Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH2:55][CH3:56])(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:57](Cl)(Cl)=[O:58]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH2:55][CH3:56])(=[O:54])=[O:53])[NH:1][C:57](=[O:58])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN(C)C(=O)C(Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1)c1ccc([C@@H](C)CO)c(C)c1
Solvent: ClCCl
Solvent: CC#N
Product: CCS(=O)(=O)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 31.9 %

Procedure:
To a solution of 3D (303 mg, 0.382 mmol) in acetonitrile (7 mL) and dichloromethane (4 mL) at 0° C., was added phosgene solution (20% in toluene) (0.241 mL, 0.458 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min while extra phosgene was removed by bubbling Ar. The resulting solution was added dropwise via syringe pump into a solution of TEA (0.426 mL, 3.05 mmol) in dichloromethane (120 mL) at rt over 3.0 h. The solution was stirred at rt for additional 45 min. Solvent was removed and the crude was purified by prep HPLC to give a mixture of diastereoisomer (237 mg). The diastereoisomers were separated by chiral HPLC ((R,R)-Whelk-01 250×21.1 mm column) to give 3E (100 mg, 63.9% yield). MS (ESI) m/z: 820 [M+1]+; 1H NMR (400 MHz, chloroform-d) δ ppm 1.29-1.41 (m, 24H) 2.21 (s, 3H) 3.18-3.33 (m, 2H) 3.33-3.39 (m, 3H) 3.38-3.48 (m, 1H) 3.95 (dd, J=10.77, 4.17 Hz, 1H) 4.28 (d, J=17.58 Hz, 1H) 4.67 (t, J=11.21 Hz, 1H) 5.43 (d, J=5.71 Hz, 1H) 5.65 (d, J=17.58 Hz, 1H) 6.39-6.48 (m, 2H) 6.63 (s, 1H) 6.76 (d, J=8.35 Hz, 1H) 6.85 (s, 1H) 7.03 (d, J=9.23 Hz, 1H) 7.08 (s, 1H) 7.50 (d, J=7.91 Hz, 1H) 7.56-7.65 (m, 2H) 7.85 (d, J=8.35 Hz, 1H) 8.05 (s, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −141.30 (br. s., 1F).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[NH2:10][C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O.C(Cl)(Cl)Cl>[N:10]([C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(N=C=S)sc(C)c1C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a mixture of thiophosgene (5.10 mL, 7.64 mmol) and calcium carbonate (1.05 g, 10.54 mmol) in CHCl3/H2O (½ by volume, 6 mL) was added dropwise a solution of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (1.05 g, 5.27 mmol) in CHCl3 (7 mL) at 0° C. over a period of 1 h. The reaction mixture was the stirred for 2.5 h at 0° C., washed with water (3×). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (1.21 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ1.32 (t, 3H, J=7.1 Hz), 2.19 (s, 3H), 2.30 (s, 3H), 4.28 (q, 2H, J=7.1 Hz).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@@H:20](O)[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].CN(C=O)C.S(Cl)([Cl:33])=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([Cl:33])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1[C@H]2C[C@H](Cl)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of the title compound of Example 1, Step G (3.3 g, 8 mmol) in 25 mL toluene and 0.02 g DMF was added at 80° C. thionyl chloride (1.31 g, 11 mmol) over a period of 15 minutes. The suspension was stirred at the same temperature for 2 h and at 105° C. for 30 minutes. After cooling to room temperature, the organic layer was washed with water, dried, and the solvent was evaporated under reduced pressure to yield the title compound of Step A, a compound of this invention, in quantitative yield as a crude powdery product melting at 169-170° C. 1H NMR (CDCl3) δ 7.64 (d, 1H), 7.36 (d, 1H), 7.20 (br s, 1H), 4.78 (m, 2H), 4.56 (s, 2H), 4.24 (dd, 1H), 3.62 (dd, 1H), 2.62 (m, 1H), 2.38 (m, 1H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[O:12]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C>[O:6]=[C:5]1[C:7](=[CH:23][C:22]2[CH:25]=[CH:26][C:19]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=2)[S:1][C:2](=[S:3])[N:4]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)CN1C(=O)C(=Cc2ccc(Oc3ccccc3)cc2)SC1=S

Procedure:
To a solution of rhodanine-3-acetic acid (1.00 g) in acetonitrile (20 ml) were added 4-phenoxybenzaldehyde (1.14) and triethylamine (1.06 g), and the mixture was heated with reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to give [4-oxo-5-(4-phenoxybenzylidene)-2-thioxo-thiazolidin-3-yl]acetic acid (1.20 g).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17](O)=[O:18])[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:33]([NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH3:34])=[O:18])[N:6]=1)=[O:4]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCNCC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC(C)(C)C)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 44 °C

Procedure:
Weigh 8.7 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid, 7.7 mg HOBt, and 11.5 mg EDC into a 13×100 mm screw cap tube. Add 7.6 mg N-ethyl-2,2-dimethylpropan-1-amine hydrochloride followed by 0.5 mL DMF and 13.6 mg DIEA in that order. The mixture was stirred at 44° C. over night and purified by RP-HPLC using 50-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.04 min. (m/Z=388.3, 410.3).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:16]1[CH2:20][CH2:19][CH2:18][S:17]1>C1C=CC=CC=1>[S:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]=1[OH:14]
Reactant: ClC1CCCS1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: c1ccccc1
Product: O=C1CC(c2ccccc2)CC(O)=C1C1CCCS1
Temperature: 25 °C

Procedure:
A mixture of 4.0 parts of 5-phenyl-1,3-cyclohexanedione and 120 parts by volume of a 5% benzene solution of 2-chlorotetrahydrothiphene was refluxed by heating while stirring. After cooling to room temperature, the reaction mixture was washed with 40 parts by volume of water and then treated three times with 30 parts by volume of a 5% aqueous solution of sodium hydroxide. The aqueous layer was collected and washed with 30 parts by volume of ether. While maintaining the temperature of the solution below 10° C., the pH of the solution was controlled between 4 and 5 with the addition of 6 N hydrochloric acid. The light orange colored crystals thus deposited were collected and purified by passing through a column containing a silica gel using a solvent mixture of chloroform and benzene (5:1) as a spreading agent to obtain 2-(2-tetrahydrothienyl)-3-hydroxy-5-phenyl-2-cyclohexen-1-one in a form of colorless fine crystals. The melting point was 141° to 142° C. The yield was 2.4 parts.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>C(O)C>[CH3:18][N:19]1[CH2:20][CH:21]=[C:22]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:23][CH2:24]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 74.5 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (5 mL) was treated with pyrrolidine (0.77 mL, 9.250 mmol), N-methyl-4-piperidone (0.75 mL, 6.167 mmol) at room temperature. The resulting solution was refluxed for 2 days. The reaction was brought to room temperature, the solid was filtered off, washed with ethanol (2×5 mL) and dried to obtain compound (39) (0.591 g, 75%). Solid decomposed at 215° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.50-2.59 (m, 4H), 3.06-3.08 (m, 2H), 6.17 (br s, 1H), 7.55 (d, 1H, J=9.0 Hz), 7.66 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.68 (d, 1H, J=2.1 Hz), 11.86 (brs, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)C(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.25 g of product from Example 25, 0.881 g of product from Example 12, 0.282 g of 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at 0° C. for 1 hour, room temperature for 18 hours and at reflux temperature for 6 hours. The residue is purified by column chromatography (silica gel: 90% ethyl acetate/hexane) to give 1.57 g of product as pale yellow crystals. Spectral data shows the product as 2 rotomers.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH2:49])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9].C1([O:56][C:57](=O)[NH:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=2)C=CC=CC=1>CO>[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH:49][C:57]([NH:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)=[O:56])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NCc1cccc(O)c1)Oc1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
(2S,3S,4R,5R)-5-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide trifluoroacetate (Intermediate E) and (3-Hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate UA) are dissolved in methanol and TEA. The reaction mixture is heated using microwave radiation at 100° C. for 30 minutes in the Personal Chemistry Emrys™ Optimizer microwave reactor. The reaction mixture is concentrated in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile:water (0.1% TFA) (gradient 0-100% acetonitrile) to afford the titled compound.
Reaction SMILES: [C:1](O)(=[S:3])[CH3:2].[O:5]1[C:16]2[C:8](=[CH:9][C:10](=[CH:14][CH:15]=2)[CH2:11]C=C)[O:7][CH2:6]1.[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.O>[O:5]1[C:16]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:2][CH2:1][SH:3])=[CH:9][C:8]=2[O:7][CH2:6]1
Reactant: CC(O)=S
Reactant: C=CCc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
25 g of thioacetic acid was added to 53.5 g of safrole in portions, while stirring the mixture at a room temperature or under cooling with ice/water. The reaction was carried out for 30 minutes. A solution of 20 g of sodium hydroxide in a mixture comprising 100 ml of water and 200 ml of ethanol was added to the reaction mixture. The obtained mixture was heated under reflux for 20 minutes, cooled, neutralized with dilute sulfuric acid and extracted with 1 l of benzene. The extract was washed with water and the benzene layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (hexane) to obtain 42.8 g of the title compound as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][CH2:15][C:16]1[CH:17]=[C:18]([C:26](OC)=[O:27])[C:19](=[CH:24][CH:25]=1)[C:20](OC)=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O.[OH-].[Na+]>C(OCC)C.C1COCC1>[Si:7]([O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][OH:21])=[C:18]([CH2:26][OH:27])[CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)c(CO)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
17.8 g (469 mmol) of lithium aluminum hydride are placed in 800 ml of ethyl ether in a round-bottomed flask and under a stream of nitrogen. At 0° C., a solution of 66.4 g (196 mmol) of dimethyl 4-(tert-butyldimethylsilanyloxymethyl)phthalate in 200 ml of ether and 100 ml of THF is added dropwise. The reaction medium is stirred at 0° C. for 2 hours. 18 ml of water, 18 ml of 15% sodium hydroxide solution and then 54 ml of water are added very slowly. The precipitate formed is filtered off and rinsed with ether, and the filtrate is evaporated. 52 g (94%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[N:20]([CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[C:21]=S.IC>C(Cl)Cl.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:21]([NH:20][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:15][N:14]=1
Reactant: S=C=NCCN1CCCCC1
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: ClCCl
Solvent: CI
Solvent: CCO
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnc(NCCN2CCCCC2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (300 mg; 0.81 mmol; 1 eq) in DCM (5 mL), 1-(2-Isothiocyanato-ethyl)-piperidine (192 mg; 1.13 mmol; 1.4 eq) was added. The reaction mixture was refluxed for 4 hrs under argon. A yellow solid precipitated out and filtered to afford an intermediated that was suspended in ethanol (5 mL). Iodomethane (148 mg; 1.05 mmol; 1.3 eq) was added to the reaction mixture and stirred overnight at RT, then heated to 80° C. and stirred for another 2 hr. The mixture was filtered to give a yellow solid product 40 mg. LC/MS (Method A) [3.89 min; 509(M+1)]
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].OB(O)[C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH2:35]([O:34][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([C:44]4[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:31][CH2:32][CH3:33])=[O:37])[CH3:36]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4ccc(C(=O)O)cc4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 100 °C
Yield: 26.8 %

Procedure:
Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate (20.0 mg, 0.0304 mmol), 4-(Dihydroxyboryl)benzoic acid (10.1 mg, 0.0608 mmol), potassium carbonate (12.6 mg, 0.0911 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (2.48 mg, 0.00304 mmol), 1,4-dioxane (0.6 mL) and water (0.15 mL) were mixed and heated in microwave at 100° C. for 30 minutes. The crude mixture was passed through Thiol-SPE cartridge to remove Pd and was subsequently purified by MDP to obtain the title compound (5.7 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.13 (t, J=7.1 Hz, 6 H), 3.08 (s, 3 H), 3.34 (d, J=21.5 Hz, 2 H), 3.75 (s, 3 H), 3.85-4.02 (m, 4 H), 4.67 (s, 2 H), 6.94 (d, J=8.1 Hz, 1 H), 7.08 (br. s., 1 H), 7.43 (br. s., 1 H), 7.58 (d, J=8.6 Hz, 1 H), 7.75 (m, J=8.3 Hz, 2 H), 8.02 (m, J=8.6 Hz, 2 H), 8.42 (s, 1 H), 9.20 (s, 1 H), 13.05 (s, 1 H). MS (ES+): m/z 700.25 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[Se:15][C:14]=1[C:22]([NH2:24])=[O:23].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:19])[CH3:20])[Se:15][C:14]=1[C:22]([NH2:24])=[O:23])=[O:28]
Reactant: CC(C)(C)c1cc(Nc2ncnc3ccc(N)cc23)c(C(N)=O)[se]1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2ncnc3ccc(NC(=O)CCl)cc23)c(C(N)=O)[se]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 3-(6-aminoquinazolin-4-ylamino)-5-tert-butylselenophene-2-carboxamide (510 mg, 1.31 mmol) in THF (10 mL) was added a solution of chloroacetyl chloride (0.105 mL, 1.31 mmol) in THF (1.0 mL) at rt. The mixture was stirred at rt for 30 min (solid separated). The solution was poured into ice cold water and stirred for 15 min. The separated solid was filtered, washed with water and dried to give the product as a yellow color solid (540 mg, 80%). This crude product was further chromatographed and recrystallized from chloroform-methanol. Mp 262-264° C.; IR (KBr) vmax 3437, 3109, 2961, 1706, 1652, 1608, 1575, 1541, 1464, 1386, 1355, 1311, 1241, 1137, 1086, 858, 834, 790 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, s, exchangeable with D2O), 10.83 (1H, s, exchangeable with D2O), 8.83 (1H, s), 8.73 (1H, s), 8.60 (1H, br s), 8.01-8.03 (1H, m), 7.89 (1H, d, J=8.8 Hz), 7.68 (2H, br s), 4.41 (2H, s), 1.47 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 167.9, 167.2, 164.9, 154.9, 153.2, 146.3, 145.5, 137.2, 128.7, 126.7, 121.1, 115.2, 113.1, 110.0, 43.3, 36.5, 32.2; LC-MS (negative ion mode): m/z 462, 464, 466 (M−H)−.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH:21]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([P:15](=[O:18])([OH:17])[OH:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:39]([O:45][CH:46](I)[CH3:47])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(#N)C.C(Cl)Cl>[OH:18][P:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[CH:10][CH:11]=1)([O:17][CH:46]([O:45][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH3:47])=[O:16]
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)Nc2nccs2)c1
Reactant: CC(I)OC(=O)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(O)OC(C)OC(=O)C(C)(C)C)cc2)cc(C(=O)Nc2nccs2)c1
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
A mixture of {-4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonic acid (250 mg, 0.58 mmol) and DIEA (0.193 mL, 1.16 mmol) in 6 mL of acetonitrile was stirred for 15 min and then 1-iodoethyl pivalate (177 mg, 0.69 mmol) was added. The resulting mixture was stirred for 2 h at rt, then diluted with CH2Cl2, washed with 1 M aqueous NaHSO4, dried (MgSO4) and evaporated. The residue was dissolved in 3:1 acetonitrile/water and subjected to MPLC purification through a 25 g C18 column eluting with % acetonitrile in water (time): 15-50 (15 min). Lyophilization of the eluent containing the desired product provided 31 mg (10%) of the title compound as an amorphous solid: 1H NMR (500 MHz, DMSO-d6): δ 0.91 (s, 9H), 1.29 (d, 6H, J=6 Hz), 1.30 (d, 3H, J=6 Hz), 4.73 (septet, 1H, J=6 Hz), 6.34 (br s, 1H), 6.75 (s, 1H), 7.01 (d, 2H, 1=7 Hz), 7.24 (s, 1H), 7.28 (d, 1H, J=3 Hz), 7.45 (s, 1H), 7.56 (d, 1H, J=3 Hz), 7.63 (br s, 2H), 12.61 (br s, 1H); LCMS (m/z): 563.4 [C26H31N2O8PS+H]+. Anal. calcd. for (C26H31N2O8PS+1H2O): C, 53.79; H, 5.73; N, 4.82. Found: C, 52.93; 11, 5.93; N, 5.92.