Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][CH2:12][C:13]2[C:14]3[O:22][CH:21]=[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32](=[O:42])[CH2:33][C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])[CH2:27][CH2:26]5)[C:15]=3[C:16]([NH2:19])=[N:17][CH:18]=2)C=CC=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.O1CCCC1>C(O)C.[Pd].O.CN(C)C=O>[NH2:10][CH2:11][CH2:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:42])[CH2:33][C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])[CH2:27][CH2:26]4)[C:15]=2[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: Nc1ncc(CCNC(=O)OCc2ccccc2)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cnc(N)c2c(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)coc12
Temperature: 50 °C
Reaction time: 19 h
Yield: 25.7 %

Procedure:
A suspension of phenylmethyl[2-(4-amino-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-7-yl)ethyl]carbamate (91 mg, 0.156 mmol) and Pd/C (10 wt. % dry basis), wet (ca. 50% water), Degussa type E101 NE/W (27 mg, 0.013 mmol) in Ethanol (1 mL) and Tetrahydrofuran (THF) (5 mL) was stirred under an atmosphere of hydrogen for 3 hours. LCMS showed no conversion, and it appeared that the starting material was not very soluble in the reaction mixture. Some N,N-Dimethylformamide (DMF) (2 mL) was added along with another portion of Pd/C (10 wt. % dry basis), wet (ca. 50% water), Degussa type E101 NE/W (65 mg, 0.031 mmol), and the mixture was stirred under an atmosphere of hydrogen for another 19 hours. LCMS showed a mixture of product and a byproduct. The mixture was filtered and the filtrate was concentrated in vacuo. An attempt was made to convert the byproduct to the desired product by taking the mixture up in MeOH (ca. 10 mL), adding 2 M HCl (ca. 1 mL), and stirring at room temperature for 5 hours. No reaction was observed, so it was heated to 50° C. for another 16 hours. HPLC still showed no conversion, so the mixture was concentrated in vacuo. The residue was taken up in MeOH (1.5 mL) and purified by reverse phase HPLC (Gilson, C18, 20% to 27% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were concentrated in vacuo and azeotroped with acetonitrile three times. The residue was then taken up in DCM and passed through a Varian PL-HCO3 MP-resin cartridge, rinsing with more DCM. The filtrate was then concentrated in vacuo and dried in the vacuum oven overnight to give the free base of 7-(2-aminoethyl)-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (18 mg, 24.41% yield) as a white solid. LC/MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 1.53 (br. s., 2H), 2.72-2.79 (m, 2H), 2.79-2.86 (m, 2H), 3.28 (t, J=8.34 Hz, 2H), 3.96 (s, 2H), 4.30 (t, J=8.59 Hz, 2H), 5.33 (s, 2H), 7.14-7.33 (m, 4H), 7.41 (s, 1H), 7.69 (s, 1H), 7.93 (s, 1H), 8.12 (d, J=8.34 Hz, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:25]=[C:26]([CH:34]=[C:35]([CH:37]([OH:42])[C:38]([F:41])([F:40])[F:39])[CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:23][C:24]1[CH:25]=[C:26]([CH:34]=[C:35]([C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])[CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(=O)C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Dess-Martin reagant (7.8 g, 18.6 mmol) was added to a solution of tert-Butyl 3-bromo-5-[(R/S)-2,2,2-trifluoro-1-hydroxyethyl]benzoate (4.4 g, 12.4 mmol) in DCM (75 mL). The reaction was stirred for one hour and saturated aq. Na2S2O3 and aq. NaHCO3 were added. The reaction was extracted with DCM (3×) and the organic layers combined and washed with brine, dried over Na2SO4 and concentrated to dryness. Purification using automated flash chromatography (SiO2, 120 g, 0-10% MeOH(NH4OH)/DCM) gave final compound as a mixture of hydrate and ketone which was used directly in step B.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([O:17][C@@H:18]([C@@H:20]2[CH2:24][C:23](=[O:25])[NH:22][CH2:21]2)[CH3:19])[C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1)(=O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.[Cl-].[Na+].O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:7]2[CH:8]=[C:9]([O:17][C@@H:18]([C@H:20]3[CH2:21][NH:22][C:23](=[O:25])[CH2:24]3)[CH3:19])[C:10]3[S:14][C:13]([CH3:15])=[N:12][C:11]=3[CH:16]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: Cc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(O[C@H](C)[C@H]3CNC(=O)C3)c2s1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3sc(C)nc3c2)cc1OC
Reaction time: 4 h

Procedure:
2-methyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)benzo[d]thiazol-5-yl trifluoromethanesulfonate (4.06) (32 mg, 0.075 mmol), 3,4-dimethoxyphenylboronic acid (27 mg, 0.15 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.5 mg, 0.002 mmol), and potassium phosphate (53 mg, 0.25 mmol) were taken up in 1,4-dioxane (1 mL) and water (0.11 mL). The stirred mixture was heated to 100 deg. C. After 4 h, the reaction mixture was diluted with EtOAc (2 mL), water (1 mL), and brine (1 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-15% MeOH in DCM) to provide (R)-4-((R)-1-(5-(3,4-dimethoxyphenyl)-2-methylbenzo[d]thiazol-7-yloxy)ethyl)pyrrolidin-2-one (4.29). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H25N2O4S: 413.2; found: 413.1. 1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=1.3 Hz, 1H), 7.18-7.12 (m, 2H), 6.98-6.94 (m, 2H), 6.02 (s, 1H), 4.68-4.59 (m, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.58-3.50 (m, 1H), 3.35 (dd, J=9.6, 6.6 Hz, 1H), 2.94-2.84 (m, 1H), 2.83 (s, 3H), 2.59-2.43 (m, 2H), 1.41 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:22]=[CH:21][C:11]([CH2:12][NH:13][C:14](=O)OC(C)(C)C)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.F[C:40]1[CH:41]=[C:42]([CH:52]=C[C:54]=1[N+:55]([O-:57])=[O:56])[O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1>C(Cl)Cl.O.CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]3[CH:52]=[C:42]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=4)[CH:41]=[CH:40][C:54]=3[N+:55]([O-:57])=[O:56])=[CH:21][CH:22]=2)=[N:4][CH:3]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ncc(Cl)cn2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(-c4ncc(Cl)cn4)cc3)c2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl 4-(5-chloropyrimidin-2-yl)benzylcarbamate (355 mg, 1.11 mmol) in DCM (10 mL) was added TFA (1 mL). The reaction mixture was stirred for 5 h at RT and concentrated to dryness. To the resulting residue was added DMA (3 mL), DIPEA (0.57 mL) and 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (0.29 g, 1.11 mmol). The mixture and heated to 80° Celsius for 6 h. The mixture was then poured into water and the solids were collected by filtration to provide of the title compound (475 mg). 1H NMR (400 MHz, CDCl3) δ 8.77-8.72 (s, 2H), 8.41-8.32 (m, 2H), 8.21-8.13 (d, J=9.5, 1H), 7.49-7.39 (m, 3H), 7.26-7.21 (m, 3H), 6.38-6.30 (dd, J=9.5, 2.5, 1H), 6.27-6.21 (d, J=2.5, 1H), 5.14-5.09 (s, 2H), 4.60-4.53 (d, J=5.8, 2H), 2.30-2.25 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]2[C:23](=[O:24])[N:22]([C:25]([CH:35]([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26](=[O:28])[NH2:27])[C:21]3[CH:38]=[CH:39][CH:40]=[CH:41][C:20]=3[C:19]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[N:18]2)=[O:15])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:35]([C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:26](=[O:28])[NH2:27])[N:22]1[C:21]2[CH:38]=[CH:39][CH:40]=[CH:41][C:20]=2[C:19]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[N:18][CH:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:48])=[O:5])[C:23]1=[O:24])([CH3:37])[CH3:36]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)N=C(c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A solution of 3-{3-[1-(Isopropyl-phenyl-carbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-ureido}-benzoic acid tert-butyl ester (145 mg, 0.225 mmol), prepared as in Example 5A, in anhydrous DCM (2 mL) at 0-5--C. under nitrogen is treated with triflouroacetic acid (2 mL). After stirring for 2 hrs., the reaction mixture is concentrated in vacuo and triturated with anhydrous ether. The resulting slurry is filtered and the product dried overnight under high vacuum at ambient temperature to provide the title compound as a crystalline solid (80 mg, 0.136 mmol). 1H NMR (300 MHz, d6-DMSO) δ=0.96 (d, J=6.8 Hz, 6H); 4.12 (d, J=16.6 Hz, 1H); 4.23 (d, J=16.6 Hz, 1H); 4.71-6.76 (m, 1H); 5.18-5.27 (m, 1H); 7.24-7.70 (m, 19H); 8.02 (b, 1H); 9.22 (b, 1H). MS (FAB): [M+H]+ =590.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]([O:36]CC)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:13]=2[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH3:20])[N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]([OH:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:13]=2[CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nc2ccc(NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nc2ccc(NCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C

Procedure:
1.30 g (2.5 mmol) of ethyl 4'-[(6-benzylamino-2-n-butylbenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate are dissolved in 20 ml of ethanol, treated with 20 ml of 2N sodium hydroxide and heated at reflux for 2 hours. After cooling to ambient temperature, the solution is diluted to 500 ml using water and acidified to pH 5 using glacial acetic acid. The precipitate thus obtained is filtered off once again under suction, suspended in acetone, filtered off once again under suction and dried at 90° C. in vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[CH:14]([O:13][C:12](=[O:22])[NH:11][C:8]1([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[CH2:10][CH2:9]1)[CH2:15]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(NC1(c2ccc(Br)cc2)CC1)OC1CN2CCC1CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(-c2ccc(C3(NC(=O)OC4CN5CCC4CC5)CC3)cc2)cc1
Yield: 0.1 %

Procedure:
Using general procedure E, quinuclidin-3-yl 1-(4-bromophenyl)cyclopropylcarbamate (0.485 g, 1.33 mmol), 4-methoxyphenyl boronic acid (0.404 g, 2.66 mmol) and Pd(OAc)2 (0.016 g, 0.071 mmol) gave the title compound as a grey solid (0.337 mg, 65%). 1H NMR (CDCl3) δ 7.48 (dd, J=8.6, 5.5 Hz, 4H), 7.29 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.58 (d, J=48.7 Hz, 1H), 4.83-4.63 (m, 1H), 3.84 (s, 3H), 3.20 (dd, J=24.0, 15.5 Hz, 1H), 2.97-2.42 (m, 5H), 1.97 (d, J=30.9 Hz, 1H), 1.81 (s, 1H), 1.75-1.33 (m, 3H), 1.28 (d, J=6.8 Hz, 4H) ppm. 13C NMR major rotomer (CDCl3) δ 159.1, 156.0, 141.4, 139.0, 133.4, 128.0, 126.7, 125.9, 114.2, 71.5, 55.7, 55.3, 47.4, 46.5, 35.3, 25.5, 24.6, 19.6, 17.8 ppm. Purity: LCMS>97.1% (214 nm & 254 nm); retention time 0.88 min; (M+1) 393.4.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:34])[C:19]3[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O.[Pt]=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:34])[C:19]3[CH:24]=[C:23]([C:25]([CH3:27])([CH3:28])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=3)[C:10]=2[C:9]2[NH:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)NCCC3
Yield: 50.5 %

Procedure:
A solution of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide (0.1 g, 0.19 mmol) in trifluoroacetic acid (15 mL) and platinum oxide (0.1 g) were combined and hydrogenated overnight on a Parr apparatus. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane. The dichloromethane solution was washed twice with 10% sodium hydroxide and with brine, dried and then concentrated under vacuum to provide crude product. This material was purified by chromatography eluting with 10% methanol in dichloromethane. The resulting oil was triturated with acetonitrile to provide 0.05 g of N1-[2-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 208-210° C. Analysis: Calculated for C30H44N6O2+0.1 CF3CO2H: %C, 68.17; %H, 8.35; %N, 15.79. Found: %C, 68.48; %H, 8.29; %N, 16.08.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:29])[NH:13][C:14]2[CH:26]=[C:25]([Cl:27])[C:17]([O:18][CH2:19][CH2:20][O:21]C(=O)C)=[C:16]([Cl:28])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:25]1[CH:26]=[C:14]([NH:13][C:12](=[S:29])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:15]=[C:16]([Cl:28])[C:17]=1[O:18][CH2:19][CH2:20][OH:21]
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOC(C)=O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCO)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethyl ester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL) is added 1N aqueous sodium hydroxide (1 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid(3 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(CC)CC>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH:19][C:21]3[N:29]=[C:28]([NH2:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])=[C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 6-chloro-9H-purin-2-amine (65.1 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (38 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.52 (m, 4 H), 2.68-2.86 (m, 3 H), 3.01-3.18 (m, 3 H), 3.69-3.95 (m, 9 H), 5.62-5.82 (m, 2 H), 5.88-6.08 (m, 1 H), 6.46-6.59 (m, 2 H), 6.74-6.92 (m, 1 H), 7.52-7.59 (m, 1 H), 7.59-7.74 (m, 1 H), 7.76-7.90 (m, 1 H), 12.00-12.22 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394. found 394.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C=O)C.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18].C(Cl)CCl>C(OCC)C.C1COCC1>[C:21]([O:20][C:16]([NH:17][NH:18][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-fluorobenzoic acid (35.7 mmol) in 72 mL of a mixture of DMF and THF (1:1), is added tert-butyl carbazate (37.5 mmol), EDC (39.3 mmol) and N,N-dimethylaminopyridine (0.54 mmol). After 10 minutes the mixture becomes homogeneous and stirring is continued for 3 hours until the reaction is complete by TLC and LC/MS. The reaction mixture is poured into ice. Upon addition of diethylether the organic layer is separated. The organic layer is washed with sodium bisulfite, saturated sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to yield N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester: MS: (ES+) 255 (M+1)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:37]([N:36]([CH3:40])[CH3:35])=[O:38])[CH2:25][CH2:26]2)[CH2:15][CH2:14]1
Reactant: COc1ccc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(Cl)c1Cl
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(CC[C@H]3CC[C@H](NC(=O)N(C)C)CC3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.92 g (2 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (60 ml), triethylamine (1.26 ml, 9 mmol) was added followed by 0.21 ml (2.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature. The solution was washed with water (2×10 ml), dried and evaporated in vacuo. Purification with flash chromatography gave 0.66 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, melting at 196-8° C. This product was dissolved in dichloromethane (60 ml), then 6.4 ml (6.4 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added, followed by 25 ml saturated NaHCO3 solution. After separation the organic layer was dried and evaporated in vacuo. Purification with flash chromatography gave 0.4 g of the title compound, melting at 278-80° C.
Reaction SMILES: N.C[N:3](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:44]=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:42]([O:50][CH:51]([CH3:53])[CH3:52])=[CH:41][C:36]=3[C:37]=2[C:38](O)=[O:39])=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:44]=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:42]([O:50][CH:51]([CH3:53])[CH3:52])=[CH:41][C:36]=3[C:37]=2[C:38]([NH2:3])=[O:39])=[CH:29][CH:28]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(C(N)=O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Ammonia (6.1 ml, 12.2 mmol, 2M in MeOH) was added to a stirring solution of HATU (1.1 g, 2.95 mmol) and 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1.0 g, 2.46 mmol) in DMF (20 ml) at 0° C. It was allowed to warm to rt and stir for 1 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (925 mg, 93%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30-1.37 (m, 6H) 2.98 (s, 3H) 4.64-4.77 (m, 1H) 7.19 (s, 1H) 7.30-7.41 (m, 2H) 7.54 (s, 1H) 7.63-7.71 (m, 1H) 7.89 (s, 1H) 7.93-8.02 (m, 2H) 8.85 (s, 1H). LC-MS retention time: 1.26 min; m/z (MH+) 407. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[S:9][CH:10]=1)C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1csc(-c2ccc(Cl)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCc1csc(-c2ccc(Cl)cc2)n1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
Dissolve [2-(4-chloro-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (107.4 g, 381.2 mmol) in THF (800 mL) and cool to 0-5° C. Add DIBAL (1.0 M in THF, 800 mL, 800 mmol) slowly over approximately 3.5 h (somewhat exothermic) keeping the temp. <5° C. Allow the reaction to warm to room temperature with mechanical stirring overnight. Cool the reaction to 0-5° C. and slowly add more DIBAL (150 mL) over approximately 15 min keeping the temperature <5° C. Stir the reaction solution at room temperature for 2.5 b. Cool to 0-5° C. and slowly add over 5 h aqueous saturated Rochelle's salt (2900 mL, very exothermic at first, minor gas evolution) keeping the temperature <10° C. The mixture solidifies after approximately 150 mL has been added. It becomes more fluid and then solidifies again as the addition continues. Extract the mixture with EtOAc (2×3300 mL). Combine the organic layers and concentrate in vacuo to give an oil weighing 112.9 g. Take the oil up in toluene (600 mL), concentrate in vacuo and repeat. Dry the residue on a vacuum pump for 6 h to give a residue weighing 107.4 g (110% yield). MS (ES+) 240.1 (M)+. 1H NMR (400 MHz, CDCl3): δ 7.84 (dt, J=8.4, 2.2 Hz, 2H), 7.39 (dt, J=8.4, 2.2 Hz, 2H), 6.98 (s, 1H), 3.98 (m, 2H), 3.44 (bs, 1H), 3.02 (t, J=5.5 Hz, 2H).