Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[O:1]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCOc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A mixture of 15 g of ethyl p-[(3-phenoxypropyl)-amino]benzoate, 15 g of potassium hydroxide and 150 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, chilled and filtered to give yellow crystals, mp 159°-162° C. Recrystallization from ethanol gives pale yellow crystals, mp 161°-163° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH2:11]1.O>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH2:11]1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]32)C1

Procedure:
Add t-butyldimethylsilyl chloride (5.49 g, 36.4 mmol), 4-dimethylaminopyridine (0.21 g, 1.74 mmol) and triethylarmine (5.32 mL, 38.14 mmol) to a stirred solution of 3β-hydroxyandrosta-5,15-dien-17-one (M81, 10.00 g, 34.8 mmol) in anhydrous DMF (175 mL) under nitrogen. Stir the resultant suspension at room temperature for 3 days and then pour into rapidly stirred water (750 mL). Filter the resultant suspension and crystallize the white solid to give 3β-[[(1,1-dimethylethyl)dimethylsilyl]oxy]androst-5,15-dien-17-one (M82).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][C:32]#[C:33][CH2:34][OH:35])[N:18]=[C:17]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:42][O:43][CH:44]1[C:49](=S(=O)=O)[C:48]([O:53][CH3:54])=[N:47][C:46](C)=[N:45]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:35][C:46]3[N:47]=[C:48]([O:53][CH3:54])[CH:49]=[C:44]([O:43][CH3:42])[N:45]=3)[N:18]=[C:17]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ccncc2)nc1OCC#CCO
Reactant: COC1=NC(C)=NC(OC)C1=S(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OCC#CCOc2nc(-c3ccncc3)nc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2ccccc2OC)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
A suspension of 400 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide (Example 2c), 116 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 147 mg of potassium carbonate in 15 ml of DMF was stirred at 90° C. for 16 h. Further 42 mg of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine was added and stirring was continued at 90° C. for 24 h. Eventually, the solvent was removed in vacuo, and the resulting residue partitioned between 50 ml of 5% aqueous acetic acid and 50 ml of DCM. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of DCM. The combined organic layers were washed with water, dried over MgSO4 and evaporated. The remaining oil was purified by column chromatography on silica gel eluting with toluene: ethyl acetate 4:1 to 1:1. The product obtained was recrystallised from ethyl acetate:diethyl ether to give 76 mg of 4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide as white crystals. LC-MS: tR=5.84 min, [M+1]+=713.35, [M−1]−=711.45.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22]CCCCC.C([Li])CCC.[C:33]([C:37]1[CH:38]=[CH:39][C:40](=[C:42]([CH3:44])[CH3:43])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1.O>[C:33]([C:37]1[CH:38]=[C:39]([CH3:22])[CH:40]([C:42]([C:10]2[C:9]3[CH2:8][C:7]4[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)[C:14]=3[CH:13]=[CH:12][C:11]=2[C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:44])[CH3:43])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)=C1C=CC(C(C)(C)C)=C1
Reactant: CCCCCC
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1=CC(C(C)(C)C)=CC1C(C)(C)c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of 2.45 g (8.80 mmol) of 2,7-di-tert-butylfluorene in 50 ml of THF, 5.67 ml (9.24 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere at 0° C., followed by stirring at room temperature overnight. To the resulting solution, a solution of 2.85 g (17.6 mmol) of 3-tert-butyl-6,6-dimethylfulvene in 30 ml of THF was successively dropwise added in a nitrogen atmosphere at 0° C., followed by stirring at room temperature overnight to perform reaction. After the reaction, 30 ml of water was added. The organic phase was extracted with ether and dried over anhydrous magnesium sulfate. From the resulting solution, the solvent was distilled off to obtain a crude yellow solid. The solid was washed with methanol to obtain 2.77 g of a powdery white solid (yield: 71.5%). The analyzed values are given below.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([O:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH:15]([CH3:17])[OH:16])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1.[C:26]([O:34][O:35][C:36]([CH3:42])([CH3:41])[CH2:37][CH:38]([OH:40])[CH3:39])(=[O:33])[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].O=O>CC(OC)(C)C>[C:1]([O:16][CH:15]([CH3:17])[CH2:14][C:13]([O:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:18])[CH3:19])(=[O:5])[C:2]([O:40][CH:38]([CH3:39])[CH2:37][C:36]([O:35][O:34][C:26](=[O:33])[CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:42])[CH3:41])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Reactant: CC(O)CC(C)(C)OOC(=O)CCC(C)(C)C
Agent: O=O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC(CC(C)(C)OOC(=O)CCC(C)(C)C)OC(=O)C(=O)OC(C)CC(C)(C)OOC(C)(C)C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 250 mL 3-necked flask equipped with a magnetic stirring bar, a nitrogen inlet line, a thermometer and an addition funnel was charged with 75 mL ofMTBE and 2.5 g (19.3 mmoles) of oxalyl chloride and the flask contents werecooled to 0° C. Then a solution of 3.9 g (19 mmoles) of 92.6% 3-t-butylperoxy-1,3-dimethylbutanol and 1.5 g (19.0 mmoles)of pyridine in 10 mL of MTBE was added dropwise over 30 minutes while the temperature wasmaintained at 0°-5° C. After the addition was completed the reaction mass was stirred for 60 minutes at 0°-5° C. To the stirred reaction mass was added a solution of 5.0 g (19.2 mmoles) of 94.4%3-hydroxy- 1,1-dimethylbutyl peroxyneoheptanoate and 1.5 g (19.0 mmoles) ofpyridine in 10 mL of MTBE over a period of 15 minutes. The reaction mixturewas then stirred for an additional 45 minutes at 20°-25° C. after which it was quenched with water. After separating and discarding the aqueous phase the organic was washed once with cold aqueous 10% HCl solution, three times with water and once with dilute aqueous NaHCO3 solution. The product solution was dried over 5% by weight of anhydrous MgSO4, and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 9.3 g (100% of theory, uncorrected) of a hazy colorless oil. The product contained 6.78% active oxygen (theory, 6.52%), therefore, I-5 was obtained with an assay of 100% and in a corrected yield of 100%. A Differential Scanning Calorimeter (DSC) scan showed two peroxide decomposition temperatures, one at 71° C. for the 3-neoheptanoylperoxy-1,3-dimethylbutyl moiety and one at 169° C. for the 3-t-butylperoxy-1,3-dimethylbutyl moiety.
Reaction SMILES: N[C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].N([O-])=[O:14].[Na+]>CC(O)=O.OS(O)(=O)=O.O>[OH:14][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of 20.6 g (0.125 mol) of methyl 3-amino-2-methylbenzoate in 150 mL of HOAc and 25 mL of conc. H2SO4 was cooled in ice and diazotized by the dropwise addition of a solution of 8.7 g (0.125 mol) of NaNO2 in 50 mL of H2O. After stirring for 15 minutes, the diazonium solution was added dropwise to a boiling solution of 200 mL of 50% H2SO4, and the refluxing continued for 15 minutes after the addition was complete. The mixture was diluted with H2O and extracted twice with Et2O. The Et2O was washed 5 times with H2O, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 17.98 g (94.4% yield) of the product as a tan solid, mp 137-140° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10]O)[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ClC(Cl)C(O)=O.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=1[CH2:51][C:52](=[O:73])[CH:53]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CS(C)=O.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:9](/[CH:10]=[CH:53]/[C:52](=[O:73])[CH2:51][C:45]2[C:46]([Cl:50])=[CH:47][CH:48]=[CH:49][C:44]=2[Cl:43])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(Cl)Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](/C=C/C(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 23 h
Yield: 86.3 %

Procedure:
A solution of 2.759 g of 3'-O-acetyl-2'-deoxy-5-ethyluridine, 5.75 g of dicyclohexylcarbodiimide and 0.375 ml of dichloroacetic acid in 24 ml of dimethyl sulphoxide was stirred at room temperature for 27 hours. 0.375 ml of pyridine and 4.286 g of [3-(2,6-dichlorophenyl)-2-oxopropylidene]triphenylphosphorane were added and the mixture was stirred for a further 23 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of ethyl acetate and the solution was washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated. The resulting gum was subjected to flash chromatography on a column of silica gel using ethyl acetate/hexane (2:1) for the elution. There were obtained 3.84 g of (E)-3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2-oxopropylidene]-2',5'-dideoxy-5-ethyluridine in form of a white solid of melting point 165° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1([NH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:11]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:10]=2)=[O:8])[CH2:5][CH2:4]1.[H-].[Na+].I[CH3:31]>CN(C=O)C>[CH3:31][N:6]([C:3]1([C:2]([F:1])([F:26])[F:27])[CH2:4][CH2:5]1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:11]([O:21][CH2:22][CH:23]2[CH2:24][CH2:25]2)[N:10]=1)=[O:8]
Reactant: CI
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1(C(F)(F)F)CC1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide (20 mg, 51.1 μmol) and sodium hydride (3.3 mg, 76.7 μmol) in DMF (0.2 mL) was stirred for 15 min. at ambient temperature. Iodomethane (14.5 mg, 6.38 μL, 102 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/sat. aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice water/brine (2×20 mL), dried over Na2SO4 and brought to dryness. The crude brown oil was purified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 4:1, elution with EtOAc) to give the title compound (13 mg, 63%) as colorless oil; MS (EI): m/e=406.4 [MH]+.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.[CH2:31]([NH2:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>O1CCCC1>[CH2:31]([NH:39][C:2]1[N:4]=[C:5]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:7]=[C:8]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:2]4[N:4]=[C:5]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:7]=[C:8]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:1]=4)=[CH:30][CH:29]=3)=[CH:27][CH:26]=2)[N:1]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: Nc1ccc(OCCCCCOc2ccc(N)cc2)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCNc1nc(NCCCCCCCC)nc(Nc2ccc(OCCCCCOc3ccc(Nc4nc(NCCCCCCCC)nc(NCCCCCCCC)n4)cc3)cc2)n1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A solution of cyanuric chloride (6.44 grams, 34.9 mmol; obtained from Aldrich Chemical Co.) in dry tetrahydrofuran (50 milliliters) was added dropwise to a solution of 1,5-bis(4-aminophenoxy)pentane (5.00 grams, 17.46 mmol; prepared as described in Part B of Example VIII) in dry tetrahydrofuran (100 milliliters) at −78° C. The mixture was stirred and allowed to warm up to room temperature for 2 hours. Octylamine (23.0 milliliters, 139 mmol; obtained from Aldrich Chemical Co.) was then added and the mixture was stirred at reflux for 3 hours. The mixture was cooled to room temperature, water was added, and the resulting gummy precipitate (like glue) was filtered. The precipitate was dissolved in chloroform and filtered over silica gel. The volatiles were removed under reduced pressure to afford 1,5-Bis[4-[N-[4,6-bis(N-octylamino)-1,3,5-triazin-2-yl]amino]phenoxy]pentane (7.51 grams, 7.88 mmol, 45 percent yield) as a white solid: IR (KBr) 3410, 3279, 2926, 2855, 1575, 1506, 1423, 1369, 1230, 1031, 810 cm−1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1.O>C(Cl)Cl>[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([N:9]([CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:36])[CH:29]=1
Reactant: c1ccc(C(CCNCCC2CCCCC2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)N(CCC2CCCCC2)CCC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
46 mg of (2-cyclohexyl-ethyl)-(3,3-diphenyl-propyl)-amine (0.147 mmol, 1 eq) were diluted in 1 mL of DCM. 30 mg (0.172 mmol, 1.2 eq) of 3-isocyanato-benzoic acid methyl ester were then added to the mixture. The reaction mixture was stirred at room temperature for 90 min before adding water, then the aqueous phase was extracted with DCM. The organic phase was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel (eluant: gradient Hept/EtOAc 5/1). 63 mg of the desired urea were obtained. MS (ES+): 499.5+ (M+H)+. TLC: Rf: 0.57 (eluant: heptane/EtOAc: 1/1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:49])[C:21]3[CH:47]=[C:46]([OH:48])[CH:45]=[C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][C:40](=[O:44])[O:41]5)=[CH:36][CH:35]=4)=[O:25])[CH:22]=3)=[CH:7][CH:8]=2)[O:3]1.[Cl:50][CH2:51][CH2:52][CH2:53][CH2:54]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:49])[C:21]3[CH:47]=[C:46]([O:48][CH2:54][CH2:53][CH2:52][CH2:51][Cl:50])[CH:45]=[C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][C:40](=[O:44])[O:41]5)=[CH:36][CH:35]=4)=[O:25])[CH:22]=3)=[CH:7][CH:8]=2)[O:3]1
Reactant: O=C(OCCCCCCOc1ccc2ccc(=O)oc2c1)c1cc(O)cc(C(=O)OCCCCCCOc2ccc3ccc(=O)oc3c2)c1
Reactant: OCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(OCCCCCCOc1ccc2ccc(=O)oc2c1)c1cc(OCCCCCl)cc(C(=O)OCCCCCCOc2ccc3ccc(=O)oc3c2)c1

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 6.71 g (10.0 mmol) bis{6-[(2-oxo-2H-chromen-7-yl)oxy]hexyl}5-hydroxyisophthalate, 1.14 g (10.5 mmol) 4-chloro-1-butanol, 2.88 g (11.0 mmol) triphenylphosphine and 4.79 g (11.0 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene to yield bis{6-[(2-oxo-2H-chromen-7-yl)oxy]hexyl}5-(4-chlorobutoxy)isophthalate.
Reaction SMILES: Cl.[NH2:2][OH:3].CC(O)=O.[Cl:8][C:9]1[C:14]([CH:15]=O)=[C:13]([Cl:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=1>CCO>[Cl:8][C:9]1[C:14]([CH:15]=[N:2][OH:3])=[C:13]([Cl:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1nc(Cl)c(C=NO)c(Cl)n1
Temperature: 70 °C
Yield: 39.9 %

Procedure:
To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50° C. for about 1 hour, 60° C. for about 30 minutes and 70° C. for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M+H)+1.57 minute, 1.65 minute; 1H-NMR (CDCl3) δ 2.62, 2.65 (3 H), 7.53, 8.30 (1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.[Na].C(=O)([O-])O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(Br)cc1CN1CCOCC1
Reaction time: 0.5 h

Procedure:
5-Bromo-2-fluorobenzaldehyde (2.5 g, 12.3 mmol) and morpholine (1.62 g, 18.5 mmol) are dissolved in 50 mL DCE and stirred for 0.5 h. Acetic acid (0.42 mL, 7.4 mmol) and sodium trisacetoxyboronhydride (3.92 g, 18.5 mmol) are added and the reaction mixture is stirred for 2 h. Then 50 mL of a saturated aqueous solution of sodium hydrogencarbonate is added and the reaction mixture is stirred for another 0.5 h. The reaction mixture is extracted with DCM and the combined organic phases are dried over MgSO4 and concentrated in vacuo. Yield: 3.02 g.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.C([N:22]([CH:25](C)C)CC)(C)C.[CH3:28][O:29]CCN(S(F)(F)F)CCOC>C(Cl)Cl>[CH3:28][O:29][N:22]([CH3:25])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(C(=O)O)c1ccc(-c2nnc(C)o2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 26 %

Procedure:
To an ice-cold solution of 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid (6.8 g, 27.4 mmol) in anhydrous CH2Cl2 (270 mL) and diisopropylethylamine (17 mL, 97 mmol) under argon was added bis(2-methoxyethyl)aminosulfur trifluoride (5.6 mL, 30.3 mmol) dropwise. After stirring over an ice bath for 45 min, N,0-dimethylhydroxylamine hydrochloride (3.40 g, 34.8 mmol) was added in three aliquots over a period of 15 min. The mixture was stirred for 15 min then the ice bath was removed. After 3 hrs, saturated aqueous NaHCO3 was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3, H2O and brine, dried over MgSO4, filtered through Celite and concentrated in vacuo. Purification by chromatography (75-100% EtOAc-hexanes then 0-5% EtOH-EtOAc) gave N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide as an oil that solidified upon standing (2.06 g, 26% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([CH3:24])[CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C)c2)C1=O
Yield: 62.4 %

Procedure:
Using (4-bromo-2-methylphenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (233 mg) described in Preparation Example 118 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (163 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)CCO.BrC1C=C([CH2:18][CH2:19][O:20][CH:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[CH:31]=3)[NH:26][C:25]([CH3:42])([CH3:41])[CH:24]=2)[CH3:22])C=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(OS(C)(=O)=O)C)=CC1(C)C)=O)(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][C:10]=1[CH2:18][CH2:19][O:20][CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH:31]=2)[NH:26][C:25]([CH3:42])([CH3:41])[CH:24]=1)[CH3:22]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1cccc(Br)c1)=CC(C)(C)N2
Reactant: OCCc1cccc(Br)c1
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)OS(C)(=O)=O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCc1ccccc1Br)=CC(C)(C)N2

Procedure:
4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 3-Bromophenethyl alcohol (37 μL) was treated with 277 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 86 mg of 4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester to give alkylated product, which was deprotected to yield 13.6 mg of the title compound as a foam.