Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[OH:4].O.NN>C(O)C.O1CCCC1.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[C:2]([F:1])([F:14])[F:15])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(O)C(F)(F)F)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanol (2.0 g, 9 mmol) in ethanol (100 ml) and tetrahydrofuran (37 ml) was treated under argon with Pd/C (250 mg) and hydrazine hydrate (80% in water, 6.15 ml, 127 mmol, 14 equiv.) The mixture was stirred at room temperature for 30 min, then the black solid was filtered and the solvent evaporated. 1-(4-Amino-phenyl)-2,2,2-trifluoro-ethanol was obtained as a light yellow deliquescent solid, 1.8 g (100%). δH (300 MHz; CDCl3) 7.24 (2H, d), 6.67 (2H, d), 4.87 (1H, m), 3.72 (2H, bs), 3.32 (1H, bs).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:40])[C:11]([OH:39])([CH3:38])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[CH2:26][N:25]([CH2:27][C:28]3[CH:33]=[CH:32][C:31](OC)=[CH:30][CH:29]=3)[C:24](=[O:36])[N:23]2[CH3:37])=[CH:15][CH:14]=1)[CH3:8].CN1C(CCOS(C2C=CC(C)=CC=2)(=O)=O)CN(CC2C=CC([C:67]([F:70])([F:69])[F:68])=CC=2)C1=O>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:40])[C:11]([OH:39])([CH3:38])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH:22]2[CH2:26][N:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:67]([F:70])([F:69])[F:68])=[CH:32][CH:33]=3)[C:24](=[O:36])[N:23]2[CH3:37])=[CH:17][CH:18]=1)[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1

Procedure:
Cesium carbonate (8.72 g, 26.76 mmol) is added to a solution of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (2.0 g, 8.92 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (4.34 g, 9.51 mmol) in DMF (50 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, dried, concentrated, and purified by flash chromatography (25% acetone in hexanes) to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.50 (d, 2H, J=8.2 Hz), 7.32 (d, 2H, J=8.2 Hz), 7.03 (d, 2H, J=8.2 Hz), 6.65 (d, 2H, J=8.2 Hz), 4.40, 4.32 (ABq, 2H, J=14.7 Hz), 4.14-4.07 (m, 2H), 3.91 (t, 2H, J=5.7 Hz), 3.61-3.55 (m, 1H), 3.33 (t, 1H, J=8.2 Hz), 2.96-2.79 (m, 6H), 2.22-2.15 (m, 1H), 1.87-1.80 (m, 1H), 1.40 (s, 3H), 1.21 (t, 3H, J=7.4 Hz). Rf=0.38 in 50% acetone in hexanes.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[C:18]3[O:17][CH2:16][C:15](=[O:19])[C:14]=3[CH:13]=[CH:12][C:11]=2[OH:20])[CH2:3]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[N:22]1.N1CCCCC1>CO>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[C:16]2\[O:17][C:18]3[C:10]([CH2:9][N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[C:11]([OH:20])[CH:12]=[CH:13][C:14]=3[C:15]\2=[O:19])=[N:22]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: C[C@@H]1CN(Cc2c(O)ccc3c2OCC3=O)C[C@H](C)N1
Solvent: CO
Solvent: C1CCNCC1
Product: C[C@@H]1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)C[C@H](C)N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.166 g, 0.601 mmol) in methanol (2.4 mL) was added with 1H-indazole-3-carbaldehyde (0.0878 g, 0.601 mmol), and piperidine (0.00512 g, 0.0601 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (8 mL), suspended in methanol, and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.197 g, 81%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[S:54]([N:57]1[CH2:62][CH2:61][NH:60][C@@H:59]([CH3:63])[CH2:58]1)(=[O:56])=[O:55])[C:49]#[N:50]>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([N:60]2[CH2:61][CH2:62][N:57]([S:54]([C:53]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[CH3:45])(=[O:56])=[O:55])[CH2:58][C@@H:59]2[CH3:63])=[O:35])=[CH:28][CH:27]=1
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(Cl)nc2C)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (425 mg, 1.12 mmol) was added to a solution of 6-chloro-2-methyl-3-pyridinecarboxylic acid (commercially available, e.g. from Anichem, or may be prepared according to known methods) (160 mg, 0.93 mmol) in DMF (3 ml) and the mixture was treated with DIPEA (0.407 ml, 2.33 mmol). This mixture was stirred for ca. 10 min at ambient temperature. 3-Methyl-4-{[(3S)-3-methyl-1-piperazinyl]sulfonyl}benzonitrile (may be prepared as described in Description 11) (313 mg, 1.12 mmol) was added as a solution in DMF (2 ml) and stirring was continued for ca. 1 hour. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave the title compound as a pale cream foam (376 mg).
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])(O)=[O:2].B.C(OCC)(=O)C.Cl>O1CCCC1.O>[OH:2][CH2:1][CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]
Reactant: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(F)c(C2CC2CO)c(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
In 60 ml of anhydrous tetrahydrofuran was dissolved 6.00 g of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate. To the resulting solution was added 42 ml of a 1M solution of borane in tetrahydrofuran with ice-cooling. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was added to a mixture of 100 ml of ethyl acetate and 100 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=4/1) to obtain 4.40 g (yield: 77.1%) of ethyl 4-(2-hydroxymethylcyclopropyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of the diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (31.8 g, 88 mmol) in aqueous hydrochloric acid (6M, 1.4 L) was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and added very slowly to a saturated aqueous solution of aqueous sodium bicarbonate (4 L) at 0° C. The mixture was then extracted with dichloromethane (7 L), dried over magnesium sulfate and the solvent removed in vacuo to give 5-bromo-2-methyl-3-nitropyridine as an orange oil (13.8 g, 63.9 mmol, 72%) which solidified upon standing. 1HNMR (300 MHz, CDCl3): δ ppm 8.78 (s, 1H), 8.43 (s, 1H), 2.79 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[O:13][CH2:12][O:11][CH:10](O)[C:9]=3[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:26].C(Cl)Cl.O>CCOCC.N1C=CC=CC=1>[C:1]1([C:7]2[C:8]3[O:13][CH2:12][O:11][CH:10]([Cl:26])[C:9]=3[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OC1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: ClC1OCOc2c1ccc(-c1ccccc1)c2-c1ccccc1

Procedure:
To a stirred solution of 11.6 g. (38 mmol) of 3,4-diphenylmethylenedioxybenzyl alcohol in ether (80 ml.) and pyridine (0.6 ml.) at 20° C. was added dropwise a solution of SOCl2 in ether (40 ml.). The mixture was cooled to 0°-5° C., and CH2Cl2 and water were added. The layers were separated, and the organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4 and concentrated to dryness to yield 3,4-diphenylmethylenedioxybenzyl chloride (11.43 g.) as a colorless viscous oil: tlc (silica gel CH2Cl2 : Rf 0.8; ir (CCl4) no --OH--, nmr (CCl4) δ 4.34 (s, 2H), 6.74 (d,j=8) 2H, 6.67 (s, 1H), 7.1-7.6 (m, 10H). ##STR11##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH2:14](I)[CH3:15]>>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:15]
Reactant: Oc1ccc2ncccc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc2ncccc2c1

Procedure:
6-Hydroxyquinoline was treated with sodium hydride and ethyl iodide to give 6-ethoxyquinoline. This material was nitrated, reduced and coupled with 2-hexylthiodecanoic acid according to the procedure of Example 33 to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[F:28].[NH:29]1[CH2:33][CH:32]=[CH:31][C@H:30]1[C:34]([OH:36])=[O:35]>>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([N:29]3[CH2:33][CH:32]=[CH:31][C@H:30]3[C:34]([OH:36])=[O:35])=[O:21])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[F:28]
Reactant: O=C(O)[C@@H]1C=CCN1
Reactant: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Product: O=C(O)[C@@H]1C=CCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Yield: 30 %

Procedure:
An operation similar to that in Step 4 of Example 10 was performed using the compound (38.0 mg, 0.100 mmol) of Step 2 of Example 59 in place of 3-{[4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl}benzoic acid, and (2S)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (14.7 mg, 0.130 mmol) in place of L-proline to thus obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>C(Cl)Cl.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH:31]5[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Reaction time: 16 h
Yield: 60.9 %

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (27 mg, 0.26 mmol) were stirred in methylene chloride (1 mL) and AcOH (0.1 mL), and picoline borane complex (27 mg, 0.26 mmol) was added. After stirring for 16 h, the mixture was diluted with methylene chloride, washed with sodium carbonate solution and concentrated. The obtained residue was purified by flash column chromatography (silica gel, (1:1 EtOAc/hexanes)/(10:1 methanol/ammonia), 10:0 to 9:1) to provide the title compound (90 mg, 61%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.45-7.36 (m, 5H), 7.32-7.30 (m, 1H), 7.32-7.27 (m, 2H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 6.05-6.01 (m, 2H), 5.05 (s, 2H), 4.20 (s, 2H), 3.85 (s, 2H), 3.60 (s, 3H), 3.04-2.93 (m, 2H), 2.88-2.66 (m, 5H), 1.98-1.87 (m, 2H), 1.60-1.54 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:22][CH:19]([CH3:21])[CH3:20])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccccc1OCC1CO1
Reactant: CC(C)N
Solvent: CC(C)O
Product: Cc1ccc(C)n1-c1ccccc1OCC(O)CNC(C)C

Procedure:
30 g of 1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane, dissolved in 200 ml of isopropanol, are mixed with 60 ml of isopropylamine and the mixture is heated to the boil under reflux for 2 hours. The oil which remains after evaporation is recrystallised from petroleum ether with addition of active charcoal and gives 1-[o-(2,5-dimethyl-pyrrol-1-yl)-phenoxy]-3-isopropylamino2-propanol of melting point 73°-75° C. Its neutral fumarate melts at 186°-188° C (from acetone).
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1.C(OCC)C>[C:15]([NH:14][C:10]1[C:6]2[O:7][C:8]([CH3:9])=[C:4]([C:1]([OH:3])([CH3:18])[CH3:2])[C:5]=2[CH:13]=[CH:12][CH:11]=1)(=[O:17])[CH3:16]
Reactant: C[Mg]Br
Reactant: CC(=O)Nc1cccc2c(C(C)=O)c(C)oc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Nc1cccc2c(C(C)(C)O)c(C)oc12
Reaction time: 5 h

Procedure:
To a solution of 3-acetyl-7-acetylamino-2-methylbenzo[b]furan (2.92 g) in tetrahydrofuran (60 ml) was added a 3M solution of methylmagnesium bromide in diethyl ether (12.7 ml) dropwise with ice cooling. The solution was stirred at ambient temperat ure for 5 hours and to the solution was added aqueous saturated ammonium chloride. Then, the mixture was poured into water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 7-acetylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (1.82 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Temperature: 80 °C
Yield: 98 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 31.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): d 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([N:15]=[C:16](SC)[S:17][CH3:18])#[N:14]>CO>[C:13]([NH:15][C:16](=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[S:17][CH3:18])#[N:14]
Reactant: NCCSCc1ncccc1Cl
Reactant: CSC(=NC#N)SC
Solvent: CO
Product: CSC(=NCCSCc1ncccc1Cl)NC#N

Procedure:
A solution of 2-[(3-chloro-2-pyridyl)methylthio]-ethylamine (5.77 g; 28.44 mmoles) and dimethyl cyanodithioimidocarbonate [prepared according to the procedure described in J. Org. Chem., 32, 1566 (1967)] (4.16 g; 28.44 mmoles) in methanol (50 ml) was stirred at ambient temperature under a positive pressure of nitrogen for 16 hours and then at reflux for 0.5 hours to complete the reaction. The reaction mixture was evaporated under reduced pressure and the crude product was recrystallized from isopropyl alcohol with activated carbon treatment to give N-cyano-N'-{2-[(3-chloro-2-pyridyl)methylthio]ethyl}-S-methylisothiourea; mp 119.5°-121°.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[N:19][CH:20]=1>C(Cl)Cl>[F:24][C:14]([F:13])([F:23])[C:15]1[CH:16]=[C:17]2[NH:22][C:1](=[O:2])[NH:21][C:18]2=[N:19][CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 1,1′-carbonyldiimidazole (1.0 g, 6.17 mmol) to a solution of 5-trifluoromethyl-pyridine-2,3 diamine (0.90 g, 5.08 mmol) in CH2Cl2 (10 mL) and stir at room temperature for 18 hours. Heat the solution to reflux for 2 hours and filter the precipitate to obtain 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one. C. 2-Chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:28]1([C:34]2[N:35]=[C:36]([CH2:39][CH:40]([C:44]3[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=3)[CH2:41][CH2:42][CH3:43])[S:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH2:50][C:47]2[CH:48]=[CH:49][C:44]([CH:40]([CH2:39][C:36]3[S:37][CH:38]=[C:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:35]=3)[CH2:41][CH2:42][CH3:43])=[CH:45][CH:46]=2)[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CN(c2ccc(CCC(=O)OCC)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.686 g, 1.73 mmol), (4-{1-[(4-phenyl-1,3-thiazol-2-yl)methyl]butyl}phenyl)methanol (0.389 g, 1.15 mmol) and triphenylphosphine (0.603 g, 2.30 mmol) in tetrahydrofuran (15 mL) was stirred under ice-cooling, and diethyl azodicarboxylate (40% toluene solution, 1.05 mL, 2.3 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give ethyl 3-{2-fluoro-4-[[(2-nitrophenyl)sulfonyl](4-{1-[(4-phenyl-1,3-thiazol-2-yl)methyl]butyl}benzyl)amino]phenyl}propanoate as a yellow oil. To a solution of the obtained oil and mercaptoacetic acid (0.291 g, 3.16 mmol) in N,N-dimethylformamide (15 mL) was added lithium hydroxide monohydrate (0.265 g, 6.32 mmol), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (0.420 g, yield 69%, 2 steps) as a colorless oil.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[NH:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>C1(C)C=CC=CC=1>[Cl-:10].[O:16]=[C:12]1[NH:13][CH2:14][CH2:15][N:11]1[CH2:8][P+:3]([CH2:1][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])([CH2:4][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[CH2:6][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]
Reactant: OC[P+](CO)(CO)CO
Reactant: O=C1NCCN1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1NCCN1C[P+](CN1CCNC1=O)(CN1CCNC1=O)CN1CCNC1=O
Yield: 96.1 %

Procedure:
Reaction of THPC (9.53 g, 0.05mol) with 2-imidazolidinone (17.22 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 22.23 g (96.1%) of tetrakis[(2-oxo-1-imidazolidinyl)methyl]phosphonium chloride (I, R, R'=CH2CH2, R"=H, X=Cl) as a white solid, mp 220° C. The product was soluble in dilute sodium hydroxide and insoluble in water or organic solvents.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[CH:40]=[C:39]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])[CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCOCC2)CC1
Yield: 64 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white solid (64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([F:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:18])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc(OC)c(F)c2)cc1F
Agent: Br
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(O)c(F)c2)cc1F

Procedure:
10.0 g of 3,3'-difluoro-4,4'-dimethoxybiphenyl was dissolved in 150 ml of dioxane, and 150 ml of 48% hydrobromic acid was added. The mixture was heated under reflux for 50 hours. After the reaction, the reaction mixture was subjected to evaporation under reduced pressure. The residue was fully washed with water to obtain the desired 3,3'-difluoro-4,4'-dihydroxybiphenyl.