Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[SH:18])[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[C:8](=[O:9])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:18][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)C(=C(S)c1ccccc1)c1ccccc1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)sn1-c1ccccc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of 150 mg (0.450 mmol) 2,3,N-triphenyl-3-mercaptopropenamide and 25 mL methylene chloride was stirred at room temperature. Added was 115 mg (1 equiv.) of iodine followed by 116 mg (1 equiv.) of triethylamine and the mixture stirred for one hour. Solvent was evaporated and 50 mL ethyl acetate added and the mixture poured into 50 mL water. The organic layer was separated and washed with three 50 mL portions of water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was recrystallized from ethanol/water to provide 108 mg (0.327 mmol, 73%) 4,5,N-triphenyl-4-isothiazolin-3-one as a tan solid, mp=175°-176° C. NMR (CDCl3 /TMS): 7.30-7.72 (m, 15H). IR (KBr): 1656. Mass spectrum (CI): M/z=330 (M+H)+. Anal. calcd. for C21H15NOS: C 76.57, H 4.59, N 4.25, S 9.73; Found: C 76.25, H 4.40, N 4.19, S 9.81.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[K+]>CO.O>[CH3:25][S:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][NH:5][C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-N-((trans)-2-phenylcyclopropyl)acetamide (150 mg, 0.37 mmol) in a mixture of MeOH (6 mL) and H2O (4 mL) was added KOH (62 mg, 1.11 mmol) at 0° C. stirred for 2 h rt. Reaction mixture was concentrated and the residue was dissolved in water (10 mL) and acidified with 50% HCl and washed with ethyl acetate (2×10 mL). The aqueous layer was basified with saturated sodium carbonate solution and extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4 and concentrated under the reduced pressure to obtain the desired product (trans)-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2-phenylcyclopropanamine (57 mg, 51.8%) as colourless gummy oil. HPLC-97.64%, m/z 309.35 (M+H)+. H1NMR (CDCl3) δ ppm 7.23-7.25 (m, 2H), 7.16-7.13 (m, 1H), 7.02 (d, J=7.2 Hz, 2H), 3.81 (d, J=11.2 Hz, 2H), 2.76 (s, 3H), 2.60-2.66 (m, 4H), 2.30-2.34 (m, 1H), 1.82-1.88 (m, 3H), 1.52-1.56 (m, 2H), 1.29-1.36 (m, 2H), 0.95-1.06 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:25](O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCOc1c(OC)ccc2c1C(O)N(CCc1ccc(OCc3ccccc3)cc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCOc1c(OC)ccc2c1CN(CCc1ccc(OCc3ccccc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
2-[2-(4-Benzyloxyphenyl)ethyl]-3-hydroxy-5-methoxy-4pentyloxy-2,3-dihydroisoindol-1-one (142 mg, 0.30 mmol, 1.0 eq) was dissolved in dichloromethane (3 ml), and triethylsilane (0.095 ml, 0.60 mmol, 2.0 eq) was added. The mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid was added thereto, and the mixture was further stirred for 4 hours. A saturated aqueous sodium hydrogencarbonate solution (30 ml) was added to this reaction mixture. The mire was extracted twice with ethyl acetate (30 ml). The organic layers were combined, then washed with saturated brine (60 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[2-(4-benzyloxyphenyl)ethyl]-5-methoxy-4-pentyloxy-2,3-dihydroisoindol-1-one (136 mg, 99.8%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:40])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]#[C:23][CH3:24])[C:16]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]3)=[N:15][C:14]=2[N:13]([CH3:39])[C:11]1=[O:12].[C:41](=[O:44])([O-])[O-:42].[K+].[K+].O>CN(C)C=O>[C:35]([O:42][C:41]([NH:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:40])[CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]#[C:23][CH3:24])[C:16]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:26]3)=[N:15][C:14]=2[N:13]([CH3:39])[C:11]1=[O:12])=[O:44])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1OCCNC(=O)OC(C)(C)C)c(=O)n2C
Temperature: 55 °C
Reaction time: 8 h

Procedure:
187 mg of tert.-butyl 2-bromo-ethyl-carbaminate are added to 400 mg of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine and 150 mg of potassium carbonate in 6 ml N,N-dimethylformamide and the reaction mixture is stirred overnight at 55° C. Then a further 90 mg of tert.-butyl 2-bromo-ethyl-carbaminate are added. After another eight hours at 55° C. the reaction is complete. The cooled reaction mixture is combined with water, the precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][C:24]1[N:29]=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:33][S:30]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=2)(=[O:32])=[O:31])=[O:21])=[CH:19][CH:18]=1
Reactant: Cc1cccc(S(N)(=O)=O)n1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1cccc(C)n1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 6-methyl-pyridine-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 2.45 (s, 3), 3.61 (s, 3), 4.73 (s, 2), 6.38 (s, 1), 6.97 (m, 2), 7.23 (m, 2), 7.77 (m, 1), 8.17 (m, 1), 8.54 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 18.71, 48.22, 63.10, 92.48, 115.65, 115.82, 124.67, 130.24, 130.34, 131.09, 138.70, 139.36, 150.54, 152.19, 159.14, 161.66, 163.62, 170.80.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:24][CH3:25])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>N1C=CC=CC=1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:13][CH:14]=2)[N:9]([CH2:24][CH3:25])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC(F)(F)F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(-c2ccc(NS(=O)(=O)CC)cc2)c(C#N)c2ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of the compound obtained in step C (31 mg, 0.1 mmol) in dry pyridine (1.0 mL) is added ethanesulfonyl chloride (14 μL, 0.15 mmol). The mixture is stirred at room temperature overnight and diluted with water (5 mL). The organic is extracted with DCM (5 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, ethanesulfonic acid [4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (33 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][OH:14])[C:10](=[O:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[CH2:24]1[O:26][CH2:25]1.[OH-].[NH4+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][OH:14])[C:10](=[O:15])[CH2:9][N:8]3[CH2:24][CH2:25][O:26][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Reactant: C1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Reaction time: 0.33 h

Procedure:
A solution of 3.3 g (0.01 M) of 7-chloro-1-(2-hydroxyethyl)-5-(2-fluorophenyl)-1,3-dihyrdo-2H-1,4-benzodiazepin-2-one in 40 ml of 1,2-dichloro ethane under nitrogen was treated with 5.2 g (0.02 M) of stannic chloride with stirring. After 20 min, the mixture was cooled in an ice bath and 2.6 g (0.06 M) of ethylene oxide was added. After 1 hr at room temperature, the reaction mixture was made basic with ammonium hydroxide and filtered. The precipitate was washed with dichloromethane, and the combined filtrates were separated. The organic layer was washed with 40 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of ether and petroleum ether and recrystallized from toluene to give the above named product as white prisms, mp 142°-147°.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[N:26]=2)[N:4]=1)[CH3:2].[BH-](OC(C)=O)(OC(C)=O)O[C:42](C)=O.[Na+].C=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][N:37]([CH3:42])[CH2:38][CH2:39]3)[N:26]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(OCCN3CCNCC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1nn(Cc2cccc(OCCN3CCN(C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To N-(3-ethyl-1-((6-(2-(piperazin-1-yl)ethoxy)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.0095 mmol; prepared as in Example 43) in MeOH (2 mL) was added NaBH(OAc)3 (6.1 mg, 0.029 mmol) and HCHO (as a 35% aqueous solution) (19 mg, 0.19 mmol). The reaction mixture was stirred for 30 minutes, concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=539 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28]>C1COCC1>[NH2:20][C:4]1[N:3]=[C:2]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: C1CCOC1
Product: Nc1nc(N2CCN(c3ccc(Cl)c(Cl)c3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 150 °C
Yield: 5.9 %

Procedure:
To a solution of 2-chloro adenosine (80 mg, 0.27 mmol) in THF (4 mL) was added 4-(3,4-dichlorophenyl)piperazine (122 mg, 0.53 mmol) and the resulting solution heated in a Biotage microwave (150° C., absorption high, pre-stirring 30 s) for 30 min. The solvents were then removed in vacuo and the residue purified twice by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 18 min, product eluted in 80% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 9 min, product eluted in 55% acetonitrile) to yield (2R,3R,4S,5R)-2-(6-amino-2-(4-(3,4-dichlorophenyl)piperazin-1-yl)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 8 as a white solid (7.9 mg, 6%)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(C(F)(F)F)=O.[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][C@@H:3]([C:2]([F:10])([F:11])[F:1])[C@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of (E)-ethyl 4,4,4-trifluorobut-2-enoate (100 g, 0.6 mol) in DCM (1.8 L) was added dropwise TFA (20.52 g, 0.18 mol) at 0° C. and then N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (170.64 g, 0.72 mol) was added and the resulting mixture was stirred at rt overnight. The reaction mixture was washed with sat. aqueous NaHCO3 (two×500 mL), dried over Na2SO4 and concentrated in vacuo and the residue was purified by silica column chromatography eluted with petroleum ether/EtOAc=100:1 to give the title compound (142 g, 79% yield) as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:10]([C:17]1[C:18](O)=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20](OC)=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[N:4]1([C:1]2[O:3][C:18]3[C:17]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:26][CH:25]=[CH:24][C:19]=3[C:20](=[O:21])[CH:2]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(=O)N1CCOCC1
Reactant: COC(=O)c1cccc(Oc2ccccc2)c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=c1cc(N2CCOCC2)oc2c(Oc3ccccc3)cccc12
Yield: 27.8 %

Procedure:
Condensation of the lithium enolate of N-acetyl morpholine (0.21 g, 1.6 mmol) with methyl 3-phenoxy-2-hydroxybenzoate (0.25 g, 1.0 mmol) followed by cyclodehydration with trifluoromethanesulfonic anhydride (0.60 ml, 3.6 mmol) as described above yielded TGX-134 as an off-white solid (0.090 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:13]=1)=[C:8]([CH2:11]O)[O:9][CH:10]=2.O=S(Cl)Cl.[CH3:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([CH2:11][N:27]3[CH2:28][CH2:29][C:24]([CH2:23][C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:32][CH:31]=4)([OH:30])[CH2:25][CH2:26]3)[O:9][C:10]=2[CH:13]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: COc1ccc2coc(CO)c2c1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COc1ccc2cc(CN3CCC(O)(Cc4ccc(C)cc4)CC3)oc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
To a solution of 6-methoxy-2-benzofuranmethanol (89 mg, 0.5 mmol) in dioxan (3 ml) at room temperature was added dropwise SOCl2 (0.11 ml, 1.5 mmol). After 1.5 hr, the reaction mixture was concentrated at room temperature under high vacuum. The residue was dissolved in dioxan (3 ml) and treated with 4-(4-methyl-benzyl)-piperidin-4-ol (225 mg, 1.1 mmol). After stirring 17 hr at room temperature, the solvent was evaporated. The residue was taken up in H2O (4 ml) and extracted with CH2Cl2 (6×4 ml). The combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH (19:1) to provide 1-(6-methoxy-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (140 mg, 77%) as a yellow oil, MS:m/e=366.3 (M+H−+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:35][C:36]1[CH:41]=[C:40]([O:42][CH2:43][CH:44]=[CH2:45])[C:39]([Br:46])=[C:38]([O:47][CH2:48][CH:49]=[CH2:50])[CH:37]=1)[C@H:8]([CH2:23][O:24][Si](C(C)C)(C(C)C)C(C)C)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].N1C=CC=CC=1.F.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:4][C:5]([N:7]([CH2:35][C:36]1[CH:37]=[C:38]([O:47][CH2:48][CH:49]=[CH2:50])[C:39]([Br:46])=[C:40]([O:42][CH2:43][CH:44]=[CH2:45])[CH:41]=1)[C@H:8]([CH2:23][OH:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Oc1ccc(C[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)N(Cc2cc(OCC=C)c(Br)c(OCC=C)c2)C(=O)OCC=C)cc1
Agent: F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCOC(=O)Oc1ccc(C[C@@H](CO)N(Cc2cc(OCC=C)c(Br)c(OCC=C)c2)C(=O)OCC=C)cc1
Yield: 93.6 %

Procedure:
To 24 (1.15 g, 1.49 mmol, 1.0 equiv) in THF (20 mL) in a high density polyethylene vial was added hydrogen fluoride-pyridine (1 mL) once an hour for 4 hours (4 mL total), after which time saturated aqueous ammonium chloride was added and the THF was removed under reduced pressure. The remaining solution was extracted with CH2Cl2. The organics were combined, washed with brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20→60% EtOAc/hexane) afforded 25 (0.86 g, 94%) as a colorless oil. Rf=0.23 (50% EtOAc/hexane); [α]28D=−29.24° (c=1, CH2Cl2); FTIR (neat, cm−1) 3447, 2932, 1761, 1695, 1588, 1435, 1421, 1242; 1H NMR (400 MHz, DMSO, 80° C.) δ7.18-7.12 (m, 2H), 7.10-7.04 (m, 2H), 6.63 (s, 2H), 6.07-5.94 (m, 3H), 5.90-5.78 (m, 1H), 5.42 (dd, J=15.2, 2.0 Hz, 2H), 5.39 (dd, J=14.0, 1.6 Hz, 1H), 5.30 (dd, J=10.4, 1.6 Hz, 1H), 5.25 (dd, J=10.6, 1.8 Hz, 2H) 5.18 (d, J=16.8 Hz, 1H), 5.13 (d, J=10.4 Hz), 4.73-4.71 (m, 2H), 4.55-4.54 (m, 4H), 4.72 (d, J=4.0 Hz, 2H), 4.36 (d, J=16.0 Hz, 1H), 4.24 (d, J=16.4 Hz, 1H), 4.21-4.12 (m, 1H), 3.62-3.57 (m, 1H), 3.53-3.49 (m, 1H), 2.90-2.77 (m, 2H); 13C NMR (100 MHz, DMSO, 80° C.) δ155.3, 155.1, 152.2, 148.8, 140.1, 136.3, 132.9, 132.8, 131.5, 129.3, 120.1, 116.8, 116.6, 116.3, 105.8, 105.6, 99.1, 69.2, 69.0, 68.1, 64.7, 61.3, 60.5, 48.1, 34.3; HRMS (ES+) calculated for C30H34BrNO8 (M+H)+: 616.1468, found: 616.1570.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11]
Reactant: CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C(C)=O

Procedure:
Ethyl 2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (46 mg, 19%) in the same manner as described in the above example 6 (20) from ethyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.23 g, 0.67 mmol) and p-toluenesulfonic acid monohydrate (25 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[C:24]([Cl:36])[CH:23]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:24]1[CH:23]=[C:22]([NH:21][C:13]2[C:12]3[C:11]4[CH2:10][CH2:9][NH:8][CH2:20][C:19]=4[S:18][C:17]=3[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCNC4)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a 4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (3.6 g, 6.87 mmol) in DCM (45 mL) solution was added TFA (5.2 mL, 68.7 mmol, 10 equiv). The reaction mixture was stirred at rt for 8 h. The solution mixture was concentrated in vacuo. To the residue was added sat. NaHCO3 solution and stirred at rt for 1.5 h. The mixture was then filtered and washed with water. The damp solid was placed in a vacuum oven and dried for overnight to yield a yellow solid (2.0 g, 67%). 1H NMR (DMSO-d6) δ 9.41 (broad s, 2H), 8.71 (d, J=5.0 Hz, 1H), 8.40 (s, 1H), 8.11 (t, 1H), 7.75 (m, 2H), 7.57 (m, 1H), 7.53 (dd, J=2.7, 9.0 Hz, 1H), 7.25 (d, J=9.4 Hz, 1H), 5.35 (s, 2H), 4.48 (m, 2H), 3.49 (m, 2H), 3.41 (m, 2H); LCMS RT=2.11 min, [M+Na]+=446.1.
Reaction SMILES: N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][OH:20].[Br:22][C:23]1[CH:24]=[CH:25][C:26](O)=[N:27][C:28]=1[F:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])=[N:27][C:28]=1[F:29]
Reactant: Oc1ccc(Br)c(F)n1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(Br)c(F)n1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
(E)-Diisopropyl diazene-1,2-dicarboxylate (15.80 g, 78.13 mmol) was added drop wise to 3-(dimethylamino)propan-1-ol (8.06 g, 78.13 mmol), 5-bromo-6-fluoropyridin-2-ol (10 g, 52.09 mmol) and triphenylphosphine (20.49 g, 78.13 mmol) in DCM (150 mL) cooled to 0-5° C. under an inert atmosphere. The resulting solution was stirred at ambient temperature for 16 h then the solvent, removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and the solid removed by filtration and discarded. The filtrate was acidified with hydrogen chloride in dioxane. The solid was collected by filtration then dissolved in a sat. aqueous solution of Na2CO3 (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the desired material (9.00 g, 62.3%). NMR Spectrum: 1H NMR (300 MHz, CDCl3) δ 1.89-1.98 (2H, m), 2.26 (6H, s), 2.34 (2H, t), 4.30 (2H, t), 6.53 (1H, d), 7.74 (1H, t). Mass Spectrum: m/z (ES+)[M+H]+=277.