Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.Cl.Cl.Cl.[CH2:6]([NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:17])=[NH:14])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][C:32]([CH3:34])=[O:33]>>[C:10]([OH:11])(=[O:33])[CH3:9].[CH3:31][C:32]1([CH3:34])[N:14]=[C:13]([NH:12][CH2:6][C:7]2[O:11][CH:10]=[CH:9][CH:8]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[N:17]1
Reactant: CCCCCCCCCCCCNC(=N)NC(=N)NCc1ccco1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)O
Product: CCCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccco2)N1

Procedure:
150 ml of methanol, 120 ml of acetone and 0.6 ml of concentrated hydrochloric acid were added to 10.0 g (23.7 mmol) of N1-furfuryl-N5-dodecyl-biguanide dihydrochloride. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added 11 ml of 5N sodium hydroxide. The mixture was stirred, washed with 10% aqueous sodium acetate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (9:1:1)) to obtain 8.4 g of a pale yellow resinous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[CH3:13].[Li][CH:15](CC)C.CI>O1CCCC1>[CH2:12]([C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:15]
Reactant: [Li]C(C)CC
Reactant: COc1ccc(C(=O)O)c(C)c1C
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(C(=O)O)ccc(OC)c1C
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
2.50 g of 4-methoxy-2,3-dimethylbenzoic acid (G1) are dissolved in 160 ml of tetrahydrofuran under a nitrogen atmosphere and cooled to (−) 78° C. 11.5 ml of sec-BuLi are subsequently added dropwise at such a rate that the temperature of the reaction solution does not exceed (−) 65° C. When the addition is complete, the reddish reaction solution is stirred for a further 30 min with cooling. 3.59 ml of methyl iodide are then slowly added drop-wise. The cooling is subsequently removed, and the mixture is stirred for 1 h. For work-up, 160 ml of water are carefully added. The solution is subsequently extracted twice with 130 ml of ethyl acetate each time. The aqueous phase is cooled in an ice bath with stirring, acidified using 1.0 M HCl and filtered after 30 min. The filter cake is rinsed with cold water and subsequently recrystallised from 2-propanol. The crystals are filtered off with suction and dried for 2 h at 70° C. in vacuo, giving 1.90 g of the title compound as a colourless, crystalline solid having a melting point of 176.7° C.; MS: 194.2 (M+); TLC: Rf=0.29 (diethyl ether/petroleum ether 1:1 parts by volume).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11].CO.C1(C)C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][CH:25]=[N:24][CH:23]=1
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Product: c1ccc2[nH]c(-c3cnco3)cc2c1
Yield: 79.8 %

Procedure:
To a 100 mL round-bottom flask was added 1H-indole-2-carbaldehyde 18 (1.52 g, 10.48 mmol), methanol (50 mL), p-toluene sulfonylmethyl isocyanide (2.25 g, 11.52 mmol), followed by potassium carbonate (1.86 g, 13.45 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq.NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (3×30 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-(1H-indol-2-yl)oxazole 19 (1.54 g, 79% yield). MS (ES) m/z 185 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[O:13][CH3:14].C([Li])CCC.[Cl:20][Si:21](Cl)([CH3:23])[CH3:22]>CCCCCC.O1CCCC1>[C:9]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([Si:21]([Cl:20])([CH3:23])[CH3:22])[CH:7]=[C:6]([CH3:8])[CH:5]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(Br)cc(C)cc1C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a solution composed of tetrahydrofuran (31.5 ml), hexane (139 ml) and 1-bromo-3-tert-butyl-2-methoxy-5-methylbenzene (45 g) synthesized in the above-described procedure (2) was added a 1.6 mol/liter hexane solution (115 ml) of n-butyllithium dropwise at −40° C. over 20 minutes. The resultant mixture was kept at −40° C. for 1 hour, and tetrahydrofuran (31.5 ml) was then added dropwise. To a solution composed of dichlorodimethylsilane (131 g) and hexane (306 ml) was added the above-described mixture dropwise at −40° C. The resultant mixture was allowed to warm to room temperature over 2 hours, and further stirred at room temperature for 12 hours. The solvent and excess dichlorodimethylsilane were removed under reduced pressure from the reaction mixture, hexane-soluble components were extracted from the residue with hexane, and the solvent was distilled off from the resultant hexane solution to obtain 41.9 g of (3-tert-butyl-2-methoxy-5-methylphenyl)chlorodimethylsilane as a pale yellow oil. Yield was 84%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[OH-:42].[Na+].[BH4-].[Na+]>C1COCC1.O.C1COCC1.[Hg](OC(C)=O)OC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)([OH:42])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COc1cc(C(=O)N2CCN(C(=O)CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)CCCCC(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
To a solution of 6,6-bis-(4-fluoro-phenyl)-1-[4-(3,4,5,-trimethoxy-benzoyl)-piperazin-1-yl]-hex-5-en-1-one (1.62 g, 2.87 mmol) in dry THF (20 ml) a solution of Hg(OAc)2 (0.9 g, 2.87 mmol) in water:THF (1:1, 6 ml) was added. The mixture was then refluxed overnight. NaOH (3M, 3 ml) was added followed by addition of NaBH4 (54 mg, 1.43 mmol). The mixture was stirred for 4 hrs and separated organic layer was saturated with NaCl
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:11][CH:10]=1.Br[CH2:20][C:21]([NH2:23])=[O:22]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH:18][CH2:20][C:21]([NH2:23])=[O:22])=[CH:13][CH:14]=1
Reactant: NC(=O)CBr
Reactant: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
To a suspension of K2CO3 (3.48 g, 25.4 mmol, 2.1 equiv) in dry DMF (30 mL) a solution of (trans)-2-(4-bromophenyl)cyclopropanamine hydrochloride (3 g, 12.09 mmol, 1 equiv) in dry DMF (6 mL) was added at 0° C. and stirred for 10 min, then 2-bromoacetamide (1.82 g, 13.3 mmol, 1.1 equiv) was added and stirred at RT for 2 h. After completion, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using MeOH:CHCl3 (3:97) to get 2-((trans)-2-(4-bromophenyl)cyclopropylamino)acetamide (1 g, 31% yield) as a white solid.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH3:38][O:39][C:40]1[CH:59]=[CH:58][C:43]([CH2:44][C@H:45]([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])C(O)=O)=[CH:42][CH:41]=1>>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][C@H:45]([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])=[CH:58][CH:59]=1
Reactant: COc1ccc(C[C@H](CC(=O)N2CCOCC2)C(=O)O)cc1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccc(OC)cc1)C(C)C
Yield: 69.8 %

Procedure:
The procedure described in Example 1(b) was repeated, but using 200 mg (0.37 mmole) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-methylhexanamide [prepared as described in Example 1(a)] and 137 mg (0.45 mmole) of 2(R)-(4-methoxybenzyl)-3-(morpholinocarbonyl)propionic acid, to afford 188 mg (yield 70%) of the title compound as white crystals, melting at 128°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2]>ClC1C=CC=CC=1.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:5]1[C:13]2[CH:12]=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:8]=2[S:7][CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)CSc1cccc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1csc2cc(OC)ccc12
Temperature: 112 °C

Procedure:
306 g Polyphosphoric acid (Riedel-de-Haen 04101) are heated up to 70° C. Then 250 ml chlorobenzene are added, followed by a solution of 50.5 g (0.2 Mol) of crude 3-(3-methoxy-phenylsulfanyl)-2-oxo-propionic acid ethyl ester in 280 ml chlorobenzene. The mixture is heated up to 112° C. for 4 h. From the resulting 2-phasic hot mixture, the yellow-brownish upper layer is sucked off. The black lower phase is extracted by 3 portions of 250 ml boiling toluene. The upper layer and the 3 toluene extracts are combined and concentrated in vacuo (→crude 1). The residue from the black lower phase is hydrolysed in 7 l water. Extraction with 2 portions of CH2Cl2 gives more material (→crude 2). Both batches (crude 1 & 2) are combined and diluted with CH2Cl2, water and sat. NaHCO3. The aq. phase is separed off and extracted twice with CH2Cl2. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/CH2Cl2 9:1→7:3→1:1) and crystallization from hexane at −20° C. gives the title compound: m.p.: 68-69° C.; TLC(hexane/acetone 4:1): Rf=0.47.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[C:9](=O)[CH2:8]2)=[CH:4][CH:3]=1.C(NN)(N)=N.Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=3[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccc(Cl)s1)C2
Agent: Cl
Agent: N=C(N)NN
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1CCC(c1ccc(Cl)s1)C2
Yield: 60.9 %

Procedure:
A mixture of 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.79 g), aminoguanidine hydrochloride (0.33 g), concentrated hydrochloric acid (0.7 ml), water (0.7 ml) and ethanol (40 ml) was refluxed for 8.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethanol and recrystallized from ethanol-water. The resulting crystals were washed with ethanol to give 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 72) (0.26 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([C:12](=[C:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])#[N:11]>C(OCC)C.[Cu]I>[C:10]([CH:12]([C:17]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])#[N:11]
Reactant: COC(=O)C(C#N)=C1CCOCC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C1(c2ccc(F)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A round bottom flask was equipped with a condenser, addition funnel and rubber septum with nitrogen inlet was charged with a solution of p-fluorophenylmagnesium bromide (2.0 M in diethyl ether, 1.99 ml, 3.97 mmol) and CuI (63 mg, 0.331 mmol) in 10 ml dry diethyl ether (10 ml). Methyl 2-cyano-2-(oxan-4-ylidene)acetate (600 mg, 3.31 mmol) in diethyl ether (10 ml) was added drop-wise over 30 min while cooling the reaction flask in an ice bath. The mixture was then stirred for 3 h. The reaction mixture was poured into a 50 g ice/1 N HCl (25 ml) mixture. The product was extracted with Et2O (3×50 ml), washed with brine (50 ml), dried (NA2SO4) and concentrated. Purified by normal phase SiO2 chromatography (7% to 60% EtOAc/hexanes) to give methyl 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate as a white solid (730 mg, 80%, m/z: 277.1 [M+Na]+ observed).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:25])=O>CN(C=O)C>[ClH:25].[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCCCC1
Product: Cl

Procedure:
A mixture of 6-methoxy-7-(2-piperidinoethoxy)-3,4-dihydroquinazolin-4-one (440 mg, 1.45 mmol), thionyl chloride (15 ml) and DMF (3 drops) was heated at reflux for 3 hours then allowed to cool. The excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene to give a crude 4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline hydrochloride (640 mg).
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:11]2[N:12]=[C:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2N=C(C[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)N=C(O)C=2C1)=O)(C)(C)C.CC([O-])(C)C.[K+].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)[F:75])(=O)=O)=CC=1>C1COCC1.O>[CH2:24]([C:13]1[N:14]=[C:15]([C:53]2[CH:54]=[CH:55][C:50]([F:75])=[CH:51][CH:52]=2)[C:10]2[CH2:9][NH:8][CH2:32][CH2:31][C:11]=2[N:12]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)nc(O)c2C1
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CNCC3)cc1
Reaction time: 0.25 h
Yield: 81 %

Procedure:
2-Benzyl-4-trifluoromethanesulfonyloxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester. To a solution of 2-benzyl-4-hydroxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (2.0 g, 5.9 mmol; prepared from 2-phenyl-acetamidine hydrochloride as described in Example 1, Step A) in THF (15 mL) was added KOtBu (0.408 g, 3.6 mmol). After 15 min, the mixture was treated with N-phenyl-bis(trifluoromethanesulfonimide) (1.18 g, 3.3 mmol) and the mixture was stirred for 18 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (10-40% EtOAc/hexanes) to give 1.15 g (81%) of the title compound which was contaminated with byproducts from N-phenyl-bis(trifluoromethanesulfonimide). Step B. 2-Benzyl-4-(4-fluoro-phenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester. The title compound was prepared as described in Example 1, Step C. MS (ESI): exact mass calcd. for C25H26FN3O2, 419.20; m/z found, 420.5 [M+H]+. 1H NMR (CDCl3): 7.53 (dd, J=5.3, 8.7, 2H), 7.43-7.41 (m, 2H), 7.31-7.28 (m, 2H), 7.23-7.14 (m, 3H), 4.55 (s, 2H), 4.27 (s, 2H), 3.75 (t, J=6.1, 2H), 3.00 (t, J=6.0, 2H), 1.43 (s, 9H). Step C. 2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine. A solution of the product from Step B (0.131 g, 0.312 mmol) in CH2Cl2 was treated with TFA. After stirring for 4 h, the mixture was concentrated and partitioned between saturated (satd.) aq. NaHCO3 and CH2Cl2 (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.084 g (84%) of the title compound. MS (ESI): exact mass calcd. for C20H18FN3, 319.15; m/z found, 320.4 [M+H]+. 1H NMR (CDCl3): 7.51 (dd, J=5.4, 8.8, 2H), 7.41 (d, J=7.4, 2H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 7.15 (dd, J=8.7, 2H), 4.27 (s, 2H), 3.95 (s, 2H), 3.24 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H). Unless otherwise specified, the compounds in Examples 3-57 were prepared using methods similar to those described in Examples 1 and 2, utilizing the appropriate β-ketoesters, amidine hydrochlorides, and arylboronic acids.
Reaction SMILES: C(O)C.O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:9]#[N:10]>C(O)(=O)C>[NH2:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:5]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(C#N)ccc1N
Temperature: 85 °C
Yield: 93 %

Procedure:
To an ethanol (500 ml)-water (60 ml)-acetic acid (30 ml) mixed solvent were added 3-methyl-4-nitrobenzonitrile (8.40 g, 51.8 mmol) and reduced iron (18 g, 322 mmol), and the mixture was stirred with heating at 85° C. for 3 hr. The reaction mixture was cooled, filtered through celite, and the solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (6.37 g, yield 93%) as a pale-yellow solid.
Reaction SMILES: [C:1](Br)(=[O:3])[CH3:2].[C:5]([O:22][CH2:23][CH:24]([CH2:45][O:46][Si](C(C)(C)C)(C)C)[O:25][C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCCCCCC>[C:5]([O:22][CH2:23][CH:24]([CH2:45][O:46][C:1](=[O:3])[CH3:2])[O:25][C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC(COC(=O)CCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Br
Solvent: CCCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC(COC(C)=O)COC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
Acetylbromide (123 g) was added into heptane solution of 1-palmitoyl-2-linoleoyl-3-t-butyl-dimethylsilyl-glycerol, which was obtained in Example 4, and the reaction mixture was stirred for 12 hours at room temperature. Heptane (400 ml) was added into the reaction mixture, and the cooling purified water (400 ml) was dropwisely added thereto for extracting the organic layer. The separated organic layer was washed with a solution of saturated sodium bicarbonate (100 ml) and purified water (400 ml), and then the washed organic layer was dehydrated with anhydrous MgSO4, and filtered. 1-palmitoyl-2-linoleoyl-3-acetyl-glycerol (178 g) was obtained with a silica gel (Si-60, 230-400 mesh) column chromatography(heptane:ethyl acetate=36:1 by volume) (theoretical amounts: 63.5 g, yield: 28.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:16][CH:15]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2ccc(C)cc2[N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
To a solution of 1-Bromo-4-methyl-2-nitro-benzene (0.76 g, 3.5 mmol), 1-methoxy-4-vinyl-benzene (0.59 g, 4.4 mmol), triethylamine (0.88 g, 8.8 mmol), tri-o-tolylphosphine (0.022 g) and palladium acetate (0.008 g) in N,N-dimethylformamide (7 mL) was placed in a high-pressure tube and purged with nitrogen for 10 mins. The tube was sealed and heated at 120° C. for 16 hours. The mixture was partitioned with water and ethyl acetate adjusting the pH to 3. The organic layer was washed with brine, dried (sodium sulfate) and filtered through a plug of silica. The filtrate was evaporated under vacuum and the residue was triturated with hexane/ethyl acetate (9:1) to provide the title compound (0.55 g, 58%).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][C:38]=1[N+:47]([O-:49])=[O:48]>[Pd]>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:11][CH:12]([CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])(=[O:45])=[O:44])=[CH:39][C:38]=1[N+:47]([O-:49])=[O:48]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 33.7 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (500 mg) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-chloro-3-nitrobenzenesulfonyl chloride (524 mg) to obtain (RS)-2-(4-chloro-3-nitrobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (198.2 mg).