Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:29])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:28][O:27]4)[CH2:21][CH2:20]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:30][NH2:31]>>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([OH:29])[CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH:26]([OH:27])[CH2:28][NH:31][CH3:30])[CH2:23][CH2:24]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: CN
Reactant: OC(CN1CCN(CC2CO2)CC1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Product: CNCC(O)CN1CCN(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To (±)-1-(3,6-dibromo-carbazol-9-yl)-3-(4-oxiranylmethyl-piperazin-1-yl)-propan-2-ol (0.110 g, 0.21 mmol) is added methyl amine (3 mL, 2M in MeOH). The resulting mixture was stirred for 16 hr at rt. Concentration in vacuo, flash chromatography on a 2×14 cm2 column of SiO2 using (ACN:(aqueous NH4OH-25%)) (5:1) as eluting solvent gives the title compound as a white foam in a 90% yield. M.p.: 65-75° C. Slow addition of HCl (1 mL, 1M in Et2O) into a solution of the above compound in DCM (2 mL) gives the hydrochloride salt of the title compound (0.39 g) as a white solid in a 35% yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:5]=1[CH:6]=O.Cl.[CH3:22][C:23]([CH3:25])=[O:24]>O>[CH3:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:5]=1[CH:6]=[CH:22][C:23](=[O:24])[CH3:25]
Reactant: Cc1cc(OCc2ccccc2C)ccc1C=O
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(OCc2ccccc2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
2N NaOH(aq) (0.6 mL) was added to a solution of 31.3 (100 mg, 0.42 mmol) in acetone (1 mL). The reaction was stirred at room temperature overnight and then taken up in water. The aqueous solution was acidified with 1N HCl(aq) (1.5 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The resultant residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 74 mg (63%) of 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-one (31.4). LC/MSD m/e: 281.4 (M+H); 1H NMR (400 MHz) (acetone-d6) δ 7.83 (1H, d, J=16), 7.70 (1H, m), 7.46 (1H, m), 7.25 (3H, m), 6.96 (2H, m), 6.63 (1H, d, J=16 Hz).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH2:10][O:11][C:12](/[CH:14]=[CH:15]/[CH2:16]P(OCC)(OCC)=O)=[O:13].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[C:32]2[CH:40]=O)[CH:26]=1>O1CCCC1>[CH2:10]([O:11][C:12]([CH:14]=[CH:15][CH:16]=[CH:40][C:32]1[N:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C:39]2[C:34]([CH:33]=1)=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:13])[CH3:9]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1cc2ccccc2n1-c1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cc2ccccc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of lithium diisopropylamide (from 0.57 ml of diisopropylamine and 2.5 ml of 1.6M n-butyllithium in hexane) in 20 ml of dry tetrahydrofuran under nitrogen is cooled to -70° and 0.78 ml of triethyl 4-phosphonocrotonate is added dropwise. The reaction mixture is stirred for 30 minutes at -70°, and then a solution of 0.9 g of N-(3-pyridyl)indole-2-carboxaldehyde in 5 ml of tetrahydrofuran is added slowly. The reaction mixture is allowed to warm to room temperature, is stirred for 14 hours and is evaporated to an oil which is partitioned between 15 ml of half-saturated ammonium chloride solution and 40 ml of ethyl ether. The organic phase is washed with 10 ml of water, dried over sodium sulfate and evaporated to yield 2-[4-(ethoxycarbonyl)butadienyl]-N-(3-pyridyl)indole as a waxy solid; Rf (10% methanol and toluene, silica gel)=0.7.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl.O>[CH3:11][S:12]([O:10][CH2:9][CH2:8][C:3]1([CH2:1][CH3:2])[O:7][CH2:6][CH2:5][O:4]1)(=[O:14])=[O:13]
Reactant: CCC1(CCO)OCCO1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCC1(CCOS(C)(=O)=O)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.2 %

Procedure:
To a solution of 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 1.59 mmol) and TEA (327 mg, 3.2 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.23 ml, 2.92 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (500 mg, 100%) as yellow oil that was used without purification. Product tlc [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.6]
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)O)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A mixture of methyl ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate (2.52 g, 5.19 mmol) and 5N NaOH (5.18 mL) in THF (32 mL) and methanol (32 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in water and neutralized with HCl to pH˜6. The precipitated solid was filtered to provide 1.61 g of ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetic acid as a white solid. Yield 66%. mp 245-247° C. Electrospray Mass Spec 473.2 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH2:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[N:13]=[CH:12][C:11]=2[NH:20][C:21](=O)[CH2:22][O:23][CH2:24][CH3:25])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>CO>[CH2:24]([O:23][CH2:22][C:21]1[N:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH3:25]
Reactant: CCOCC(=O)Nc1cnc2cccnc2c1NCc1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Product: CCOCc1nc2cnc3cccnc3c2n1Cc1ccccc1
Temperature: 150 °C
Yield: 87.1 %

Procedure:
N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamide hydrochloride (5.8 g, 15.5 mmol) was combined with a 7% solution of ammonia in methanol (100 mL), placed in a sealed Parr vessel and then heated at 150° C. for 6 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, washed with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was recrystallized from methyl acetate to provide 4.3 g of 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine, m.p. 11.8-119° C. Analysis: Calculated for C19H18N4O: % C, 71.68; % H, 5.70; % N, 17.60; Found: % C, 71.44; % H, 5.60; % N, 17.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.O.NN.[OH-].[Na+].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][NH2:15])[O:10][CH2:11][CH2:12][O:13]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2(CN)OCCO2)cc1
Temperature: 25 °C

Procedure:
2-[2-(4-Methoxyphenyl)-[1,3]dioxolan-2-ylmethyl]isoindole-1,3-dione (Preparation 41, 2.0 g, 5.90 mmol) and hydrazine hydrate (5 mL) were combined. The stirred reaction mixture was heated under reflux for 48 h then allowed to cool to rt. Aqueous sodium hydroxide (2M, 10–15 mL) and water (20 mL) were added and the mixture stirred until a solution was formed. Diethyl ether (20 mL) was added and the biphasic mixture stirred vigorously for 16 h. The layers were separated and the aqueous layer was extracted with diethyl ether (3×20 mL), then the combined organic extracts were washed with brine (20 mL). The ethereal solution was passed through a filter paper then evaporated to dryness in vacuo to give the title compound as a yellow oil, which solidified on standing. δH (CDCl3): 1.42 (2H, br s), 3.06 (2H, s), 3.97 (3H, s), 4.00 (2H, t), 4.21 (2H, t), 7.04 (2H, d), 7.53 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10]C(=O)OC.C1(C)C=CC(S(O[CH:25]2[CH2:29][CH2:28][CH2:27][CH:26]2[CH3:30])(=O)=O)=CC=1.[OH-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:25]2[CH2:29][CH2:28][CH2:27][CH:26]2[CH3:30])=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1CCCC1Oc1cc(N)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 40 %

Procedure:
A solution of methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.53 g, 6.98 mmol) synthesized by the process described in Reference Example 3, 2-methylcyclopentyl p-toluenesulfonate (1.78 g, 6.99 mmol) and N,N-dimethylformamide (15 ml) was charged into a 50 cc round-bottom flask, and then potassium hydroxide (400 mg, 7.15 mmol) in a powder form was added thereto, followed by stirring for 7 hours while heating on an oil bath at 80° to 100° C. After completion of the reaction, the reaction solution was cooled to room temperature, 2N hydrochloric acid (50 ml) was added thereto, and the mixture was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (1.51 g). The product was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=17/3) to obtain 2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyaniline as a colorless oily substance (666 mg, 2.73 mmol, 40% yield).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][CH:10]([O:13][P:14](Cl)Cl)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][CH:10]([O:13][P:14]([C:24]3[NH:23][CH:27]=[CH:26][N:25]=3)[C:24]3[NH:23][CH:27]=[CH:26][N:25]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)OC1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: c1c[nH]cn1
Product: c1ccc(C2(c3ccccc3)CCC(OP(c3ncc[nH]3)c3ncc[nH]3)CC2)cc1

Procedure:
A process for preparing (4,4-diphenylcyclohexyl)phosphooxymethyl diethylene triaminepenta-acetic acid comprising the steps of: (a) phosphorylating 1.0 equivalents of 4,4-diphenylcyclohexanol with about one equivalent of phosphorous trichloride to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula: ##STR20## (b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenycyclohexyloxy-diimidazolylphosphine having the formula: ##STR21## where imido refers to imidazolyl (c) coupling of the 4,4-diphenylcyclohexyloxy- diimidazolylphosphine formed in step (b) with from about 0.75 to about 1.0 equivalents of hydroxymethyl-DTPA penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA -oxy, penta tert-butyl ester) imidazolyl-phosphine having the formula: ##STR22## where imido refers to imidazolyl (d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester) imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form (4,4-diphenylcyclohexyl)phosphonooxymethyl diethylene triamine, penta t-butyl ester having the formula: ##STR23##
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:16][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])(C(C)(C)C)(C)C.Cl>C(O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:37])[N:14]([CH3:36])[C:15]=3[N:16]=[C:17]2[O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl (1 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a golden oil. The oil was purified using a 2000 micron preparative TLC plate eluted with ethyl acetate. Target band was scraped off plate, eluted off silica gel with ethyl acetate and evaporated under reduced pressure to give 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.028 g, 14% yield) as a white solid. LCMS retention time=3.656 min and 98% purity, LCMS MH+ 433. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J=12 and 48 Hz), 5.34-5.40 (m, 1H), 5.18 (s, 2H), 4.42 (t, 1H, J=4 Hz), 3.89 (t, 2H, J=8 Hz), 3.38-3.45 (m, 2H), 3.36 (s, 3H), 1.55-1.93 (m, 8H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:17][C:5]1[C:6]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Temperature: 90 °C
Yield: 39 %

Procedure:
To a mixture of 6-fluoro-3-nitro-2-phenylaminobenzonitrile (2.7 g, 10.5 mmol) in a mixture of MeOH (50 mL) and water (20 mL) were added NH4Cl (3.23 g, 62.9 mmol) and iron powder (2.3 g, 41.9 mmol) and the reaction mixture was heated at 90° C. for 1 h. After cooling to RT, the solid was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (930 mg, 39%). LCMS (Method B): RT 3.27 min [M+H]+ 227.8.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:23].[OH-]>O1CCCC1.CO>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:23]
Reactant: CCOC(=O)c1cnc(C2CCN(c3ccccc3)CC2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1cnc(C2CCN(c3ccccc3)CC2)s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(1-phenylpiperidin-4-yl)thiazole-5-carboxylate (31 mg, 0.098 mmol) in 1 ml of 1:1 tetrahydrofuran/methanol was treated with 1M aqueous LiOH (0.11 ml, 0.11 mol) and stirred at 65° C. for 3 hours. The mixture was taken to dryness and used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:39][O:40][C:41]([C:43]1([NH2:52])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]>CN(C=O)C>[CH3:39][O:40][C:41]([C:43]1([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([F:13])[C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=2)[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1c(F)cc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cc(F)c(OC)c(Br)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
2.4 g (9.64 mmol) of the compound of step 3 were dissolved in 40 ml of DMF and 2.49 g (19.27 mmol) of EDIA and 4.03 g (10.60 mmol) of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were added. Then a solution of 2.19 g (9.64 mmol) of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 10 ml of DMF was added. After stirring overnight, the mixture was evaporated to dryness and the residue purified by preparative RP HPLC (water/ACN gradient). 3.6 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1b), the alkylation of 4-benzyloxy-phenol with methyl bromoacetate using cesium carbonate as the base yielded the (4-benzyloxy-phenoxy)-acetic acid methyl ester as white crystals; MS: m/e=272 (M)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH2:33])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH:33][C:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:17][CH:16]=3)[CH:12]=2)=[O:15])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1cnn(Cc2ccc(CO)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-Hydroxymethyl-benzyl)-1H-pyrazole-4-carboxylic acid (220 mg, 0.95 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (238 mg, 0.95 mmol), HATU (7206 mg, 1.90 mmol) and DIPEA (0.64 mL, 2.84 mmol) in 5 mL DMF was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, dissolved in ethylacetate and extracted with aq. NaHCO3-solution. The organic layer was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). LCMS (method A) RtA=1.243 min; [M+H]+=466.0.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1(O)CCCC1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(C#CC3(O)CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (73) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1-ethynylcyclopentanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.56 (m, 3H), 7.39 (d, J=8 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.26 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.93 (m, 4H), 1.78 (m, 4H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10](O)=[O:11])=[C:4]([N+:13]([O-])=O)[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:8][CH2:9][C:10](=[O:11])[NH:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1CNc2ccc(F)cc2N1
Temperature: 90 °C
Yield: 103.1 %

Procedure:
Iron powder (6.52 g, 116.8 mmol, 5.0 eq) is added at room temperature to a stirred solution of (4-fluoro-2-nitro-phenylamino)-acetic acid (6.85 g, 23.4 mmol, 1.0 eq) in glacial acetic acid (40 mL). The resulting suspension is heated at 90° C. for 3 hours, then cooled to room temperature, diluted with ethyl acetate (40 mL), and filtered through silica gel. The filtrate is concentrated to give a crude that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:3, v/v) to afford 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one as a brown solid (4.01 g, 72% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:10](=O)[CH2:11][CH3:12])[C:6](=O)[CH2:7][CH3:8])=[O:4].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:16]=1[NH:26][NH2:27]>C(O)C>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[C:17]([Cl:25])[C:16]=1[N:26]1[C:10]([CH2:11][CH3:12])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]([CH2:7][CH3:8])=[N:27]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCC(=O)C(C(=O)CC)C(=O)OC
Solvent: CCO
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1C(=O)OC
Yield: 43 %

Procedure:
A solution of 7.5 g (40 mmol) of the compound of step A and 11.85 g (48 mmol) of 2,6-dichloro-4-trifluoromethylphenyl hydrazine in 50 mL of ethanol was heated at reflux for 8 hours. The ethanol was removed by evaporation and the residues were partitioned between ethyl acetate and dilute hydrogen chloride. The organic extracts were dried and evaporated to give the desired product in 43% yield as a maroon oil. 1H-NMR (CDCl3) δ 1.08 (3H, t, J=7), 1.24 (3H, t, J=7), 2.22 (2H, q, J=7), 2.58 (4H, q. J=7), J=7), 3.86 (3H, s), 7.46 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.[OH:15][C@:16]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[F:1][C:2]1[CH:3]=[C:4]([S:28][C:25]2[S:26][CH:27]=[C:23]([C@@:16]3([OH:15])[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]3)[CH:24]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc(I)cc(F)c21
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Product: C[C@H]1C[C@@](O)(c2csc(Sc3cc(F)c4c(c3)CCC(=O)N4C)c2)CCO1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in Example 5, 8-fluoro-6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one with (2S,4R)-4-hydroxy-4-(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-[2-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]-4-hydroxy-2-methyltetrahydropyran in 40% yield as a foam;