Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:35][CH2:36][O:37]C(C)=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:36](=[O:37])[CH3:35])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2Sc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-{4-(4-bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 2 g, 4.38 mmol), (1-ethoxyvinyul)tributyltin (1.7 g, 4.82 mmol), PdCl2(PPh3)2 (67 mg, 0.2 mmol), and 15 mL of toluene under nitrogen was heated at 100° C. overnight. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered. To the filtrate was added KF/Celite (50% wt from Aldrich) which was stirred for 1.5 h. Upon filtration and concentration, the residue was taken up in 20 mL of EtOH and 10 mL of 2 N HCl, stirred at rt for 1 h. The precipitate was collected by filtration, washed with water and a small amount of EtOAc. The solid was further purified by silica gel column chromatography (10-50% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CDCl3): 8.62 (d, 1H), 8.38 (d, 1H), 8.26 (d, 2H), 8.19 (d, 2H), 7.83 (t, 1H), 7.31 (t, 1H), 7.23 (d, 2H), 7.04 (d, 2H), 4.13 (s, 3H), 2.61 (s, 3H). LCMS: m/z 420 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[S:14]1[C:18]2=[CH:19][CH:20]=[CH:21][C:22]([S:23]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[C:17]2[N:16]=[CH:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:13][CH:2]([F:1])[CH:3]([CH3:12])[CH2:4][C:5]1([OH:11])[CH2:6][CH2:7][N:8]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[S:14][CH:15]=[N:16][C:17]=34)(=[O:25])=[O:24])=[CH:35][CH:34]=2)=[O:32])[CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Reactant: CC(CC1(O)CCNCC1)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CC1(O)CCN(C(=O)c2ccc(NS(=O)(=O)c3cccc4scnc34)cc2)CC1)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added 4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (110 mg 0.57 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (190 mg, 0.57 mmol), DIPEA (367 mg, 2.8 mmol), HATU (261 mg, 0.69 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 5.90-5.61 (m, 1H), 4.36 (s, 1H), 3.57-3.42 (m, 1H), 3.21 (s, 2H), 2.24 (d, J=7.6 Hz, 1H), 2.05 (s, 1H), 1.86-1.77 (m, 2H), 1.36 (dd, J=14.8, 6.3 Hz, 4H), 1.10 (d, J=7.0 Hz, 3H). LC-MS: m/z 510.5 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=[N:10]1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:12]1[CH:11]=[N:10][N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1ccnn1-c1c(Cl)cccc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(Br)cnn1-c1c(Cl)cccc1Cl
Reaction time: 60 h

Procedure:
14.3 g of ethyl 1-(2,6-dichlorophenyl)-pyrazole-5-carboxylate from Example 4 were dissolved in 100 ml of glacial acetic acid, 10 g of Na acetate were added, and 4.5 g of bromine were added dropwise at room temperature. After 60 hours, the reaction mixture was poured into 1 liter of water, washed with water and recrystallized from ethanol.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:12]([O:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=2)(=[O:24])=[O:23])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41](N(CCCC)CCCC)[CH2:42]CC.C(O)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH2:41]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([O:21][C:12]2[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:23])=[O:24])=[CH:26][C:27]=1[OH:34])[CH3:42]
Reactant: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Reactant: CCCCN(CCCC)CCCC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)(=O)Oc2c(-c3ccccc3)cc(C(=O)c3ccccc3)cc2-c2ccccc2)cc1O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A stirred solution containing 4-(5'-benzoyl-[1,1';3',1"]terphenyl-2'-yloxysulfonyl)-2-hydroxy-benzoic acid (0.106 g, 0.192 mmol), tributylamine (0.110 mL, 0.462 mmol), ethanol (0.0677 mL, 1.15 mmol) and 2-chloro-1-methyl pyridinium iodide (0.0607 g, 0.231 mmol) in CH2Cl2 (2 mL) was refluxed for 18 h. The reaction was cooled to ambient temperature, quenched with 1N HCl (20 mL) and extracted with EtOAc. The organic extracts were successively washed with 1N HCl (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 0.039g (35%) of the title compound as a white solid, mp 75-85° C. 1H NMR (DMSO-d6) δ 1.36 (t, 3H), 4.38 (q, 2H), 6.67 (d, 1H), 6.73 (dd, 1H), 7.30-7.36 (m, 6H), 7.45-7.52 (m, 5H), 7.57-7.61 (m, 2H), 7.68-7.71 (m, 3H), 7.84 (d, 2H), 10.60 (s, 1H). mass spectrum (El) m/z 578 (M+). Anal. Calcd. for C34H26O7S 0.5H2O: C,69.49; H,4.63; N,0.00. Found: C,69.38; H,4.76; N,0.10.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:9][C:8]([CH3:21])=[C:7]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[O:23])[N:6]=1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[CH3:21][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 61.7 %

Procedure:
To a solution of 0.315 g (0.66 mmol) of 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (example 45) in 10 ml of THF/MeOH 1:1 were added 1.32 ml of lithium hydroxide (1 molar in H2O) and the reaction mixture was stirred at RT for 28 hours. Then, the solvents were evaporated and the residue was dissolved in H2O/CH2Cl2, neutralized with the help of hydrochloric acid and solid NaHCO3 and then extracted four times with CH2Cl2/2-propanol 3:1; the organic phases were dried over magnesium sulfate, filtered and evaporated, to give 0.188 g (62%) of the title compound as off-white solid. MS: 462.3 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C[OH:21].[OH-].[K+]>O>[OH:21][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1

Procedure:
2(2-Fluoro-4-biphenylyl)propionic acid (1 g.) ethylene glycol (10 ml.) and potassium hydroxide (0.8 g.) were refluxed under nitrogen for 24 hours. The mixture was diluted with water, washed with ether, acidified with hydrochloric acid and extracted with ether. The ether extract was washed with water, dried and evaporated to dryness. The product was subjected to thin layer chromatography to give 2-(2-hydroxy-4-biphenylyl)propionic acid, which was recrystallised from light petroleum (b.p. 80°-100° C.) to give the purified acid having a m.p. of 112°-119° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([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)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 45.1 %

Procedure:
A solution of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 1.99 mmol) in dimethylformamide (20 mL) was treated with phenylboronic acid (0.485 g, 3.8 mmol), tetrakis(triphenylphosphine)palladium (0.138 g, 0.119 mmol), and a solution of sodium carbonate (0.506 g, 4.78 mmol) in water (10 mL). The reaction mixture was stirred at 80° C. for 18.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (15 mL) was added. The precipitate was filtered and was washed with water. The crude solid was triturated with diethyl ether (30 mL). The resulting solid was dried over night on the lyophilizer to give 0.407 g (45%) of 3-phenyl-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.9416 (s, 1H), 7.6190-7.6011 (m, 2H), 7.5369-7.4493 (m, 3H), 7.3995-7.2248 (m, 15H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rf=11.813 min (97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Yield: 89.2 %

Procedure:
Following the procedure of example 1115 A, N-t-butoxycarbonyl-2-hydroxymethylpyrrolidine (0.80 g, 4.00 mmol) and phenol (1.13 g, 12.00 mmol) provided 0.99 g (89%) of the title compound. MS (DCI, NH3): 278 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:24])[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h
Yield: 53.9 %

Procedure:
Benzyl 4-hydroxy-1-piperidinecarboxylate (1.0 g, 4.25 mmol), succinic anhydride (0.425 g, 4.25 mmol) and 4-DMAP (52 mg, 0.425 mmol) were dissolved in CHCl3 (10 mL) and stirred for 24 hours. The volatiles were removed in vacuo. Aqueous NaHCO3 (100 mL) was added and the mixture was washed with Et2O (2×50 mL). The aqueous layer was acidified to pH=6 to 7 with 2N HCl and extracted with CH2Cl2 (2×60 mL). The combined organic extracts were washed with brine (60 mL), dried over Na2SO4 and concentrated in vacuo to afford compound 64 (768 mg, 54%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.62 (m, 2H), 1.85 (m, 2H), 2.60-2.70 (m, 4H), 3.38 (m, 2H), 3.74 (m, 2H), 4.97 (m, 1H), 5.12 (s, 2H), 7.35 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)([Cl:26])(=O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([Cl:26])=[O:6]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=S(=O)(Cl)Cl
Product: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 86 %

Procedure:
In 100 ml sulfonylchloride was heated 20.0 g (0.057 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid to reflux for 1 hour, and then thionylchloride was removed by distillation. By vacuum distillation of the residue, 18.2 g (0.049 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride was obtained; yield 86.0%, b.p. 142°-155° C./0.35 mmHg, nD25 1.5652.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O=C1CCC(=O)N1[O:41][C:42](=O)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][NH:57][C:58](=[O:68])[CH2:59][CH2:60][N:61]1[C:65](=[O:66])[CH:64]=[CH:63][C:62]1=[O:67].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([C:4]2([CH2:3][CH2:2][NH:1][C:42](=[O:41])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][NH:57][C:58](=[O:68])[CH2:59][CH2:60][N:61]3[C:65](=[O:66])[CH:64]=[CH:63][C:62]3=[O:67])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1)=[O:33]
Reactant: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reaction time: 1 h

Procedure:
To a solution of (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (191.5 mg, 0.39 mmol) and 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (200 mg, 0.39 mmol) in DMSO (2 mL) was added an excess of DIPEA (151 mg, 203 uL, 1.17 mmol) at room temperature under nitrogen atmosphere. The resulting light yellow solution was stirred for 1 h at which time LCMS analysis indicated the absence of starting material. Then, the excess DIPEA was removed under vacuum and the desired product was isolated by purification using an HPLC method to obtain 90 mg (26% yield) of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-[[1-[2-[3-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydropyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]propionylamino]ethyl]cyclopentanecarbonyl]amino]propionic acid as a white solid. ES(+)-HRMS m/e calcd. for C42H53Cl2N5O12 (M+H)+ 890.3141, obsd. 890.3140.
Reaction SMILES: [OH-].[K+].[CH:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:5]([NH:6][C:7]3=[O:14])[CH2:4]1)[CH2:11]2.[CH2:15](Br)[C:16]#[CH:17]>CO>[CH2:17]([N:6]1[C:7](=[O:14])[CH:8]2[CH2:13][CH:3]3[CH2:11][CH:10]([CH2:12][CH:5]1[CH2:4]3)[CH2:9]2)[C:16]#[CH:15]
Reactant: O=C1NC2CC3CC(C2)CC1C3
Reactant: C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCN1C(=O)C2CC3CC(C2)CC1C3
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
A solution of potassium hydroxide (0.56 gram, 10 mmol) in 3 ml of absolute methanol was added to 4-azatricyclo[4.3.1.13,8 ]undecan-5one (1.65 gram, 10 mmol) and the solvent was slowly removed under reduced pressure with the internal temperature not exceeding 25° C. When solid began to separate, anhydrous toluene was added and the solvent removal continued (a total of 30 ml of toluene were removed), then the temperature was raised to 90° C. (with the distillation continuing at atmospheric pressure--a total of 10 ml of toluene were distilled). The reaction mixture was cooled to 40° C. and propargyl bromide (0.9 ml, 10 mmol) was added dropwise. The temperature was raised to 65° C. and the mixture stirred for 4 hours. The solid precipitate was filtered off, and the filtrate was evaporated to yield 1.82 gram of compound 5a. Melting point 168°-170° C. (recrystallized from a petr. ether-ethanol 10:1 mixture by volume).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]3[CH3:23])[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:29]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:29])=[O:15])[CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]3[CH3:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(N)cc2)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(4-Aminophenyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylic acid (1.15 g) was dissolved in methanol (15 mL), sulfuric acid (0.01 mL) was added and the reaction was heated at 80° C. for 24 h. A small quantity of activated molecular sieve 4A was added to the reaction and stirred for 2 h. The reaction was filtered, vacuumed to dryness then suspended in ethyl acetate (250 mL) and washed once with a saturated solution of sodium bicarbonate (250 mL). The organic layer was filtered, dried over magnesium sulphate and vacuumed to dryness to give the desired material as a brown solid (405 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: CC(=O)OC(C)=O
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(C)=O)cc3CO1)CC2
Yield: 96.9 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and acetic anhydride (61.1 ul, 0.646 mmol) according to the procedure described for Example 48. Obtained the title compound as a light brown foam (110 mg, 97%), MS (ISP) m/e=352.2 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[C:12]1([CH2:18][C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:19](=[O:20])[CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: COc1cccc(CC#N)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C(C#N)C(=O)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
To a mixture of [3-(methyloxy)phenyl]acetonitrile (2.0 g, 14 mmol) and ethyl phenylacetate (2.8 g, 17 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 10.2 mL, 27 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3-(methyloxy)phenyl]-3-oxo-4-phenylbutanenitrile as a brown oil (0.8 g, 3.4 mmol, 38% yield), MS (EI) for C17H15NO2: 266 (MH+).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:8][CH:7]=1.[C:18](OCC)(=[O:22])[C:19]([NH2:21])=[O:20]>CO>[C:18]([NH:14][NH:13][C:12]([NH:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:17][CH:16]=1)=[S:15])(=[O:22])[C:19]([NH2:21])=[O:20]
Reactant: COc1ccc(CNC(=S)NN)cc1
Reactant: CCOC(=O)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNC(=S)NNC(=O)C(N)=O)cc1
Yield: 91 %

Procedure:
Sodium methoxide (5.4 g., 0.1 mole) and 4-(p-methoxybenzyl)-thiosemicarbazide (2.1 g., 0.1 mole) were stirred in methanol (200 ml.) for a period of five minutes. Ethyl oxamate (11.7 g., 0.1 mole) was then added to the mixture and the resulting mixture was refluxed for a period of three hours. At this point, most of the solvent was evaporated under reduced pressure, water (200 ml.) was added to the residue and the pH adjusted to 2.0 with dilute hydrochloric acid. The resulting solid was then filtered and subsequently dried in vacuo at 50° C. to yield pure 1-oxamoyl-4-(p-methoxybenzyl)-3-thiosemicarbazide (25.7 g., 91% yield), m.p. 185°-190° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[CH:12]([OH:27])[CH2:11][CH2:10]1.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38].[Cl-].[Na+]>CN1CCCC1=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCBr)[C@H]3[C@@H]1CCC2O
Reactant: CNCCCCCCC(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Yield: 94.8 %

Procedure:
A solution of 466 mg of 7α-(5-bromopentyl)-11β-fluor-estra-1,3,5(10)-triene-3,17-diol in 10 ml of 1-methyl-2-pyrrolidinone is stirred with 702 mg of methyl-(7,7,8,8,8-pentafluor-octyl)-amine for 3 hours at a bath temperature of 80° C. For working-up, the batch is added to saturated sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 595 mg of 11β-fluoro-7α-{5-[methyl-(7,7,8,8,8-pentafluor-octyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+39° (c=0.5 in CHCl3).