Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH2:10][CH3:11])[CH:8]=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[CH:26])[CH:20]=1>O1CCCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH2:10][CH3:11])[CH:8]([OH:9])[C:26]#[C:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1
Reactant: CC[C@@H](C=O)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Freshly activated (dried in oven at 300° C.) powdered molecular sieves (20 g, 3 Å, <5 micron) were added to (2S)-2-(4-bromophenoxy)-1-butanol (5.24 g, Example 87b)) and pyridinium dichromate (12.07 g) in anhydrous dichloromethane (200 ml). This mixture was treated with anhydrous acetic acid (2 drops) and stirred under nitrogen for 2 hours. Celite® (10 g) was added to the reaction mixture which was stirred for 20 minutes. Isohexane (100 ml) was added to this and the mixture filtered. The filtrate was concentrated under reduced pressure and the residue obtained was triturated in diethyl ether. This was filtered through anhydrous magnesium sulfate and the filtrate concentrated under reduced pressure. The residue obtained was assumed to be (2S)-2-(4-bromophenoxy)-1-butanal and dissolved in anhydrous tetrahydrofuran (40 ml). n-Butyl-lithium (5.88 ml, 2.5M solution in hexanes) was added dropwise to a solution of pyridin-3-ylacetylene (1.6g, J. Amer. Chem. Soc. 1935, 57, 1284) in anhydrous tetrahydrofuran (80 ml) at −70° C., under nitrogen. After stirring for 20 minutes the solution of the (2S)-2-(4-bromophenoxy)-1-butanal in tetrahydrofuran was added dropwise, maintaining the reaction temperature at −70° C.. The reaction mixture was then allowed to warm slowly to 0° C. and poured into brine (200 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic fractions were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give an oil which was purified by flash column chromatography over silica eluting with isohexane : ethyl acetate (2:1). This gave the sub-title compound as an oil (3.42 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:28]3[CH2:29][CH2:30][NH:25][C:26](=[O:31])[CH2:27]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CCN1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (400 mg, 1.52 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (5 mL) was added triethylamine (0.637 mL, 4.57 mmol) and 2-piperazinone (168 mg, 1.675 mmol, Sigma-Aldrich). The reaction mixture was heated to 120° C. for 20 min in a microwave reactor.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCOC(C)=O>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccncc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CCc2ccncc2)cc1
Yield: 99.5 %

Procedure:
To the EtOAc solution (30 mL) of 4-[2-(4-nitro-phenyl)-vinyl]-pyridine (160 mg, 0.71 mmol) was added palladium on carbon (0.1 g, 50% wet). The suspension was hydrogenated at 50 psi of hydrogen for 2 hours. The mixture was filtered over a celite pad. The filtrate was concentrate to give 4-(2-pyridin-4-yl-ethyl)-phenylamine as a yellow solid (140 mg, 100%).
Reaction SMILES: [H-].[Na+].I[CH3:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[CH:20]=3)[N:15]=[C:14]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([O:27][CH3:4])([CH3:25])[CH3:26])[CH:20]=3)[N:15]=[C:14]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:10][CH:11]=1
Reactant: CI
Reactant: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(C)(C)OC)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.186 g of 60% sodium hydride and 2.90 ml of iodomethane in THF at room temperature is added 1.00 g of 3-[(4-bromophenyl)methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone. The reaction mixture is stirred overnight at room temperature and then quenched with ammonium chloride solution and diluted with water. The aqueous layer is extracted with ether and the combined organics are dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash chrmoatography eluting with ethyl acetate/hexanes (1:3) to provide the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 682.7 %

Procedure:
To a solution of 3-benzyloxybenzoic acid (22 g, 96 mmol) in toluene (200 ml) was added dropwise thionyl chloride (14.1 ml, 19 mmol). The reaction mixture was heated at 90° C. for 2 hours, cooled to ambient temperature and volatiles removed under reduced pressure to afford crude 3-benzyloxybenzoyl chloride (32 g, quant.). The crude 3-benzyloxybenzoyl chloride was dissolved in CH2Cl2 and added dropwise over 30 min., to a vigorously stirred solution of (R)-(-)-2-phenylglycinol (15.8 g, 115 mmol) and triethylamine (16 ml, 15 mmol) in CH2Cl2 (200 ml) cooled to 0° C. The reaction mixture was allowed to warm ambient temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (1 L) and water (1 L). The aqueous layer was separated, extracted with ethyl acetate (2×500ml) and the combined organic phase washed with 1N HCl (500 ml), aqueous 4% NaHCO3 solution (500 ml) and brine (500 ml), dried over MgSO4 and concentrated under reduced pressure to give 2-(3-benzyloxybenzamido)-2(R)-phenylethan-1-ol (29 g, 88%) as pale yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19].Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC

Procedure:
8.4 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissolved in 450 ml of methanol, admixed with 2 ml of conc. hydrochloric acid and hydrogenated after the addition of 500 mg of Pd/C 10%. The reaction mixture is filtered and the filtrate is concentrated. M.p.: 84-86.5° C.; Yield quantitative.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH:14]([NH2:16])=O>>[O:9]1[C:5]2=[CH:4][C:3]3[C:11](=[O:13])[NH:16][CH:14]=[N:1][C:2]=3[CH:10]=[C:6]2[O:7][CH2:8]1
Reactant: NC=O
Reactant: Nc1cc2c(cc1C(=O)O)OCO2
Product: O=c1[nH]cnc2cc3c(cc12)OCO3
Temperature: 140 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A mixture of 6-amino-benzo[1,3]dioxole-5-carboxylic acid (4.3 g, 23.7 mmol) and formamide (15 mL) was heated to 140° C. for 2 hours, then to 170° C. for 2 hours. After cooling to room temperature, precipitate was collected to give 7H-[1,3]dioxolo[4,5-g]quinazolin-8-one (1.11 g, 27%).
Reaction SMILES: [CH2:1]([N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:5][CH2:6][CH2:7][N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH3:3]>CO>[CH2:1]([N:4]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:5][CH2:6][CH2:7][N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1)[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:2][CH3:3]
Reactant: CCCN(CCCN(CCCN(CCc1ccccn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CO
Product: CCCN(CCCN(CCCN(CCC1CCCCN1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A mixture of 2.084 g (3.6 mmol) of 1-propyl-9-[2-(2-pyridyl)-ethyl]-1,5,9-tri-BOC-1,5,9-triazanonane, 20 ml of methanol and 0.2 g of pre-hydrogenated rhodium oxide/platinum oxide (Nishimura catalyst) is hydrogenated at room temperature and under normal pressure until the absorption of hydrogen has ceased. After filtration and washing the catalyst with methanol, the filtrate is concentrated by evaporation in vacuo, yielding the title compound in the form of a colorless resin, Rf value=0.51 (silica gel/tert-butyl methyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][Si](C)(C)C)=[CH:9][N:8]([C@@H:17]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[CH:12])=[CH:9][N:8]([C@@H:17]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2ncnc(N)c12
Yield: 73 %

Procedure:
200 mg of compound (23) are dissolved in 20 ml of MeOH. Adding 8 mg of K2CO3 results in hydrolysis after 1 h of stirring. After the solution has been subjected to rotary evaporation, the residue is chromatographed on silica gel in the eluent methylene chloride/MeOH (8:1). Recrystallization from MeOH results in colorless crystals (73%). Calc. C 56.93, H 5.15, N 20.43; found C 56.77, H 5.71, N 20.42. 1H-NMR (DMSO): 8.13 (s, 1H, H-2), 7.81 (s, 1H, H-6), 6.65 (broad, 2H, NH2), 6.49 (t, 1H, H-1′), 5.25 (m, 1H, 3′-OH), 5.05 (m, 1H, 5′-OH), 4.36 (m, 1H, H-3′), 4.26 (s, 1H, ethyne), 3.84 (s, 1H, H-4′), 3.56 (m, 2H, H-5′), 2.47 (m, 1H, H-2′), 2.21 (m, 1H, H-2′).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N+:23]([O-:9])[CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
m-Chloroperbenzoic acid (6.9 g, 40.0 mmol) was slowly added to a solution of 3-(4-nitrophenyl)pyridine (P1, 4 g, 20.0 mmol) in tetrahydrofuran (200 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solution was poured into aqueous sodium thiosulfate and the resultant mixture was concentrated. Trituration with ethyl acetate afforded the title compound as a solid.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.O>CS(C)=O>[C:1]1([C:7]2([O:13][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
A mixture of 4-phenyl-4-piperidinol (7.1 g, 40 mM), DMSO (50 ml) and sodium hydride (2 g of a 50% dispersion in oil) was heated at 80° until homogenous, cooled to ambient temperature and treated with 4-fluorobenzotrifluoride (6.6 g, 40 mM) in DMSO (10 ml). After 24 hours the reaction mixture was poured on to cold water (250 ml) and extracted with ether (2×250 ml). The combined organic layers were washed with brine, dried and the solvent removed under reduced pressure. The residue was triturated with cyclohexane, filtered and the mother liquors evaporated and the residue triturated with pentane. Sublimation of the resulting crystals at 0.1 mm Hg (bath temp. 100°) gave the title compound (1.5 g), m.p. 104°-5°.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.097 mmol), 5-aminovaleric acid (740 mg, 6.32 mmol), and NaOMe solution (10 mL, 4.86 mmol) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 19 mg of the title compound. MS: (+) m/z 549.31 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:22]([O:21][C:20]([NH:19][C@@H:3]1[C:2](=[O:1])[N:8]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@@H:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:26])([CH3:23])([CH3:25])[CH3:24]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (150 mg, 0.423 mmol) in dry DMF (4 mL) under nitrogen was added methyl bromoacetate (97 mg, 0.634 mmol) and powdered cesium carbonate (207 mg, 0.635 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the organic extract was purified by flash chromatography on silica gel eluting with 4:1 (v/v) hexane:ethyl acetate to afford the title compound (175 mg, 97%) as a white solid. TLC Rf=0.20 (4:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.38 (s, 9H), 3.80 (s, 3H), 4.54 and 4.69 (AB quartet, 2H, J=17.1 Hz), 4.93 (m, 1H), 5.02 (m, 1H), 5.70 (d, 1H, J=7.0 Hz), 7.19-7.29 (m, 4H), 7.35-7.48 (m, 5H). MS APCI, m/z=327 (M-BOC). LC/MS: 2.76 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:26]([CH3:36])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:29]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[C:26]([CH3:36])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn(-c4ccccn4)nc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cn(-c4ccccn4)nc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (680 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (620 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 126–127° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: BrCc1ccccc1
Product: N#Cc1ccc(N(Cc2ccccc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and benzyl bromide
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)(=O)=O)=[N:19][CH:20]=2)[N:15]([CH3:27])[C:14]1=[O:28].[CH3:29][C:30]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[C:31]=1[NH2:32].C([O-])(C)(C)C.[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:32][C:31]3[C:33]([N+:37]([O-:39])=[O:38])=[CH:34][CH:35]=[CH:36][C:30]=3[CH3:29])=[N:19][CH:20]=2)[N:15]([CH3:27])[C:14]1=[O:28]
Reactant: COc1cc(OC)c(Cl)c(N2Cc3cnc(S(C)(=O)=O)nc3N(C)C2=O)c1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3N(C)C2=O)c1Cl
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a mixture of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (450 mg, 1.01 mmol) and 2-methyl-6-nitroaniline (230 mg, 1.51 mmol) in 5 mL of N,N-dimethylformamide was added potassium tert-butanolate (339 mg, 3.02 mmol) at RT and stirred for 0.5 h. LCMS showed the reaction was completed. The mixture was quenched by 80 mL of water, and the precipitate was collected via the filtration and dried to give the title compound (290 mg, 56%) as a yellow solid, which was directly used in the next step without further purification. MS (ES+) C22H20Cl2N6O5 requires: 518, 520. Found: 519, 521 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(Cl)([Cl:25])=O)C=CC=CC=1>>[Cl:25][C:12]1[C:11]([C:15]#[N:16])=[CH:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)[nH]c1=O
Product: N#Cc1ccc(-c2ccc(Cl)cc2)nc1Cl

Procedure:
6-(4-Chlorophenyl)-3-cyano-2-pyridone (42 grams) and phenylphosphonic dichloride were heated for 2.5 hours at 175°-180° C. taking precautions to keep the reaction dry. Upon cooling, the reaction mixture was poured into 500 ml of ice water and was made slightly alkaline by the addition of concentrated NH4OH. A solid product formed which was thoroughly washed with water and recrystallized from ethanol/DMF, yield 42 grams, m.p. 179°-181° C.
Reaction SMILES: Cl.O.[C:3]([C:10]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:11]=1[OH:12])(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Zn].C1(C)C=CC=CC=1>[CH2:3]([C:10]1[C:11]([OH:12])=[CH:13][CH:14]=[CH:15][C:16]=1[OH:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Subsequently, 30.0 g of zinc powder was mixed with 2.50 g of mercuric chloride, 1.5 ml of concentrated hydrochloric acid and 38 ml of water and shaken for 5 minutes, followed by decantation to discard the aqueous phase. Thereafter, 20 ml of water, 45 ml of concentrated hydrochloric acid, 25 ml of toluene and 14.6 g of the previously obtained n-hexanoyl resorcinol were added in this order, followed by refluxing under heating conditions for 30 hours. During the refluxing, 12.5 ml of concentrated hydrochloric acid was added four times every 6 hours in order to keep the concentration of the acid. The reaction solution was cooled down to room temperature and subjected to liquid separation. The resultant aqueous phase was extracted three times with 50 ml of isopropyl ether and combined with the organic phase, followed by washing with 100 ml of water. The solvent was distilled off by means of an evaporator and the residue was crystallized from n-hexane to obtain 4.3 g of n-hexyl resorcinol as colorless needle crystals.
Reaction SMILES: [CH:1]1([NH:5][C@@H:6]2[CH2:11][C:10]3[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[C:15]([F:16])[C:9]=3[O:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][CH2:20][CH:21]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:1]1([N:5]([C@@H:6]2[CH2:11][C:10]3[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[C:15]([F:16])[C:9]=3[O:8][CH2:7]2)[CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCC1)CO2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(C1CCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
(R)-3-(N-Cyclobutylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.01 g, 4.02 mmol) was dissolved in anhydrous methanol (20 mL) and to this was n-propionaldehyde (3.0 mL, 40.2 mmol) added. After 1 h the reaction was cooled (ice-bath) then sodium cyanoborohydride (0.46 g, 7.24 mmol) was added, the pH was adjusted to 4-5 with acetic acid and the reaction was allowed to stir at room temperature over the weekend. The solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent 11% ethyl acetate/hexane) gave 0.95 g (80% yield) of the title compound as a clear oil. [α]21D =-95.4° (C=0.1; CHCl3). GC-MS (70 eV) M=293 (1%).