Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:33])[F:34])[CH:18]=2)[CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Yield: 66.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-(trifluoromethyl)phenylamino)benzamide was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.220 g; 0.951 mmol), 3-(3-(trifluoromethyl)phenylamino)benzoic acid (0.294 g; 1.05 mmol), HATU (0.470 g; 1.24 mmol) and N,N-diisopropylethylamine (0.439 mL; 2.38 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.290 g (65%) of the title compound as a white solid.
Reaction SMILES: ClC(Cl)(Cl)F.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:12]F.[F:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17].[Na+]>C(#N)C>[F:14][C:15]([F:21])([F:20])[S:16]([O-:19])(=[O:18])=[O:17].[F:12][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccncc1
Reactant: FF
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: FC(Cl)(Cl)Cl
Product: F[n+]1ccccc1
Temperature: -40 °C

Procedure:
To a 50 ml trichlorofluoromethane solution containing 1.0 g (12.6 m moles) of pyridine a mixed gas of fluorine and nitrogen in a volumetric ratio of 1:9 was introduced at a rate of 30 ml/min. at -78° C. under vigorous stirring. The amount of the fluorine gas introduced amounted to 34.8 mmoles. Subsequent to the fluorine introduction, 20 ml of anhydrous acetonitrile and 2.2 g (12.8 mmoles) of sodium trifluoro-methanesulfonate as a XM reactant were added to the reaction solution after which the temperature of the solution was raised to -40° C., while removing the solvent with the aid of an aspirator. The solvent, after filtering sodium fluoride formed as a byproduct, was distilled off and the resultant residue was recrystallized from THF to give 1.75 g (yield: 67%) of N-fluoropyridinium trifluoromethanesulfonate, the physical properties of which are shown in Table 6.
Reaction SMILES: [CH2:1]([N:5]1[CH:9](P(=O)(OCC)OCC)[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[Cl-].[Li+].C1CCN2C(=NCCC2)CC1.[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39]([CH:42]=O)=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]>C(#N)C>[CH2:33]([C:37]1[N:38]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][C:46]=2[Cl:55])[C:39](/[CH:42]=[C:9]2\[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:19])[NH:7][C:8]\2=[O:18])=[CH:40][N:41]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1Cl
Reactant: CCCCN1C(=O)NC(=O)C1P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCc1ncc(/C=C2/C(=O)NC(=O)N2CCCC)n1Cc1ccc(C(=O)OC)cc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-butyl-2,5-dioxo-4-imidazolylphosphonate (0.49 g, 1.72 mmol) in acetonitrile (5 mL) was added lithium chloride (0.15 3.47 mmol) and then DBU (0.52 mL, 3.47 mmol). This mixture was stirred for 5 minutes under N2. Methyl 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-3-chlorobenzoate (0.48 g, 1.43 mmol) in acetonitrile (5 mL) was added and the mixture stirred for 4 days. The solvent was removed in vacuo and the isomers separated by chromatography eluting with (1-5)% methanol in chloroform.
Reaction SMILES: [CH:1]([N:4]([CH2:8]C)C(C)C)(C)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].[O:23]=[C:24]1[NH:33][CH:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=2[CH3:42])[C:31]2[C:30](=[O:43])[CH2:29][CH2:28][CH2:27][C:26]=2[N:25]1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=1.CN>CN(C)C1C=CN=CC=1.C(#N)C>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([CH:32]2[C:31]3[C:30](=[O:43])[CH2:29][CH2:28][CH2:27][C:26]=3[N:25]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:51])[F:52])[CH:45]=3)[C:24](=[O:23])[N:33]2[C:8]([NH:4][CH3:1])=[O:12])=[C:35]([CH3:42])[CH:36]=1)#[N:39]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C
Temperature: 25 °C

Procedure:
N,N-Diisopropylethylamine (88 μL, 0.51 mmol), 4-dimethylaminopyridine (48 mg, 0.39 mmol) and 4-nitrophenyl chloroformate (78 mg, 0.39 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-methylbenzonitrile (example 55, 55 mg, 0.13 mmol) in acetonitrile (1.5 mL), and the mixture is stirred at room temperature over night. Methylamine (2 M in tetrahydrofuran, 97 μL, 0.19 mmol) is added, and the mixture is stirred at room temperature over night and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 35 mg; ESI mass spectrum [M+H]+=483; Retention time HPLC: 0.74 min (X012_S01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:19][CH:18]=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:33][CH:34]=1)=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reaction time: 12 h
Yield: 90.3 %

Procedure:
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2Cl2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH2Cl2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1N HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure to afford N-(2-methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 1H NMR (DMSO-d6) δ3.95 (s,3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M+H)+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][N:28]2C(=O)C3C(=CC=CC=3)C2=O)[N:23]=[C:22]1[C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:28][CH2:27][CH2:26][C:24]1[N:23]=[C:22]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:21]([CH:17]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=2)[CH:18]([CH3:20])[CH3:19])[CH:25]=1
Reactant: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc(CCN)cn2C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To 2-(2-{1-[1-(1-Benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-yl}-ethyl)-isoindole-1,3-dione (0.371 g, 0.619 mmol) in EtOH (14 mL) was added hydrazine monohydrate (0.138 g, 2.48 mmol) and the reaction was stirred at room temperature for 72 h. The reaction was filtered and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (90:9:1 CH2Cl2:MeOH:NH4OH) to give the title compound as a white solid (0.209 g, 72%). MS(ES)+m/e 470 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:19][N:20]([CH3:25])[S:21]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.4 %

Procedure:
To 6.8 g (0.04 mole) 2-hydroxybenzenesulfonamide in 100 ml methylene chloride was added 4.4 g (0.044 mole) triethylamine and 6.3 g (0.044 mole) dimethylsulfamoyl chloride in 5 ml methylene chloride, keeping the reaction temperature <10° C. The mixture was then warmed to room temperature and stirred 72 hours. The reaction mixture was then diluted with 100 ml methylene chloride washed with 100 ml water, 100 ml 1% HCl and dried over MgSO4. The solvent was evaporated to give a crude yellow oil that slowly solidified on standing. The solids were then triturated with hexanes and filtered to give 6.1 g of a tan solid, m.p. 88°-89° C.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1[O:25][C@@H:24]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([OH:34])[CH3:33].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:32]([O:25][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:23][N:20]1[CH2:19][CH2:18][C:17]([CH2:16][CH2:15][O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH2:21]1)(=[O:34])[CH3:33]
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: C1=C(CCOC(c2ccccc2)c2ccccc2)CCNC1
Reactant: CCO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CN1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1)c1ccccc1

Procedure:
With reference to FIG. 8, 4-(2-(benzhydryloxy)ethyl)-1,2,3,6-tetrahydropyridine 5 (0.5 g, 1.704 mmol), R-styrene oxide 6a (0.205 g, 1.704 mmol), ethanol (20 ml). Yield (after purification)=0.7 g. For acetylation, the mixture of regioisomers (0.7 g, 1.693 mmol), pyridine (10 ml) and acetic anhydride (0.208 ml, 2.2 mmol, 1.3 equiv). Yield (after purification)=0.26 g. 1H-NMR (CDCl3; 400 MHz): 2.03-2.07 (brs, 5H, H-3, COCH3), 2.31-2.34 (t, 2H, J=6.4 Hz, OCH2CH2), 2.54-2.71 (m, 3H, H-2, NCHHCHOAc), 2.91-2.97 (dd, 1H, J=8.8 Hz, NCHHCHOAc), 3.04 (brs, 2H, H-6), 3.51-3.54 (t, 2H, OCH2CH2), 5.34 (s, 1H, PhCH(O)Ph), 5.39 (brs, 1H, CH═C), 5.95-5.98 (dd, 1H, CHOAc), 7.03-7.34 (m, 15H, ArH). [a]25D=−20.22° (c=1.05, CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[NH:11][C:12](=[O:30])[C@H:13]([CH:27]([CH3:29])[CH3:28])[NH:14][C:15](=[O:26])[C@H:16]([CH3:25])NC(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[NH:54]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C@H:55]([C:60](OC1C=CC([N+]([O-])=O)=CC=1)=[O:61])[CH2:56][CH2:57][S:58][CH3:59].CC[N:81](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[NH:11][C:12](=[O:30])[C@H:13]([CH:27]([CH3:28])[CH3:29])[NH:14][C:15](=[O:26])[C@H:16]([CH3:25])[NH:81][C:60](=[O:61])[C@H:55]([CH2:56][CH2:57][S:58][CH3:59])[NH:54][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Reaction time: 4 h

Procedure:
Partial deprotection of compound XXI (3.4 g, 5.3 mmole) was carried out as described in the previous paragraph. The trifluoroacetate salt (RfC, 0.75) was acylated in DMF (50 ml) with Boc-L-Met-ONp (2.18 g, 5.9 mmole, Bachem) in the presence of DIEA (1.9 ml, 12 mmole) and HOBt (0.9 g, 5.9 mmole). After 4 hr at room temperature the reaction was complete. Evaporation of most of the solvent in vacuo was followed by trituration with EtOAc. The precipitate was washed with EtOAc, with ether and dried: 3.8 g (93%); m.p. 169°-171° C., [α]D24 -21.5° (c 1.2, DMF) RfK, 0.65; RfI, 0.52.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C([O-])(=O)C.[Na+].O.Br[CH:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH:18]=O>CO>[CH3:31][O:30][C:28](=[O:29])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:17]2[C:5]3[C:4](=[O:9])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:18]=2)=[CH:23][CH:24]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: COC(=O)c1ccc(CCC(Br)C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To 1.69 g (13.4 mmol) of 2,4-diamino-6-hydroxypyrimidine, 2.20 g (26.8 mmol) of sodium acetate and 20 ml of water at 80° C. were added 3.82 g (13.4 mmol) of 2-bromo-4-(4-carbomethoxyphenyl)butanal, prepared in Preparation 2, in 7 ml of methanol over 5 minutes. The mixture was maintained at 80° C. for 5 minutes, cooled to room temperature and stirred for 30 minutes. The mixture was filtered, washed with water, and dried for 18 hours at 50° C. @ 10 torr to provide 3.32 g of 4-(2-[2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoic acid methyl ester (m.p.>220° C.) in a yield of 79.4 percent. The remaining filtrate was cooled to 5° C. and filtered to provide an additional 0.069 g of the above product, for a combined yield of 81 percent. 1H NMR (DMSO-d6) δ 2.80 (m, 2H), 2.93 (m, 2H), 3.78 (s, 3H), 5.97 (s, 2H), 6.26 (d, J=2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 10.12 (s, 1H), 10.58 (s, 1H); FDMS 312 (M+), Anal. for C16H16N4O3, Calcd: C, 61.53; H, 5.16; N, 17.94; Found: C, 61.79; H, 5.33; N, 17.66.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26].B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26]
Reactant: Oc1c(Cl)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Oc1ccc(-n2ncc3c(O)c(Cl)ccc32)cc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
A solution of 5-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D24) (0.072 g, 0.2 mmol) in dichloromethane (4 mL) was cooled to −78° C. and boron tribromide (0.4 mL of 1M solution in dichloromethane, 0.4 mmol) was added dropwise over 5 mins. After stirring at −78° C. for 3 hrs under argon, methanol (1 mL) was added and the mixture was diluted with dichloromethane (30 mL) and water (30 mL). The pH was adjusted to 7 with NaHCO3 solution and the aqueous layer was separated and extracted with ethyl acetate (35 mL×2). The combined extracts were washed with brine (25 mL), and evaporated. The product was purified by MDAP to give the title compound (E12) as a white solid (0.022 g).
Reaction SMILES: [C:1]([C:3]1([NH:28][C:29](=[O:47])[CH:30]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:7][CH2:6][N:5]([CH2:8]C2C3C(=CC=CC=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)[CH2:4]1)#[N:2].[NH4+:48].[Cl-]>CO>[C:1]([C:3]1([NH:28][C:29](=[O:47])[CH:30]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:31][C:32]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:30]2[NH:48][C:42]3[C:41]([CH:40]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:4]1)#[N:2]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCC(C#N)(NC(=O)C(CC(=O)N4CCOCC4)CC4CCCCC4)C3)c3ccccc32)cc1
Agent: [Cl-]
Solvent: CO
Product: N#CC1(NC(=O)C(CC(=O)N2CCOCC2)CC2CCCCC2)CCN(Cc2cc3ccccc3[nH]2)C1
Yield: 76 %

Procedure:
A suspension of N-{3-cyano-1-[1-(toluene-4-sulfonyl)-1H-indole-3-ylmethyl]-pyrrolidin-3-yl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide (0.052 g, 0.079 mmol) and Mg (powder) (0.038 g, 1.6 mmol) in MeOH (5 mL) was sonicated at room temperature reaction was monitored by MS. When completed, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated to provide the title compound in 76% yield. The compound was recrystallized from Et2O/hexanes. 1H NMR (CDCl3) 8.1 (1H, s), 7.71-7.69 (1H, m), 7.39-7.37 (1H, m), 7.25-7.15 (3H, m), 6.9 (1H, s), 4.0-3.8 (2H, m), 3.7-3.3 (11H, m), 3.2-3.1 (1H, m), 3.0-2.5 (3H, m), 2.3-2.15 (2H, m), 1.8-1.4 (5H, m), 1.35-1.03 (5H, m), 0.95-0.78 (3H,m). MS, m/z 506=M+1.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[OH:27])=[N+:2]=[N-:3].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a solution of phenyl 3-azido-4-O-benzoyl-3,6di-deoxy-1-thio-β-L-galactopyranoside (β-18) (118 mg, 0.307 mmol) in 5 mL of CH2C2 is added TEA (256 μL, 1.87 mmol), pivaloyl chloride (114 μL, 0.921 mmol) and DMAP (19 mg, 0.154 mmol). The reaction mixture is stirred at room temperature for 12 h, diluted with 15 mL of CH2Cl2, washed with 1M HCl (2×10 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (20% EtOAc/petroleum ether) to give 114 mg (80%) of phenyl 3-azido-4-O-benzoyl-3,6-di-deoxy-2-O-pivaloyl-1-thio-β-L-galactopyranoside (β-19): Rf 0.54 (20% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.93 (d, 2H, ArH), 7.59-7.56 (m, 3H, ArH), 7.46-7.26 (m, 5H, ArH), 5.53 (d, J=2.6 Hz, 1H, H-4), 5.25 (t, J=9.9 Hz, 1H, H-2) 4.73 (d, J=9.9 Hz, 1H, H-1), 3.92 (q, J=6.3 Hz, 1H, H-5), 3.79 (dd, J=2.6, 9.9 Hz, 1H, H-3), 1.42-1.21 (m, 12H, H-6, CH3); 13C NMR (CDCl3, 68 MHz) δ 176.8, 165.9, 133.8, 133.7, 131.8, 130.2, 129.0, 128.9, 128.6, 128.4, 86.1, 74.4, 71.6, 68.3, 63.9, 39.1, 27.3, 16.9; FAMS C24H27O5N3 (MNa+) calcd 492.1569, found 492.1579.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH2:1]([N:8]1[C:9](=[O:12])[S:10][N:21]([CH:18]([CH3:20])[CH3:19])[C:22]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N=C=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: S=C=NCc1ccccc1
Agent: Cl
Agent: [K+]
Product: CC(C)n1sc(=O)n(Cc2ccccc2)c1=O

Procedure:
Reagents: Benzyl isothiocyanate (0.81 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), isopropyl isocyanate (0.64 ml, 6.5 mmol).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCCl
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCNCC2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OCCCN1CCN(c2cc(C3CC3)nc(C(C)(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2.9 g of 2-tert-Butyl-4-piperazin-1-yl-6-cyclopropyl-pyrimidine (11.1 mmol), 1.8 g acetic acid 3-chloro-propyl ester (13.2 mmol), 1.38 g of triethylamine (13.7 mmol), and a spatula tip of sodium iodide were dissolved in 50 ml of dimethylformamide and stirred for 8 h at 80° C. After cooling to room temperature, the dimethylformamide was evaporated. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product (3.7 g) was directly used in the subsequent reaction step.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[NH2:30][CH2:31][CH2:32][OH:33]>>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([NH:30][CH2:31][CH2:32][OH:33])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: NCCO
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2NCCO)cc1F
Yield: 24 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methane sulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) was reacted with 2-aminoethanol (excess) to give the title compound (10 mg, 24%).