [NH2:1][C:2]1([CH2:18][CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[C:21]([N:29]=[C:30]=S)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1.O>C1COCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:2]3([CH2:18][CH2:19][O:20][C:30]([NH:29][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:1]3)[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([I:17])[CH:4]=3)[O:9][C:10]2=[N:11][CH:12]=1
Reactant: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Reactant: O=C(N=C=S)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1=NC2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a 250-mL flask, the 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (2.24 g, 5.01 mmol) was dissolved in THF (30 mL). Benzoyl isothiocyanate (0.607 mL, 4.51 mmol) was added. After 1 h, the mixture was concentrated. The residue was taken up in ACN (30 mL), and catalytic TEA (0.069 mL, 0.501 mmol) was added, followed by DCC (1.137 g, 5.51 mmol). A water-cooled condenser was affixed, and the solution was stirred in an 80° C. oil bath for 2 h. The reaction was then concentrated. The residue was used directly in the next step without further purification or purified by column chromatography (silica gel, 10-50% EtOAc/hexanes) to obtain N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide as a yellow solid. MS (m/z) 575.8/577.7 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:25])([CH3:24])[C:9](=[O:23])[C:10]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:11]2[OH:14])=[CH:6][CH:5]=1>C1COCC1.C(Cl)Cl>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:25])([CH3:24])[C:9](=[O:23])[C:10]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]2[OH:14])=[CH:6][CH:5]=1
Reactant: COC(=O)CCC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)C(=O)C(C(=O)CCC(=O)O)=C(O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of aqueous NaOH (5M, 2.0 mL) was added to a solution of methyl 4-(7-bromo-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalen-2-yl)-4-oxobutanoate (0.061 g, 0.16 mmol) in THF (1.5 mL). The mixture was stirred for 15 minutes at room temperature, diluted with DCM, and extracted with water. The water phase was acidified to pH=1 using aqueous HCl (5M) and extracted with EtOAc. The combined organic layers were dried over MgSO4 and evaporated. The product was rinsed with diethyl ether and dried to afford the title compound in 31% yield. 1H-NMR (300 MHz, DMSO-d6) δ ppm 12.19 (1H, br. s.), 8.17, 8.16 (1H, 2 s), 7.91-7.88 (1H, m), 7.75-7.72 (1H, m), 3.45-3.35 (2H, m, partially covered by HDO signal), 2.60-2.56 (2H, m), 1.54 (6H, br. s.). MS m/z: 368 (M+).
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:17]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]>COCCOC>[CH2:17]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:38])=[CH:40][CH:41]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]
Reactant: C=CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCCCCCCCCC=CCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-(1-pentadeca-4,14-dienylamino) benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 4-(1-pentadeca-4,14-dienylamino)benzoylmalonate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:30][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[C:20]([CH2:28][CH3:29])=[N:19]4)(=O)=O)=CC=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH:36]=[C:35]2[C:41]1[CH2:42][CH2:43][NH:44][CH2:45][CH:46]=1>CS(C)=O.C(OCC)(=O)C>[CH2:26]([C:21]1[C:20]([CH2:28][CH3:29])=[N:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:44]4[CH2:43][CH:42]=[C:41]([C:35]5[C:34]6[C:38](=[CH:39][CH:40]=[C:32]([F:31])[CH:33]=6)[NH:37][CH:36]=5)[CH2:46][CH2:45]4)[O:30][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CCc1nc2ccc3c(c2nc1CC)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO3
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1nc2ccc3c(c2nc1CC)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of (2R)-8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.700 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.606 g, 2.800 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.161 g (49%) of the (S)-enantiomer of the title compound as a yellow crystalline solid. Rf=0.38 (silica, methanol:ethyl acetate 1:9); mp>120° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(F)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.24-7.35 (m, 2H), 7.37 (s, 1 H), 7.92-8.02 (m, 2H), 8.17 (ddd, J=9.4, 2.8, 1.7 Hz, 1H), 8.61 (d, J=3.1 Hz, 1H), 8.96 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[CH:9]=[O:10].CC(C)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:19])=[O:10]
Reactant: COc1cc(-c2ccccc2)ccc1C=O
Reactant: CC(C)=O
Product: COc1cc(-c2ccccc2)ccc1C(=O)O
Yield: 73.5 %

Procedure:
To a cold solution of 3-methoxy-biphenyl-4-carboxaldehyde (0.32 g, 1.5 mmol) in acetone (10 mL), the Jone's reagent was added slowly drop wise at 0° C. until the reaction completes. Acetone was removed completely and the resulting residue was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.25 g, 73.5%)
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:16]2[C:11](=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([Cl:17])[CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32](=[CH2:34])[CH3:33])=[O:29])[CH2:24][CH2:23]2)[N:8]=1.[OH-:35].[Na+]>O>[NH2:6][C:7]1[C:16]2[C:11](=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([Cl:17])[CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]([CH3:33])([OH:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[N:8]=1
Reactant: [OH-]
Reactant: C=C(C)COC(=O)N1CCN(c2nc(N)c3cc(Cl)c(OC)c(OC)c3n2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1c(Cl)cc2c(N)nc(N3CCN(C(=O)OCC(C)(C)O)CC3)nc2c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 24 ml. of concentrated sulfuric acid dissolved in an equal volume of water was cooled to 10°-12° C. and 0.015 mole of methallyl 4-(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1-carboxylate is added in small portions with stirring. The addition is carried out at a rate sufficient to keep the reaction temperature below 20° C. The resulting mixture is stirred for 15 minutes at 15°-20° C., then for two hours at 10°-15° C. The reaction mixture is diluted with 150 ml. of ice-water and adjusted to pH 10 with sodium hydroxide while maintaining the temperature below 12° C. After extraction with chloroform, the combined extracts are washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo and the residue recrystallized to afford 2-methyl-2-hydroxypropyl 4-(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O)(=O)C.[CH2:24]1[CH:29]([CH:30]=O)[CH2:28][CH2:27][O:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[CH2:30][CH:29]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:12])[S:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)sn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2CC2CCOCC2)sn1
Reaction time: 4 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (3-tert-butyl-isothiazol-5-yl)-amide; hydrochloride (40.4 mg; 0.11 mmol) in DMF (1 mL) is added acetic acid (0.05 mL; 0.87 mmol) and a solution of tetrahydropyranyl-4-carboxaldehyde (37.7 mg; 0.33 mmol) in DMF (1 mL). The reaction is shaken for 4 hours. To the mixture is added a solution of sodium triacetoxyborohydride (93.2 mg; 0.44 mmol) in DMF (0.4 mL). The reaction mixture is shaken for 16 hours at room temperature. After this time, the reaction is quenched with water (0.1 mL) and the mixture is concentrated in vacuo. Purification by preparative HPLC provides the title compound, m/z 366 [M+H+].
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C@H:8]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][CH:9]1[OH:10])=[O:6])=[N+:2]=[N-:3].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:10][CH:9]1[O:11][C@H:12]([CH2:17][O:18][C:23](=[O:25])[CH3:24])[C@@H:13]([O:16][C:12](=[O:11])[CH3:13])[C@H:14]([O:15][C:9](=[O:10])[CH3:8])[C@@H:8]1[NH:7][C:5](=[O:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:6])[CH3:4]
Reactant: [N-]=[N+]=NCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
A solution of 20 (25 mg, 0.095 mmol) in pyridine (2 mL) was cooled to 0° C. To this solution was added acetic anhydride (1.0 ml, 11 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (1×50 mL), water (1×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:10 to 1:2 EtOAc/hexanes to afford 39 mg (95%) of a light yellow oil. IR (thin film): 3317, 2106, 1744, 1677, 1529 cm−1. 1H NMR (500 MHz, CDCl3): δ2.05 (app s, 6H), 2.10 (s, 3H), 2.12 (s, 3H), 3.82 (ddd, 1H, J=2.4, 4.5, 9.6), 3.93 (s, 2H), 4.13 (dd, 1H, J=2.4, 12.6), 4.29 (dd, 1H, J=4.5, 12.6), 5.15 (app t, 1H, J=9.6), 5.21 (app t, 1H, J=5.7), 5.78 (app t, 1H, J=4.5), 6.37 (d, 1H, J=5.7). 13C NMR (125 MHz, CDCl3): δ20.5, 20.5, 20.6, 20.6, 20.6, 20.8, 20.8, 51.2, 52.4, 52.5, 53.2, 61.4, 61.5, 67.4, 67.6, 69.8, 70.3, 72.0, 72.1, 72.9, 90.2, 92.1, 166.9, 168.6, 169.1, 169.2, 170.6, 170.8, 171.5. HRMS (FAB) m/z 437.1496 (MLi+C16H22LiN4O10 requires 437.1496).