Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[NH2:5].[Cl:19]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:19][C:6]1[C:7]([CH3:18])=[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:2]([Cl:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(N)cc(Cl)c1Oc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: Cc1c(Cl)c(N)cc(Cl)c1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.9 %

Procedure:
Into a magnetically stirred solution of 3-chloro-4-(2,4-dichlorophenoxy)-5-methylaniline (9.0 grams, 29.7 mmol) in benzene (60 milliliters) was added solid N-chlorosuccinimide (4.4 grams, 32.7 mmol). The mixture was stirred at room temperature for 1.5 hours, transferred to a separatory funnel and washed with saturated Na2SO3 solution (3x), water (2x) and brine (1x). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product (10.08 grams) as a dark brown oil. Flash column chromatography on 500 grams of silica gel (3:1 hexane:ethyl acetate) afforded pure 2,5-dichloro-4-(2,4-dichlorophenoxy)-3-methylaniline (2.85 grams, 7.4 mmol, 25%) having a melting point of 96° C.-97° C. and 2,3-dichloro-4-(2,4-dichlorophenoxy)-5-methylaniline (2.16 grams, 6.4 mmol, 22%) having a melting point of 95° C. Recrystallization from methanol afforded analytical samples. Elemental analysis of the samples indicated the following:
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[OH:1][N:2]=[CH:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[S:9][C:8]=12
Reactant: ON=Cc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C=NO)c2s1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
7-Hydroxyiminomethylimidazo[5,1-b]thiazole (a low-polarity geometrical isomer) (831 mg) was dissolved in 25 ml of THF and 5 ml of hexamethylphosphoramide (HMPA). A 1.55 N n-butyllithium/n-hexane solution (7.67 ml) was dropwise added in an argon atmosphere at −70° C. to the solution. The mixture was stirred at the same temperature for 40 min. Tri-n-butylstannyl chloride (1.84 ml) was added thereto. The mixture was stirred for 1.5 hr while raising the temperature to −40° C. An ammonium chloride solution was a added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 to 1:1) to give 680 mg of 7-hydroxyiminomethyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole (a geometrical isomer derived from a starting compound as a low-polarity oxime isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1ccc(Cl)c(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Temperature: 100 °C
Yield: 66.7 %

Procedure:
3.6 g. (0.02 mol) of 2,5,6-trichloropyridine are dissolved in a mixture of 20 ml of 100% strength fuming nitric acid and 16 ml of concentrated sulphuric acid and are then heated at 100°C in an oil bath for 12 hours. After cooling to approx. 20°C, the reaction mixture is poured onto ice. The crude product is produced in the form of slightly yellowish crystals, which are filtered off with suction, washed with water and dried at 30°C in vacuo over KOH. 3 g (66.7% of theory) of 2,5,6-trichloro-3-nitropyridine are obtained in the form of crystals which, after sublimation at 30° - 40°C/12 mm Hg. melt at 68° - 70°C.
Reaction SMILES: [C:1]([O:11][CH:12]([C:14]([C:17]([O:19]C)=[O:18])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[Na+:22]>>[C:1]([O:11][CH:12]([C:14]([C:17]([O:19][Na:22])=[O:18])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [Na+]
Reactant: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: [OH-]
Product: O=C(O[Na])C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F

Procedure:
The procedure of Preparation 1 was followed except using 16.3 grams of C3F7OCHFCF2COOCH3 instead of the CF3O(CF2)3OCHFCF2COOCH3 and using 2 grams of sodium hydroxide (50 mmol) instead of potassium hydroxide.
Reaction SMILES: O.[F:2][CH:3]1[CH:8]([OH:9])[NH:7][C:6](=[O:10])[NH:5][C:4]1=O.Cl[Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15]>>[CH2:14]([Si:13]([C:4]1[NH:5][C:6](=[O:10])[N:7]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:8](=[O:9])[C:3]=1[F:2])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: O=C1NC(=O)C(F)C(O)N1
Reactant: CC[Si](Cl)(CC)CC
Solvent: O
Product: CC[Si](CC)(CC)c1[nH]c(=O)n([Si](CC)(CC)CC)c(=O)c1F

Procedure:
5-fluoro-6-hydroxy-5,6-dihydrouracil monohydrate, 4.15 g, was boiled under reflux with chlorotriethylsilane, 50 ml. Distillation of the resulting product gave a quantitative recovery of bis-triethylsilyl-5-fluorouracil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:39][CH3:40])([OH:15])=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:45]4[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]4)=[O:15])=[C:21]([O:39][CH3:40])[CH:22]=3)[N:27]=[CH:26][N:25]=2)=[C:32]([F:38])[CH:33]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg, 0.75 mmol) was added to a mixture of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (250 mg, 0.62 mmol), (prepared as described for the starting material in Example 42), 1-methylpiperazine (0.21 ml, 2.32 mmol) and 4-dimethylaminopyridine (300 mg, 2.46 mol) in DMF (7.5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The combined organic extracts were washed with brine and the solvent was removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazoline (133 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and isovaleryl chloride (0.04 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give 2-(2,4-dichlorophenoxy)-N-[1-(3-methylbutyryl)piperidin-4-yl]benzamide (97 mg, 79%) as a colorless oil. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.44 min, m/z 451.43 (68), 449.42 (M++H, 100). HPLC tr=3.17 min (98.27%) 1H NMR (270 MHz, CDCl3) δ 0.95 (6H, d, J=6.7 Hz, 2CH3), 1.33 (3H, m, CH2+½CH2), 2.19 (2H, d, J=6.7 Hz, CH2CO), 2.83 (1H, m, ½CH2), 3.15 (1H, m, ½CH2), 3.76 (1H, m, ½CH2), 4.16 (1H, m, CH), 4.44 (1H, m, ½CH2), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.86 (1H, d, J=8.6 Hz, ArH), 7.20 (1H, dd, J=8.7, 2.5 Hz, ArH), 7.25 (1H, m, ArH), 7.29 (1H, br s, NH), 7.41 (1H, m, ArH), 7.49 (1H, d, J=2.5 Hz, ArH) and 8.16 (1H, dd, J=7.7, 1.7 Hz, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:25])[C:11](=[CH:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:25])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][N:17]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)C=Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: COC(=O)C1=CN(c2ccc(F)cc2)C(c2ccc(Cl)cc2)CC1=O
Yield: 55 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 5-(4-chlorophenyl)-2-(4-fluorophenylaminomethylene)-3-oxo-4-pentenoate, and they were reacted at 140° C. for 4 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: benzene/ethyl acetate (3:1 by volume) mixture) to obtain 1.1 g of oily methyl 6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([F:15])[CH:5]=[CH:4][C:3]=1[C@H:16]([O:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[S:21][C:20]=1[C:39]([NH2:41])=[O:40])[CH3:17].[CH:42]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH2:43]>>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:43][CH2:42][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:11][CH2:10]2)=[C:6]([F:15])[CH:5]=[CH:4][C:3]=1[C@H:16]([O:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[S:21][C:20]=1[C:39]([NH2:41])=[O:40])[CH3:17]
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1ccc(F)c(OC2CCNCC2)c1Cl
Reactant: C=CS(C)(=O)=O
Product: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1ccc(F)c(OC2CCN(CCS(C)(=O)=O)CC2)c1Cl
Yield: 79 %

Procedure:
3-({(1R)-1-[2-chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Example 33, Step A, 80 mg, 0.13 mmol) and methyl vinyl sulfone (13 μL, 0.15 mmol) were coupled using a procedure analogous to Example 23 to give 72 mg of the title compound (79%). 1H NMR (400 MHz, d6-DMSO) δ 8.52 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.79 (br s, 1H), 7.56 (m, 2H), 7.45-7.35 (m, 2H), 7.13 (s, 1H), 7.08 (br s, 1H), 5.94 (m, 1H), 4.13 (m, 1H), 3.85 (s, 3H), 3.17 (t, J=6.2 Hz, 2H), 2.97 (s, 3H), 2.69-2.58 (m, 4H), 2.07 (m, 2H), 1.81-1.66 (m, 7H). HRMS calculated [M+H]+ C32H35ClFN6O5S2 701.17774, found 701.17740.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[N:14]1[CH:15]=[CH:16][C:11]([S:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])=[CH:12][CH:13]=1
Reactant: Nc1cccc(S)c1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(Sc2ccncc2)c1
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90 mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) followed by K2CO3 (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was back-extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et2O/hexane solution to afford the desired product (4.6 g, 66%): TLC (100% ethyl acetate) Rf 0.29; 1H-NMR (DMSO-d6) δ 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d, J=4.8, 2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8, 2H). A14b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[CH:32]12[O:38][CH:37]1[CH2:36][CH2:35][O:34][CH2:33]2>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][C@H:32]6[C@H:37]([OH:38])[CH2:36][CH2:35][O:34][CH2:33]6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CC2OC2CO1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Agent: [Cs+]
Agent: [F-]
Product: O=c1c2ccc(O[C@@H]3COCC[C@H]3O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
According to Method T, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-hydroxy-2H-isoquinolin-1-one, with cesium fluoride as auxiliary base, was reacted with 3,7-dioxa-bicyclo[4.1.0]heptane. In this way the product was obtained with molecular weight 493.58 (C28H32FN3O4); MS (ESI): 494 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(N2CCC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2c(c1)N(c1ccc(C)cc1)CCC2(C)C
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 0.18 g (0.52 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)-7-[2-(trimethylsilyl)ethynyl]quinoline (Compound 2) in 12.0 mL of methanol and 1.0 mL of tetrahydrofuran was added 0.088 g (0.64 mmol) of potassium carbonate, and the resulting mixture was stirred at room temperature for 6 hours and at 30° C. for 1 hour. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with diethyl ether (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound as an orange oil. PNMR (300 MHz, CDCl3): d 1.34 (6 H, s), 1.83 (2 H, t, J=6.0 Hz), 2.35 (3 H, s), 2.86 (1 H, s), 3.56 (2 H, t, J=6.0 Hz), 6.73 (1 H, d, J=1.6 Hz), 6.82 (1 H, dd, J=7.9, 1.6 Hz), 7.11 (2 H, d, J=8.4 Hz), 7.17 (1 H, J=7.9 Hz), 7.18 (2 H, d, J=8.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]CC)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene (5.0 g, 15.35 mmol) in dichloromethane (20.0 mL) cooled to 0 degrees Celsius under nitrogen was added drop-wise over 30 minutes a 1M solution of boron tribromide in dichloromethane (17.0 mL, 17.0 mmol). After the addition was complete, the reaction was allowed to warm to room temperature overnight (˜16 hours). The reaction was cooled to 0 degrees Celsius and quenched with an aqueous solution of 1N hydrochloric acid. The resulting mixture was stirred for 30 minutes and extracted using dichloromethane. The organic layer was separated and the aqueous layer was extracted two times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The reaction was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (120 g silica gel column) and eluting with a gradient of 0 to 100% ethyl acetate in heptane. 3.53 g of desired product obtained (77% yield). 1H NMR (400 MHz, METHANOL-d4) delta ppm 3.94 (s, 2 H), 6.70 (d, J=8.6 Hz, 2 H), 6.98 (d, J=8.4 Hz, 2 H), 7.23-7.34 (m, 3 H).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].COC(OC)OC.[CH2:21](O)[CH2:22][OH:23]>>[CH3:3][O:4][C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:11])[O:23][CH2:22][CH2:21][O:12]1
Reactant: OCCO
Reactant: COC(=O)CCCCC(C)=O
Agent: N#N
Solvent: COC(OC)OC
Product: COC(=O)CCCCC1(C)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 6-oxo-heptanoic acid methyl ester (7.96 g, 50.32 mmol) in ethylene glycol (55.0 mL) was treated with trimethylorthoformate (10.65 mL, 110.14 mmol) followed by LiBF4 (963 mg, 10.06 mmol). The reaction mixture was heated at 95° C. for 14 h. The reaction mixture was cooled to rt and partitioned between EA and sat. aq. NaHCO3 The layers were separated and the aq. layer extracted with EA. The combined org. extracts were washed with sat. aq. NaHCO3, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (50:1→2:1 hept-EA) gave the title compound as a dark yellow oil. TLC: rf (3:1 hept-EA)=0.30.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC.Cl.[CH2:41]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH2:46])[CH3:42]>O1CCCC1>[CH2:41]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH:46][C:24](=[O:26])[C@H:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:42]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
3.49 g (10 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine and 1.21 g (12 mmole) of N-methylmorpholine were dissolved in 30 ml of anhydrous tetrahydrofuran, and then, whilst cooling the solution at -5° C., 1.30 g (12 mmole) of ethyl chlorocarbonate was added dropwise, with stirring, over a period of 15 minutes. 2.35 g (12 mmole) of L-leucine ethyl ester hydrochloride [which had been suspended in 10 ml of methylene chloride and neutralized with 1.21 g (12 mmole) of N-methylmorpholine] were added. The mixture was stirred for 2 hours with ice cooling, and then left standing overnight at room temperature. It was then condensed by evaporation under reduced pressure. Water was added to the residue, and the precipitating oily substance was extracted with ethyl acetate. The organic extract was washed with 1N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucine ethyl ester thus obtained in a syrupy form was dissolved in 30 ml of dimethylformamide, and 5.06 g (100 mmole) of hydrazine hydrate were added to the solution. The mixture was stirred for 36 hours at room temperature. The reaction product was then condensed by evaporation under reduced pressure, and water was added to the residue. The colorless crystals produced were collected by filtration, thoroughly washed with water and dried in a desiccator to yield 4.23 g of the title compound melting at 200°-204° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=CC=CC=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OC1C(C(O)=O)=NC(CC2(C3C=CC([Cl:72])=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1.[Si](OCCN)(C(C)(C)C)(C)C>>[CH2:21]([O:20][C:19]1[C:14]([C:12]([NH:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:13])=[N:15][C:16]([CH2:29][C:30]2([C:35]3[CH:44]=[CH:39][C:38]([Cl:72])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:17][C:18]=1[OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCN
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amide (346) from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) and 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c).