Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
4-Methoxy-2-methyl-1H-indole (1 g, 6.2 mmol) was added to 248 mg (6.2 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 0.74 mL (6.2 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.3 g (84% yield) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole, melting at 96-116° C.
Reaction SMILES: C(=O)(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O.[P:19]([O:31][CH2:32][C@H:33]1[O:37][C@@H:36]([N:38]2[CH:45]=[C:44](C#CCN)[C:42](=[O:43])[NH:41][C:39]2=[O:40])[CH2:35][C@@H:34]1[OH:50])([O:22][P:23]([O:26][P:27]([OH:30])([OH:29])=[O:28])([OH:25])=[O:24])(=[O:21])[OH:20].[CH3:51][CH2:52][N:53]([CH2:56][CH2:57]O)[CH2:54][CH3:55]>CN(C=O)C.O>[CH:44]1[C:42](=[O:43])[NH:41][C:39](=[O:40])[N:38]([C@@H:36]2[O:37][C@H:33]([CH2:32][O:31][P:19]([O:22][P:23]([O:26][P:27]([OH:30])([OH:29])=[O:28])([OH:25])=[O:24])([OH:21])=[O:20])[C@@H:34]([OH:50])[CH2:35]2)[CH:45]=1.[CH2:52]([NH+:53]([CH2:56][CH3:57])[CH2:54][CH3:55])[CH3:51]
Reactant: CCN(CC)CCO
Reactant: NCC#Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: O
Product: CC[NH+](CC)CC
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TMR-sieber linker free acid (4.34 mg, 5 μmol) was stirred with disuccinimidyl carbonate (1.74 mg, 7.5 μmol) and N,N-dimethyl aminopyridine (0.92 mg, 7.5 μmol) in DMF (1 mL) at room temperature. After 10 minutes, all the reaction mixture was added to tetra-(tri-butylammonium) salt of 5-(3-aminopropynyl)-2′-deoxyuridine-5′-triphosphate (10 μmol). The reaction was stirred at room temperature for 4 hrs and stored in the fridge overnight. The reaction mixture was then diluted with chilled water (10 mL) and all the resulting solution was applied onto a short column of DEAE A-25. The column was initially eluted with 0.1 M TEAB buffer and then 0.7 M TEAB buffer. The 0.7 M TEAB eluents were collected and evaporated under reduced pressure. The residue was co-evaporated with MeOH (2×10 mL) and then purified by preparative HPLC. The title compound was obtained as triethylammonium salt in 31% yield (based on the quantification of TMR at 555 nm in water (pH 7)). 1HNMR in D2O indicated two diastereoisomers, due to the sieber linker moiety and there were approximately three triethylammonium count ions. 1H NMR [D2O]: 8.18 (1H, m), 8.06 (1H, m), 7.76 (0.55H, s), 7.74 (0.45H, s), 7.36-7.09 (5H, m), 6.89-6.72 (3H, m), 6.59-6.37 (5H, m), 6.12 (0.55H, t, J 6.6), 6.05 (0.45H, t, J 6.6), 5.99 (0.45H, d, J 2.5), 5.91 (1.1H, m), 5.88 (0.45H, s), 4.49 (0.55H, m), 4.43 (0.45H, m), 4.00-3.35 (9H, m), 3.30-2.95 (32H, m), 2.65-2.52 (4H, m), 2.25-2.05 (4H, m), 1.62-1.42 (4H, m) and 1.23 (27H, t, J 7.3). −P [D2O]: −9.91 (γP, d, J 19.2), [−11.08 (αP, d, J 20.1) and −11.30 (αP, d, J 20.1), due to two diastereoisomers] and −22.57 (βP, m). MS[(ES(−)], m/z 1369.1 (M−).
Reaction SMILES: Cl.[C:2]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:8]1[CH2:7][CH2:6][C:5]([C:2](=[O:4])[CH3:3])([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:10][CH2:9]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A suspension of 4-Acetyl-4-(4-chlorobenzyl)-piperidine hydrochloride (0.600 g, 2.09 mmol) in acetonitrile (20 mL) was treated with solid sodium bicarbonate (200 mg, xs) and benzyl chloride (292 mg, 2.3 mol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 2% Methanol/chloroform to give 706 mg of the title compound.
Reaction SMILES: [NH2:1][C@:2]([CH2:9][CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].Cl[S:12]([OH:15])(=[O:14])=[O:13]>ClCCl>[S:12]([OH:15])([O:4][CH2:3][C@@:2]([NH2:1])([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: CCCC[C@](N)(CC)CO
Solvent: ClCCl
Product: CCCC[C@](N)(CC)COS(=O)(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The product (20.0 g) from step (f) was dissolved in dichioromethane (170 ml) and treated with chlorosulfonic acid (26.8 g). The reaction mixture was stirred at room temperature for 17 hours. A major part of the solvent was removed by distillation and the resulting slurry was diluted with acetone, filtered and dried to get a white solid. 1H NMR consistent with the proposed structure.
Reaction SMILES: [F:1]/[CH:2]=[CH:3]/[C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3OCCC[O:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O1CCCC1.Cl.C1(C)C=CC=CC=1>O>[F:1]/[CH:2]=[CH:3]/[C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1
Reactant: F/C=C/[C@H]1CC[C@H](c2ccc(C3OCCCO3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc([C@H]2CC[C@H](/C=C/F)CC2)cc1
Reaction time: 5 h

Procedure:
Trans-1-(E-2-fluoro-1-ethenyl)-4-{4-(1,3-dioxan-2-yl)phenyl}cyclohexane (34 g, 0.12 mol), tetrahydrofurane (130 ml) and 3N-hydrochloric acid (130 ml) were heated under reflux with stirring for 5 hours, followed by cooling the reaction mixture, adding toluene (200 ml) and water (200 ml) to the mixture, washing the resulting toluene solution with water, drying over anhydrous magnesium sulfate and distilling off toluene to obtain the objective substance (25 g, 0.11 mol; E:Z=5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[NH:5].C([O-])(O)=O.[Na+].[CH2:23]([O:25][C:26](=[O:31])[C:27](=[O:30])[CH2:28]Br)[CH3:24]>CC(O)C>[CH2:23]([O:25][C:26]([C:27]1([OH:30])[CH2:28][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:4]([C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])=[N:5]1)=[O:31])[CH3:24]
Reactant: CCOC(=O)C(=O)CBr
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C1(O)CN(c2ccc(Cl)cc2)C(c2ccccc2Cl)=N1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-N-(4-chloro-phenyl)-benzamidine (I-2a), 25.1 g, 95 mmol) and NaHCO3 (84 g, 189 mmol) in 2-propanol (473 ml) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (14.3 ml, 22 g, 113 mmol). The reaction mixture was heated at 80° C. for 17 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was diluted with CH2Cl2 and the organic solution was washed with H2O, dried over MgSO4, and concentrated in vacuo to provide the product, 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-2b, as a dark red residue (36 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([F:30])([F:31])[F:17])=[N:12]1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2C(F)(F)F)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [CH3:1][N:2]([CH:21]([CH3:23])[CH3:22])[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[C:14][Si](C)(C)C)=[CH:10][CH:11]=2)[C:6]([CH3:20])([CH3:19])[CH2:5][CH2:4]1.CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:3]([N:2]([CH:21]([CH3:22])[CH3:23])[CH3:1])[CH2:4][CH2:5][C:6]2([CH3:19])[CH3:20])#[CH:14]
Reactant: CC(C)N(C)C1CCC(C)(C)c2cc(C#C[Si](C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C(C)C
Yield: 80 %

Procedure:
Following general procedure E and using 1-(methyl-iso-propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 28, 0.14 g, 0.45 mmol), methanol (5 mL), potassium carbonate (0.61 g, 4.41 mmol) and ethyl acetate the title compound (0.092 g, 80%) was obtained as an oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[C-:21]#[N:22].[Na+].[OH-].[NH4+]>ClC(Cl)Cl.O.C(O)(=O)C>[C:21]([C:2]1([NH:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1)#[N:22]
Reactant: [C-]#N
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(C#N)(Nc2ccc(F)cc2)CC1
Reaction time: 0.5 h

Procedure:
75 Parts of ethyl 4-oxo-1-piperidinecarboxylate and 50 parts of 4-fluorobenzeneamine are added dropwise to 220 parts of acetic acid. The whole is stirred for 30 minutes. Then there is added dropwise a solution of 23 parts of sodium cyanide in 65 parts of water at room temperature (exothermic reaction). Upon completion, a second portion of 2 parts of sodium cyanide is added and the whole is stirred overnight. The reaction mixture is poured onto a mixture of 440 parts of water, 440 parts of ammonium hydroxide solution and 525 parts of trichloromethane. The trichloromethane-phase is separated and the aqueous layer is extracted with trichloromethane. The combined organic layers are washed with water, dried and evaporated, yielding 127.5 parts of ethyl 4-cyano-4-(4-fluorophenylamino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: C[N:2]([CH3:9])[CH2:3][CH2:4]CN=C=O.[CH2:10]([C:17]1[NH:25][C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:45](=O)([O-])[O-].[Na+].[Na+].C(N)C>ClCCCl>[CH2:10]([C:17]1[N:25]([CH2:45][CH2:9][NH:2][CH2:3][CH3:4])[C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCN=C=O
Reactant: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C([O-])[O-]
Agent: CCN
Agent: [Na+]
Solvent: ClCCCl
Product: CCNCCn1c(Cc2ccccc2)nc2c1c(=O)n(CCCN(C)C)c(=O)n2CCc1ccc([N+](=O)[O-])cc1

Procedure:
By methods well known in the art 3-dimethylaminopropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate and ethylamine to yield 8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]xanthine. By the method of Example 4 this substance is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-(2-ethylamino)ethylxanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(Br)cc2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCN(Cc1ccccc1)C2
Temperature: 65 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 4-benzyl-8-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (4.50 g, 13.5 mmol) in tetrahydrofuran (45 ml) was added 1M borane-tetrahydrofuran solution (54 ml, 54.0 mmol), and the mixture was stirred at 65° C. for 4 hr. Under ice-cooling, methanol (135 ml) and sodium hydroxide (11.7 g, 294 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (4.30 g, 100%) as an oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH:3]([C:5]1[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4])[S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29]
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(c1nc2ccccc2c(=O)n1-c1ccccc1)N(C)S(=O)(=O)c1ccccc1

Procedure:
In a similar manner as described above in Example 7, 2-(1-methylaminoethyl)-3-phenyl-3H-quinazolin-4-one, prepared as described above in Paragraph A, was condensed with benzenesulfonyl chloride to yield N-methyl-N-[1-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl]benzenesulfonamide; MS (ESI) 420 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](O)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:37][NH:38][OH:39].C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:38]([OH:39])[CH3:37])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)CCN1
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(O)C(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 5 °C
Reaction time: 1.17 h
Yield: 79.6 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (9.0 g 23.50 mmol) in anhydrous DMF (285 mL) was added CDMT (4.95 g 28.20 mmol 1.2 eq.) and NMM (N-methyl morpholine) (2.85 g 28.2 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 70 min. N-Methylhydroxylamine hydrochloride (23.6 g 282.0 mmol 12.0 eq) was added and stirring continued for 3 hours. The reaction was judged to be complete by HPLC-MS analysis, and was quenched by adding water (100 mL) to the reaction mixture. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a residue. Saturated aqueous sodium bicarbonate (120 mL) was added to neutralize to pH 7. White solid precipitated out, and the mixture was cooled to 5° C. The solid was filtered, washed with cold water (100 mL), and dried in vacuo to afford 7.7 g (85%) of 1-(4-fluorobenzyl)-N-hydroxy-N-methyl-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide at >95% purity by 1HNMR analysis. To obtain 99% purity, 7.7 g of the product was dissolved in a boiling mixture (700 mL) of methanol and isopropanol (1:9). The hot solution was filtered to remove trace impurities, and the filtrate was allowed to cool to room temperature. The product crystallized out as needle-like crystals, which was filtered, washed with isopropanol, and dried in vacuo to afford (3.0 g) 99% purity. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—2.27 min, m/e=412.30 (M+H+, base). 1H NMR (400 MHz, DMSO-D6) d ppm 2.55 (t, J=5.29 Hz, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.32 (s, 3H) 3.73 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.81 Hz, 2H) 7.35 (dd, J=8.56, 5.54 Hz, 2H) 7.71 (s, 1H) 7.83 (s, 1H) 8.09 (s, 1H) 8.86 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].C(N(C(C)C)CC)(C)C>C(O)(C)C.ClCCl>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:15][CH2:14][CH2:13][O:12][CH3:11])[C:7]=1[NH2:8]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: COCCNc1nc(C)nc(Cl)c1N
Temperature: 25 °C
Yield: 115.4 %

Procedure:
Heat a solution of 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (5.0 g, 0.02 mol), 2-methoxyethylamine (2.32 g, 0.03 mol) and diisopropylethylamine (3.9 g, 0.03 mol) in isopropanol (70 mL) at 150° C. in a sealed tube for 16 h. Cool the reaction mixture to room temperature, and remove the isopropanol under reduced pressure to give a residue. Dissolve the residue in dichloromethane and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue on a silica gel column eluting with methanol:dichloromethane (4:96) to give the title compound (5.0 g). ES/MS m/z 217 (M+1).
Reaction SMILES: [CH2:1](N(CC)C1C=CC=CC=1)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]#C)[C:14]=1[N:24]1[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]1=[O:36].[F-].[Cs+]>O>[F:19][C:17]1[C:16]2[CH:22]=[C:21]([CH3:1])[O:20][C:15]=2[C:14]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[N:26]([CH3:35])[C:25]2=[O:36])=[C:13]([F:12])[CH:18]=1
Reactant: C#CCOc1cc(F)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(F)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 185 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
100 ml of N,N-diethylaniline was added to 4.7 g (13 mmol) of 3-(2,4-difluoro-6-propargyloxyphenyl)-1-methyl-6-trifluoromethyluracil and 5.9 g (39 mmol) of cesium fluoride, followed by stirring at 180 to 190° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.0 g (yield: 21.3%) of the desired product as white powder. Melting point: 176-178° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:33])[CH:24]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CO.C1COCC1.O.NN>O>[NH2:3][C@@H:12]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[C:25]([F:33])[CH:24]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC[C@H](c1ccc(C(F)(F)F)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC[C@@H](N)c1ccc(C(F)(F)F)c(F)c1
Temperature: 50 °C
Yield: 59.5 %

Procedure:
To a solution of 288 (0.350 g, 0.750 mmol) and MeOH:THF (6 mL, 1:1) was added hydrazine monohydrate (0.188 mL, 3.75 mmol) and the reaction was heated to 50° C. for 4 d. The reaction was then poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:20) to afford 0.150 g (59.4%) of (R)-tert-butyl 3-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)propylcarbamate (290).
Reaction SMILES: [Br-:1].[CH3:2][C:3]([CH3:41])([CH2:30][CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[C:4](=[O:29])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(OCC)C.N>C(Cl)Cl.CO>[Br-:1].[CH3:2][C:3]([CH3:41])([CH2:30][CH2:31][NH:32][CH3:33])[C:4]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][P+:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:29]
Reactant: CN(CCC(C)(C)C(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CNCCC(C)(C)C(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
8,8,11,14,14-pentamethyl-7,12-dioxo-1,1,1-triphenyl-13-oxa-6,11-diaza-1-phosphoniapentadecane bromide (205 mg, 0.32 mmol) was dissolved in methylene chloride (1.0 mL) and methanol (0.10 mL). The solution at room temperature was treated with 2.0 M hydrogen chloride in diethyl ether (0.36 mL, 0.71 mmol). The reaction was stirred overnight at room temperature, cooled with an ice bath, and treated with 7N ammonia in methanol (0.13 mL, 0.93 mmol). After 30 minutes, the slurry that resulted was filtered, and the solids were washed with methylene chloride. The filtrate was concentrated to give the title compound (170 mg, 98%) as a white foam. The product of step 2 was used crude in next step.
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(S)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]3[O:41][CH2:40]3)=[CH:33][CH:32]=2)([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[CH:18]1[O:20][CH2:19]1>>[OH:41][CH:39]([CH2:40][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:17][CH:18]([OH:20])[CH2:19][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:27][CH:26]=2)([CH3:29])[CH3:30])=[CH:32][CH:33]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Product: CC(C)(c1ccc(OCC(O)Cc2ccccc2)cc1)c1ccc(OCC(O)Cc2ccccc2)cc1
Yield: 94 %

Procedure:
A reaction was conducted as described in Example 6 except that benzoic acid and PGE were replaced with 210 mmol of thiophenol and 100 mmol of 2,2-bis(4-glycidyloxyphenyl)propane, respectively. Desired 2,2-bis[4-(2-hydroxy-3-phenylpropyloxy)phenyl]propane was formed in an analytical yield of 94% and isolated in a yield of 90%.