Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3](N)=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:44])C>O>[CH3:1][C:2]([CH3:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:44]
Reactant: CC#N
Reactant: CC(C)(C(N)=O)c1ccccc1OCc1ccccc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: CC(C)(N)c1ccccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 60 h

Procedure:
A solution of α,α-dimethyl-2-(phenylmethoxy)-benzeneacetamide (Example 198c, 19.45 g) dissolved in acetonitrile (200 mL) and water (200 mL) was treated with (Bis(trifluoroacetoxy)iodo)benzene (31.1 g) under nitrogen. The resulting solution was stirred at 20° C. for 60 h. The reaction mixture was diluted with water (300 mL), and extracted with diethyl ether. The aqueous layer was basified at 0° C. with 2M NaOH solution and extracted with ethyl acetate. The organic was dried (MgSO4), filtered and evaporated to afford the subtitle compound (13.26 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH:19]=O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH2:19][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C=O)CCOCC3)cc2C2=CCCCC2)n1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(CN4CCOCC4)CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-formyl-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in the previous step, 30.5 mg, 0.0754 mmol), morpholine (14 μL, 0.15 mmol) and sodium borohydride (6.0 mg, 0.16 mmol) in 2 mL of 1:1 DCM/THF was stirred at RT for 3 h. The mixture was then treated with saturated NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (10-30% EtOAc/DCM) to afford the title compound (28 mg, 77%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.61 (s, 1H), 9.66 (s, 1H), 8.31 (d, 1H, J=8.6 Hz), 7.76 (s, 1H), 7.28 (dd, 1H, J=8.6, 2.3 Hz), 7.17 (d, 1H, J=2.3 Hz), 5.86 (m, 1H), 3.79 (m, 2H), 3.59 (m, 2H), 3.53 (m, 4H), 2.45 (s, 2H), 2.29 (m, 4H), 2.13-2.21 (m, 6H), 1.77-1.98 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H33N5O3, 476.3 (M+H). found 476.2.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=2)[C:5]([CH3:20])=[CH:4][C:3]=1[O:21]C.[C:23](OCC)(=O)C>CCCCCC>[CH3:20][C:5]1[CH:4]=[C:3]([OH:21])[CH:2]=[C:7]([CH3:23])[C:6]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(C)c(Sc2ccc(OC)c(C(C)C)c2)cc1C
Solvent: CCCCCC
Product: Cc1cc(O)cc(C)c1Sc1ccc(O)c(C(C)C)c1

Procedure:
3,5-dimethyl-4-(4′-hydroxy-3′-iso-propyl-phenylsulfanyl)phenol was prepared from 2,5-dimethyl-4-(3′-iso-propyl-4′-methoxy-phenylsulfanyl)anisole according to the procedure described in example 8, step d. 1H NMR (300 MHz, DMSO-d6): δ 9.58 (bs, 1H), 9.21 (bs, 1H), 6.77 (m, 1H), 6.63 (m, 3H), 6.46 (dd, 1H, J=2.7 Hz and J=8.1 Hz), 3.09 (m, 1H), 2.28 (s, 6H), 1.06 (d, 6H, J=7.2 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate 25% in hexane; Rf=0.12
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:25][NH:26][NH2:27]>C(O)(=O)C>[O:22]=[C:13]1[C:14]2[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:17])[N:12]1[CH2:11][CH2:10][C:9]1[N:26]([CH3:25])[N:27]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A modification of the method described in Part A of Example 11 was followed. A mixture of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt (prepared as described in Part A of Example 23, 100 g, 295 mmol) in glacial acetic acid (0.3 L) was cooled to 9° C. before the addition of methylhydrazine (16.0 mL, 300 mmol). During the addition, the reaction temperature did not exceed 16° C. Solids were rinsed from the inside of the flask walls into the mixture with acetic acid (50 mL) and the mixture was allowed to warm to ambient temperature and stir overnight. Water was added to the mixture and additional solid precipitated. The solid was isolated by filtration, dried, and recrystallized from ethanol. The solid was isolated and dried to yield 75.2 g of ethyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[C:16]([Cu])#[N:17]>CN1CCCC1=O.ClCCl>[C:16]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6])#[N:17]
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)O)ccc1OC(F)(F)F
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
3-Bromo-4-(trifluoromethoxy)benzoic acid (1.4 g, 4.91 mmol) and cyanocopper (0.572 g, 6.39 mmol) were mixed in N-methyl-2-pyrrolidinone (NMP) (14 mL). The mixture was heated in a microwave at 200° C. for 2 h. The reaction was diluted with dichloromethane (150 mL). Celite® was added and the mixture was stirred vigorously for 10 min. The solids were removed by filtration. The organic layer was washed with water (125 mL) and concentrated. The residue was purified by HPLC to give the title compound as an off-white solid (0.979 g). LCMS m/z=232.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>[Zn].CO>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C=CC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)c1cc(Nc2ccc(C=CC(=O)O)cc2)cc(C(C)(C)C)c1O
Yield: 19.9 %

Procedure:
A mixture of 2.0 g of 4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)cinnamic acid, 100 ml of methanol, 0.5 ml of concentrated hydrochloric acid and 2 g of zinc powder was stirred for ten minutes. The mixture was filtered and the filtrate was evaporated to give a yellow gummy solid. This material was recrystallized from a mixture of 15 ml of benzene, 4 ml of hexane and 2 ml of cyclohexane to give 0.4 g of yellow granular 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)cinnamic acid, m.p. 199°-200° C. Analysis: Calculated for C23H29NO32/3C6H6 : % C, 77.4; % H, 7.9; % N, 3.3; Found: % C, 77.2; % H, 7.8; % N, 3.3.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11]([C:37](=[O:39])[NH2:38])=[CH:10][CH:9]=2)[CH2:3]1.CCN(CC)CC.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[C:47]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[C:11]([C:37](=[O:39])[NH2:38])=[CH:10][CH:9]=2)[CH2:3]1)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a mixture of (R)-benzyl 4-(4-(6-(3-aminopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate (1.1 g, 2.077 mmol) and Et3N (0.579 mL, 4.15 mmol) in THF (10 mL) was added benzoyl chloride (0.350 g, 2.492 mmol). The reaction mixture was stirred at rt for 30 min., quenched with satd NaHCO3, and extracted twice with CH2Cl2. The combined organic layers were concentrated and the residue was triturated with CH2Cl2 to obtain 1.15 g of (R)-benzyl 4-(4-(6-(3-benzamidopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate as an off-white solid. LCMS: (M+H)+=634.40. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (1H, s), 8.30 (1H, d, J=8.06 Hz), 7.67-7.96 (3H, m), 7.30-7.37 (3H, m), 7.19-7.30 (7H, m), 6.59 (2H, d, J=9.15 Hz), 6.06 (1H, d, J=9.15 Hz), 4.98 (2H, s), 4.34-4.58 (1H, m), 3.93-4.10 (1H, m), 3.75-3.91 (1H, m), 3.08-3.36 (8H, m), 2.52-2.90 (1H, m), 1.86 (1H, s), 1.59-1.75 (1H, m), 1.47-1.58 (1H, m), 1.40 (1H, d, J=2.93 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][C:9]([NH:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)=[N:10]2)=[CH:5][CH:4]=1.C([S-])C.[Na+]>CN(C=O)C>[OH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:9]2[N:8]=[CH:7][C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[N:10]=2)[CH2:19][CH2:18]1
Reactant: COc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 110 °C

Procedure:
To a solution of trans-4-[(7-methoxyquinazolin-2-yl)amino]cyclohexanol (161 mg, 0.583 mmol) in DMF (10 mL) was added sodium ethanethiolate (248 mg, 2.95 mmol) and the mix heated to 110° C. for 16 hours. The reaction was cooled and the residue was purified directly via Biotage F/C eluting with 5-10% MeOH/DCM to afford the title compound as an off-white solid, 120 mg, 78%. 1H NMR (400 MHz, DMSO-D6) □ ppm 10.28 (1H, s) 8.79 (1H, s) 7.57 (1H, d, J=8.59 Hz) 6.96 (1H, d, J=8.08 Hz) 6.54-6.79 (2H, m) 4.54 (1H, d, J=3.54 Hz) 3.74 (1H, d, J=3.28 Hz) 3.38 (1H, s) 1.67-1.93 (4H, m) 1.20-1.39 (4H, m); MS (API+) for C14H17N3O2 m/z 260.2 (M+H)+.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][CH:22]([NH2:28])[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C>>[OH:20][CH2:21][CH:22]([NH:28][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NC(CO)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2cccs2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Then similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-1-thiophen-2-yl-ethylamine and DIEA to give 2-(2-hydroxy-1-thiophen-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 382 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:13]1([C:18](=[O:21])[CH2:19][CH2:20][C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#CCOc1ccc(Br)cc1F
Reactant: C=CC(O)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#CCOc1ccc(CCC(=O)C2CCCC2)cc1F
Temperature: 140 °C
Yield: 90.8 %

Procedure:
A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol), 1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis (triphenylphosphine) palladium (II) (151 mg, 0.22 mmol), and sodium bicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) was heated to 140° C. under N2 for 5 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes) to give the desired product (2.7 g, 93%). 1H NMR (CDCl3): δ 1.52–1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H), 6.92–7.06 (m, 3H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C[CH2:10][C:11](=[O:14])[CH2:12][CH3:13].OS(O)(=O)=O.[C:20](O)(=O)C>>[CH:3]1[CH:2]=[C:1]([C:8]2[CH:20]=[CH:13][CH:12]=[C:11]([OH:14])[CH:10]=2)[C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: CCC(=O)CC
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of o-cresol (5 g, 46.3 mmol) and 3-pentanone (2 g, 23.2 mmol) in acetic acid (20 mL) was added conc H2SO4 (4 mL). The reaction mixture was stirred at ambient temperature for 3 days, poured over ice, and diluted with 1:5 ethyl acetate/hexanes. The organic fraction was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 5% ethyl acetate in hexanes) afforded 2.2 g of diphenol 6. 1HNMR (CDCl3) δ: 6.90 (d, J=2 Hz, 2 H, Ar—H), 6.95 (dd, J=2 Hz, J=8.6 Hz, 2 H, Ar—H), 6.64 (d, J=8.6 Hz, 2 H, Ar—H), 2.21 (s, 6 H, Ar—CH3), 2.0 (q, J=7.3 Hz, 4 H, CH2CH3), 0.60 (t, J=7.3 Hz, 4 H, CH2CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH2:12]([Zn+])[CH:13]([CH3:15])[CH3:14]>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1ccc2occc2c1
Reactant: CC(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc2occc2c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
5-bromobenzofuran (500 mg, 2.56 mmol) was dissolved in THF solution of isobutylzinc(II)bromide (0.5M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd(PtBu3)2 (65 mg, 0.128 mmol, 0.05 eqv.) was added to this solution. The mixture was purged with N2 gas for 3-5 min and heated at 100° C. for 30 min under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give 0.331 g desired product (74% yield): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.35 (d, 1H), 7.07 (d, 1H), 6.70(s, 1H), 2.59 (d, 2H), 1.9 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)=[N:7][C:6]=3[CH:17]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2nc3cc(Br)ccc3o2)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3oc(-c4ccc(C)cc4)nc3c2)cc1
Temperature: 150 °C
Yield: 38.1 %

Procedure:
To a solution of 5-bromo-2-p-tolylbenzo[d]oxazole (146.1 mg, 0.50 mmol) in dioxane (1.5 mL) was added water (0.5 mL), 4-methoxyphenylboronic acid (114 mg, 0.75 mmol), potassium carbonate (138 mg, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (3 mg). The resulting suspension was heated in the microwave at 150° C. for 15 min. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:99 v/v to afford 60 mg (38%) of the title compound (LCMS RT=9.18 min, MH+ 316.1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:19]([C@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:41](=[O:44])[CH2:42]Br)[C@@H:35]1[C:30](=[CH:31][C:32](=[O:39])[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)[CH3:20]>CC(C)=O.O>[CH2:19]([C@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:41](=[O:44])[CH2:42][O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:35]1[C:30](=[CH:31][C:32](=[O:39])[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)[CH3:20]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CNC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
In a mixture of 40 ml of acetone and 8 ml of water is dissolved 0.7 g of N-t-butoxycarbonylglycine, and 0.42 g of potassium t-butoxide is added to the solution. The mixture is stirred, followed by addition of 1.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 12 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is dissolved in a small amount of diisopropyl ether-n-hexane (1:1) and chromatographed on a silica gel column. Following passage of 100 ml of diisopropyl ether, elution is carried out with 400 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.2 g of the above-identified compound as a viscous oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCNC(=O)C(C)c1ccc(C2CCNCC2)cc1
Reactant: CCOc1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccc(OCC)cc3)CC2)cc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
60 mg (0.23 mmol) N-Ethyl-2-(4-piperidin-4-yl-phenyl)-propionamide (VI.1) are added to a mixture of 46 mg (0.23 mmol) 1-bromo-4-ethoxy-benzene, 91 mg (97%, 0.92 mmol) sodium tert-butyrat, 28 mg (0.09 mmol) 2-(di-tert-butylphosphino)biphenyl and 21 mg (0.02 mmol) tris-(dibenzylidenaceton)-dipalladium(0) in 1.0 mL 1,4-dioxane. The mixture is stirred for 1.5 h at 120° C. in a microwave oven. After that time, the solvent is removed in vacuo and the residue is purified by HPLC (column: Waters XBridge 50; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH-:12])(=[O:11])=[O:10].[O-:13][C:14]#[N:15].[K+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:14]([NH2:15])=[O:13])(=[O:10])=[O:11]
Reactant: [NH-]S(=O)(=O)c1c(F)cccc1F
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)NS(=O)(=O)c1c(F)cccc1F

Procedure:
2,6-Difluorophenylsulphonylamide in an amount of 9.65 g and 6.5 g of potassium cyanate in 100 ml of ethanol are refluxed for 3 hours. After dilution with water and filtration while hot the solution is acidified with 5 ml of conc. hydrochloric acid. The desired N-(2,6-difluorophenylsulphonyl)urea is obtained in a yield of 10.0 g; melting point 198° C. (decomp.)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[CH2:13][P+:14]([CH2:19]O)([CH2:17]O)[CH2:15]O.[CH3:21][NH:22][C:23]([NH:25][CH3:26])=[O:24]>C1(C)C=CC=CC=1>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:21][N:22]([CH2:19][P+:14]([CH2:13][N:22]([CH3:21])[C:23]([NH:25][CH3:26])=[O:24])([CH2:15][N:22]([CH3:21])[C:23]([NH:25][CH3:26])=[O:24])[CH2:17][N:22]([CH3:21])[C:23]([NH:25][CH3:26])=[O:24])[C:23]([NH:25][CH3:26])=[O:24]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 89.7 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium p-toluenesulfonate (16.31 g, 0.05 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (200 ml), following Example 1, gave 27.21 g (89.7%) of tetrakis(1,3-dimethylureidomethyl)phosphonium p-toluenesulfonate (I, R=R'=CH3, R"=H, X=SO3C6H4CH3 -p) as a white, crystalline solid, mp 130°-131° C. after two recrystallizations from acetonitrile. The analytical sample was dried under vacuum for 2 hr at 100° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39]([NH:41][C@H:42]([CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH2:43]O)=[O:40])([CH3:37])([CH3:36])[CH3:35].O>C1COCC1.CC#N.C1COCC1>[Si:47]([O:46][CH2:45][CH:42]1[CH2:43][N@@:41]1[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Ph3P (19.65 g, 75 mmol) was dissolved in 9:1 THF/CH3CN (600 mL) and cooled to 0° C., DIAD (14.7 mL, 75 mmol) was added dropwise over 15 min. After stirring for 30 min, a solution of (S)-2-(t-butoxycarbonylamino)-3-(t-butyldimethylsilyloxy)propan-1-ol (15.25 g, 50 mmol) in THF (100 mL) was added dropwise over 15 min, the reaction mixture was allowed to rt and stirred for 24 h. Water (100 mL) was added and volatiles were evaporated. The residue was partitioned between water (100 mL) and EtOAc (2×100 mL). The organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by silica chromatography to provide (S)-tert-butyl 2-(t-butyldimethylsilyloxymethyl)aziridine-1-carboxylate (7.8 g, 54%) as an oil. 1H NMR (CDCl3, 400 MHz): δ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.45 (s, 9 H), 2.06 (d, J=3.6 Hz 1 H), 2.26 (d, J=6 Hz 1 H), 2.55 (m, 1 H), 3.64 (dd, J=16.4, 4.8 Hz, 1 H), 3.82 (dd, J=16.4, 4.4 Hz, 1 H).