Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:23]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[CH:24][CH:25]=3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol), and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[NH:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1.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>[NH:31]1[C:32]([CH2:34][C:35]([NH:1][CH:2]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:36])=[CH:33][N:29]=[CH:30]1
Reactant: NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cnc[nH]1)NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A flask was charged with 2-amino-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (150 mg, 0.42 mmoles), prepared as in Reference 5, 1H-imidazol-4-ylacetic acid hydrochloride (81 mg, 0.50 mmoles), HATU (188 mg, 0.50 moles) and DMF (1 mL). DIEA (370 μL, 2.1 mmoles) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized H2O. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue by preparative HPLC (ammonium acetate/acetonitrile). The purified product was taken up into methanol and the solution was neutralized with basic resin, filtered and concentrated in vacuo to give Compound 142, 2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (118 mg, 60% yield), as a white solid. 1H-NMR (400 MHz, CDCl3): 9.23 (s, 1H), 7.53-7.40 (m, 4H), 7.35-7.27 (m, 6H), 7.08 (t, 1H), 7.00-6.92 (m, 3H), 6.87 (s, 1H), 4.77 (m, 1H), 4.55 (dd, 2H), 4.18 (dd, 1H), 3.70-3.58 (m, 3H). MS (EI) for C27H26N4O4. found 471.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11].[OH-].[K+].O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)(C)c1cc(F)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1cc(F)ccc1Br

Procedure:
A mixture of methyl 2-(2-bromo-5-fluorophenyl)-2-methylpropanoate (0.529 g, 3.12 mmol, J. Am. Chem. Soc., 2008, 130, 15157-15166), potassium hydroxide (3.2 g, 57 mmol), water (10 mL) and ethanol (30 mL) was refluxed for 20 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][C:19]=3[O:27][CH3:28])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([NH:47][C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:10]2[C:11](=[O:16])[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[C:19]([O:27][CH3:28])[CH:20]=1)=[O:26])([CH3:46])([CH3:45])[CH3:43]
Reactant: COc1cc(C(=O)O)ccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(C)N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C(=O)NC(C)(C)C)ccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An amount of 50 mg (0.13 mmol) of the compound from Example 21A was introduced in 1 ml of DMF and admixed with 20 mg (0.15 mmol) of HOBt and with 31 mg (0.16 mmol) of EDC. After 10 minutes of stirring at RT, 14.5 μl (0.14 mmol) of 2-methylpropan-2-amine were added and the mixture was stirred further at room temperature for 16 h. Subsequently the reaction solution was diluted with about 5 ml of water and the precipitate formed was filtered and washed with water. Drying under reduced pressure gave 37 mg (66% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (60) (40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:39].O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:19]1[OH:39])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
This compound was prepared using the procedure for palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of guanosine 2',3'-acylic dialcohol for 2'-deoxyguanosine monohydrate.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=O)([O-])[O-:13].[K+].[K+].C=O.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:25]([O:24][C:22]([CH2:21][O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:13])=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1c(CO)c(C(F)(F)F)nn1C
Temperature: 25 °C
Yield: 81.9 %

Procedure:
In 100 ml of DMF were suspended 16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 and 20.9 g (0.15 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 4.5 g (0.15 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 41.8 g (0.30 mole) of potassium carbonate was added. Thereto was dropwise added 93.4 g (0.20 mole) of ethyl bromoacetate, followed by stirring at room temperature for 2 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 44.7 g (purity: 63.0%, yield: 81.9%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a light yellow transparent solution. N-Hexane was added to the solution. The resulting white crystals were collected by suction filtration to obtain a title compound as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7](=[NH:9])[N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:5]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](/[N:9]=[C:7]1\[S:8][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]\1[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=[O:23]
Reactant: N=c1sc(C2CC2)nn1CC1CCCO1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C2CC2)nn1CC1CCCO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of the compound from Example 2A (70 mg, 0.31 mmol), 5-chloro-2-methoxy-benzoic acid (64 mg, 0.34 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (185 mg, 0.46 mmol) and triethylamine (130 L, 0.93 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 12 hour. The mixture was diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with ethyl acetate/hexanes 2:3) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.01 (m, 2H) 1.14-1.21 (m, 2H) 1.67-1.78 (m, 1H) 1.79-1.93 (m, 2H) 1.91-2.00 (m, 1H) 2.30-2.39 (m, 1H) 3.65 (dd, J=13.81, 7.06 Hz, 1H) 3.77 (dd, J=13.50, 6.75 Hz, 1H) 3.80 (s, 3H) 4.21 (dd, J=13.20, 4.60 Hz, 1H) 4.31-4.38 (m, 1H) 4.43 (dd, J=12.89, 7.36 Hz, 1H) 7.13 (d, J=8.90 Hz, 1H) 7.49 (dd, J=8.90, 2.76 Hz, 1H) 7.73 (d, J=2.76 Hz, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>CCCCCC>[C:9]1([NH:8][C:5](=[O:7])[CH3:6])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCCC2
Solvent: CCCCCC
Product: CC(=O)Nc1cccc2c1CCCC2
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Acetic anhydride (100 ml, 1.06 mole) was added rapidly to neat 1-amino-5,6,7,8-tetrahydronaphthalene (25 g, 0.17 mole) (Aldrich) with stirring. The mixture quickly solidified and was allowed to stand overnight. The broken mass was suspended in hexane (200 ml), filtered, then resuspended in methylene chloride (150 ml). After stirring 10 minutes, the suspension was diluted with an equal volume of hexane, filtered, and the solid dried at 95° C. under reduced pressure to give N-(5,6,7,8-tetrahydro-1-naphthyl)acetamide (23 g). 1H NMR (CDCl3, 200 MHz) δ: 1.68-1.90 (m, 4H, CH2 's), 2.20 (s, 3H, CH3), 2.52-2.68 (m, 2H, ArCH,), 2.70-2.84 (m, 2H, ArCH2), 3.94 (br s, 1H, NH), 6.92 (d, J=8 Hz, 1H, Ar), 7.10 (t, J=8 Hz, 1H, Ar), 7.53 (d, J=8 Hz, 1H, Ar). Anal. Calculated for C12H15NO: C, 76.16; H, 7.993; N, 7.40. Found: C, 76.13; H, 8.04; N, 7.40.
Reaction SMILES: C=O.[CH3:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[CH:12]=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.[C:41]1(C)C=CC=CC=1>C(O)C.C(O)(=O)C>[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[C:12]([CH2:3][N:4]([CH3:41])[CH3:5])=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24]1
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: Cc1ccccc1
Reactant: CNC
Agent: C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 80 °C

Procedure:
Paraformaldehyde (600 mg) and a 50% aqueous dimethylamine solution (1.80 g) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in a mixture of ethanol (10 ml) and acetic acid (5 ml), and the resulting mixture was stirred with heating at 80° C. After the reaction solution was cooled to 25° C., toluene (30 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was acidified with a 10% aqueous potassium hydrogensulfate solution and extracted twice with chloroform (100 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (913 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]2[N:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20](=[O:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[N:5]1([CH2:4][CH2:3][CH2:2][N:26]2[CH2:25][CH2:24][CH:23]([N:19]3[C:18]4[CH:29]=[CH:30][C:15]([Cl:14])=[CH:16][C:17]=4[NH:21][C:20]3=[O:22])[CH2:28][CH2:27]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: ClCCCn1cnc2ccccc21
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2cnc3ccccc32)CC1
Yield: 14 %

Procedure:
A mixture of 9 parts of 1-(3-chloropropyl)-1H-benzimidazole, 10 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 7.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2.9 parts (14%) of 1-{1-[3-(1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 224° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:15]1([CH2:14][CH2:13][N:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)N1CCN(CCN2CCCCC2)CC1

Procedure:
A mixture of 1-ethoxycarbonylpiperazine (10.9 grams; 0.069 moles), N-(2-chloroethyl)piperidine (10.2 grams; 0.069 moles) and potassium carbonate, (9.5 grams; 0.069 moles) in 100 cc of ethanol is heated to reflux for 4 hours. After cooling, the salt is filtered, the filtrate is evaporated and the oily residue is distilled under vacuo; b.p. 133°-136° C. (0.02 mm). Dihydrochloride: m.p. 254°-256° C. (from methanol); Rf=0.74 (MeOH-concentrated NH4OH 9.5:0.5); IR (neat); 2940, 2860, 2820, 1710, 1470, 1435, 1305, 1290, 1240, 1135, 1120, 1005, 770 cm-1.
Reaction SMILES: [NH2:1][NH2:2].Cl.[C:4]([CH:6]1[C:10](=O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:5]>C(O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:5][C:4]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:10]=2[NH:1][N:2]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of anhydrous hydrazine (0.082 mL) in ethanol (6.5 mL) was added hydrogen chloride (1.43 mL, 2N solution in diethyl ether). The reaction mixture was stirred for 5 min, then tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate was added and the mixture heated to reflux. After 1 h the mixture was cooled to ambient temperature and diluted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution (1:1, 20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes followed by 0 to 20% methanol/ethyl acetate gradient) to give the title compound. LC/MS 225.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])=[C:3]1[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C)=[CH:13][C:12]=1[CH2:11][CH2:10]3.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])=[C:3]1[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(F)F)C=C[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C=CC2=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of 2.4 g of 17-difluoromethylene-3-methoxy-estra-1,3,5(10),15-tetraene in 49 ml of toluene is refluxed with 49 ml of a 1.6 M diisobutylaluminum hydride solution in toluene for 1 hour at a bath temperature of 140° C. Then, it is cooled to room temperature, slowly added to 200 g of ice, mixed with 400 ml of 2 N sulfuric acid, stirred for 1 hour at room temperature, extracted three times with ethyl acetate, the organic phases are washed with water as well as saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 1.37 g of 17-difluoromethylene-estra-1,3,5(10),15-tetraen-3-ol is obtained as colorless crystals with a melting point of 126-127° C., [α]D22 =-120.4° (c=0.505% in pyridine).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.[C:31]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C=O)c2)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(Cc1cccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A mixture of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde (0.80 g), diethyl malonate (0.37 g), benzoic acid (0.07 g), piperidine (0.05 g) and toluene (40 mL) was heated under reflux for 4 hrs. with azeotropic dehydration. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with acetone-hexane (1:5, v/v). To a mixture of the obtained oil, tetrahydrofuran (20 mL) and ethanol (20 mL) was added sodium borohydride (0.02 g) at 0° C. and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl 2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzyl]malonate as an oil (0.71 g, yield 66%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: CCOC(=O)CCl
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A solution of 6-chloro-2-nitrophenol (1.7 g.) and ethyl chloroacetate (2.1 ml.) in dimethylformamide (12 ml.) with potassium carbonate (1.5 g.) was stirred at 75°-80° C. for 3 hours. The mixture as poured into water (120 ml.) and extracted with ethyl acetate (4× 50 ml.). The organic layer on evaporation yielded 6-chloro-2-nitrophenoxyacetic acid ethyl ester as a yellow oil.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20])[C:14]([NH2:16])=[O:15]>CC(C)=O>[Cl:21][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[C:19]=1[CH3:20])[C:14]([NH2:16])=[O:15]
Reactant: Cc1c(N)cc(C(N)=O)cc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: Cc1c(Cl)cc(C(N)=O)cc1Nc1nc(Cl)nc(Cl)n1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Cyanuric chloride (65.0 mg, 0.35 mmol) was added to an acetone solution (5 mL) of 3-amino-5-chloro-4-methyl-benzamide (65.0 mg, 0.35 mmol) at 0EC. The mixture was stirred for 1 h at 0EC. Ice was added to the mixture and subsequent filtration yielded of 3-chloro-5-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-4-methyl-benzamide (101.0 mg, 87%) as white solid. MS (m/z) calced for C11H8N5O (MH+), 331: found, 331.