Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 82 %

Procedure:
To a solution of 15.0 mg 0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 3.0 mL chloroform were added 9.3 mg 0.131 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.23 gm 0.131 mMol)aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 16.1 mg (82%) of the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.4 g of 4-(4-acetamidophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid and 14 ml of 2N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling to room temperature it is filtered and the filtrate acidified with glacial acetic acid to pH = 4. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenoxy)-3-benzylamino-5-sulfamoylbenzoic acid of the formula ##SPC12##
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:27]=[CH:26][C:25]3[N:24]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:23]([CH2:39][CH3:40])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[CH:15]=2)=[CH:3][CH:2]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:27]=[CH:26][C:25]3[N:24]([S:28]([C:31]4[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=4)(=[O:29])=[O:30])[CH:23]([CH2:39][CH3:40])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[CH:15]=2)=[CH:3][CH:2]=1
Reactant: CCC1c2ccccc2-c2cc(-c3cccc4c3oc3ccccc34)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2ccccc2-c2cc(-c3cccc4c3oc3ccccc34)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A stirred and cooled solution of 2-(dibenzo[b,d]furan-4-yl)-6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (0.855 g, 1.56 mmol) and cyclohexene (1.26 mL, 12.5 mmol) in dichloromethane (5 mL) was treated drop-wise under nitrogen at −30° C. with boron tribromide (1.18 mL, 12.5 mmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for four hours. The reaction was cooled to −30° C. and quenched with methanol (1 mL). The solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel to yield the title compound (0.756 g, 1.42 mmol, 91%), which was characterized by LCMS (ES+, FA, CV=20 or 5), m.p. 218-220° C.;
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[CH:22]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([C:25]4[N:21]([CH3:20])[CH:22]=[N:23][CH:24]=4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: Cn1cncc1C(=O)O
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3cncn3C)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 3-methyl-3H-imidazole-4-carboxylic acid, the title compound was prepared. MS: m/e=389(M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C>>[CH2:14]([O:13]/[CH:3]=[CH:2]\[CH2:1][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:15][CH2:16][CH3:17]
Reactant: C=CCNc1ccccc1
Reactant: C=COCCCC
Product: CCCCO/C=C\CNc1ccccc1
Reaction time: 4 h
Yield: 52.3 %

Procedure:
Following the general procedure, N-allylaniline (50.0 mg, 0.375 mmol) was treated with butyl vinyl ether (376 mg, 3.75 mmol) and 5 mol % of in situ-generated complex 1a (188 μL, 0.10 M, 18.7 μmol; final substrate concentration=2.0 M) and allowed to stir for 4 h. The unpurified product is 96% Z (as determined by 400 MHz 1H NMR analysis). The resulting oil was purified by silica gel chromatography (50:1 hexanes:Et2O) to afford 8e (40.2 mg, 0.196 mmol , 52.0% yield, 96% Z isomer) as a light yellow oil. IR (neat): 3410 (br), 3048 (w), 2958 (m), 2932 (m), 2871 (m), 1660 (m), 1601 (s), 1503 (s), 1467 (m), 1431(w), 1375 (m), 1314 (m), 1250 (m), 1108 (s), 1094 (s), 1040 (m), 745 (s), 691 (s); 1H NMR (400 MHz, CDCl3): ™ δ 7.19-7.14 (2H, m), 6.72-6.67 (1H, m), 6.66-6.62 (2H, m), [diagnostic E isomer signal: 6.51 (1H, d, J=12.8 Hz)], 6.08 (1H, dt, J=6.4, 1.4 Hz), 4.51 (1H, td, J=6.6, 6.4 Hz), 3.82-3.74 (1H, m), 3.81 (2H, dd, J=6.8, 1.2 Hz), 3.79 (2H, t, J=6.4 Hz), 1.67-1.59 (2H, m), 1.47-1.37 (2H, m), 0.95 (3H, t, J=7.4 Hz); 13C NMR (100 MHz, CDCl3): ™ δ 148.5, 147.4, 129.3, 117.4, 113.2, 103.5, 72.6, 38.6, 32.0, 19.2, 14.0; HRMS (ESI+) [M+H]+ calcd for C13H20NO: 206.1545, found: 206.1541.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[S:25]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:27])=[O:26]
Reactant: COC(=O)CCSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
To a solution of methyl 3-((2-amino-4-chlorophenyl)thio)propanoate (412 mg, 1.67 mmol) in pyridine (2 ml) was added 1-benzofuran-2-sulfonyl chloride (363 mg, 1.67 mmol). The reaction was stirred at room temperature for 72 hours, diluted with EtOAc and extracted with HCl, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10-20% EtOAc in hexane) to yield the title compound (373 mg, 52%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:18]([NH:20][C@H:21]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[CH3:35][C:36]([O:39][C:40]([NH:42][C@H:43]([C:59](ON1C(=O)CCC1=O)=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:41])([CH3:38])[CH3:37].CN1CCOCC1>CN(C=O)C>[NH:42]([C:40]([O:39][C:36]([CH3:38])([CH3:37])[CH3:35])=[O:41])[C@H:43]([C:59]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:18]([NH:20][C@H:21]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4])=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:50]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CN)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A solution of 583 mg of H-Gly-Asp(OBzl)-Val-OBzl (Example 15Bb) and 477.5 mg of Boc-Lys(Z)-O Su in 10 ml of DMF is adjusted to pH 8.5 with N-methylmorpholine. After stirring for 18 hours the mixture is concentrated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with saturated NaHCO3 solution, 5% KHSO4 /10% K2SO4 solution and saturated NaCl solution, dried and filtered. The filtrate is concentrated and the residue is crystallized from ether. There are obtained 385 mg of Boc-Lys(Z)-Gly-Asp(OBzl)-Val-OBzl, m.p. 95°-101° C.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[N:30]1([S:34]([C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:40]2[CH:41]=[CH:42][C:37]([S:34]([N:30]3[CH2:31][CH2:32][CH2:33]3)(=[O:36])=[O:35])=[CH:38][CH:39]=2)=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(S(=O)(=O)N4CCC4)cc3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Reaction time: 25 h
Yield: 77.9 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 350 mg) in acetonitrile (7 mL) under nitrogen was treated with 4-(azetidin-1-ylsulfonyl)phenylboronic acid (163 mg) followed by sodium carbonate (0.677 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) was added. The mixture was stirred at 85° C. for 25 h. The solvent was partially evaporated and the solution was purified by chromatography on silica using ethyl acetate 50-100% in isohexane as eluent to afford the sub-titled compound as a solid (309 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[CH:7].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOCCO)c21

Procedure:
Using Method C above, 3-(2-hydroxyethoxy)-1-propyne (53 mg, 0.53 mmol) (from Example 21 above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-[3-(2-hydroxyethoxy)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:31]=[CH:30][N:16]3[C:17](=[O:29])[C:18]([CH:27]=O)=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].FC(F)(F)COP([CH2:46][C:47]([O:49][CH3:50])=[O:48])(=O)OCC(F)(F)F.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:31]=[CH:30][N:16]3[C:17](=[O:29])[C:18](/[CH:27]=[CH:46]/[C:47]([O:49][CH3:50])=[O:48])=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(N2CCOCC2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.4 %

Procedure:
N8-[4-(tert-Butyl)-1,3-thiazol-2-yl]-3-formyl-2-morpholino-4-oxo-4H-pyrido-[1,2-a]pyrimidine-8-carboxamide (98.2 mg, 0.223 mmol) was added with tetrahydrofuran (6 ml), lithium chloride (30 mg, 0.669 mmol) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (142 μl, 0.669 mmol), then added dropwise with 1,8-diazabicyclo[5.4.0]undec-7-ene (92 μl, 0.669 mmol) at room temperature, stirred at room temperature for 1 hour, and further added with bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (75 μl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (45 μl). The reaction solution was further stirred at room temperature for 30 minutes and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 145.8 mg of the title compound in a mixture with 1,8-diazabicyclo[5.4.0]undec-7-ene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2C[CH:9]1[CH2:10]C2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:31]C(N1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][O:31][CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCOCC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-morpholine-4-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.CO.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]([C:9](=[O:11])[CH3:10])=[CH:4][C:5]([F:8])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)c1cc(F)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(F)ccc1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
1-(2-Bromo-5-fluoro-phenyl)-ethanone (868 mg, 4 mmol), p-chlorophenylboronic acid (768 mg, 1.2 eq.), and tetrakis (triphenylphosphine)palladium(0) (473 mg, 0.1 eq.), were dissolved in 25 mL toluene, 6 mL methanol and 2.5 mL sat. sodium bicarbonate solution. After degassing/sonicating the solution, the sealed reaction vessel was heated to 80° C. overnight. The cooled solution was separated between ethyl acetate and water; the aqueous phase extracted two more times with ethyl acetate, and the organic fractions were combined, dried with sodium sulfate and evaporated. Silica gel chromatography (5:1 hexanes/ethyl acetate) gave 1-(4′-chloro-4-fluoro-biphen-2-yl)-ethanone (821 mg).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].Cl>C(O)C>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:29][CH2:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])#[N:9]
Reactant: C=CC(=O)OCC
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of diphenylacetonitrile (28 g) in ethanol (100 ml) were added DBU (6 ml) and ethyl acrylate (30 ml), and the mixture was heated and stirred at 80° C. for 16 hours. After cooling, 2N-hydrochloric acid (200 ml) was added and the mixture was extracted with isopropyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude crystal crop was recrystallized from hexaneisopropyl ether to provide the title compound (34 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45]([OH:47])=O)[CH:40]=2)[CH2:35][CH2:34]1.Cl.Cl.[CH3:50][C:51]1([CH3:60])[CH2:56][NH:55][CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:50][C:51]1([CH3:60])[CH2:56][N:55]([C:45]([C:41]2[N:42]=[CH:43][N:44]=[C:39]([N:36]3[CH2:37][CH2:38][CH:33]([N:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:32][C:24]4=[O:23])[CH2:34][CH2:35]3)[CH:40]=2)=[O:47])[CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)Cc2cn[nH]c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) TBTU were added to 80 mg (0.24 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 70.0 mg (0.31 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[Cl:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:11][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Fc1ccc2nncn2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Fc1ccc2nnc(Cl)n2c1
Yield: 71.2 %

Procedure:
A solution of Intermediate 14a (789 mg, 5.98 mmol) and N-chlorosuccinimide (878 mg, 6.57 mmol) in chloroform (15 mL) was heated at 65° C. overnight. The cooled mixture was washed with sat. aq. NaHCO3 solution (2×15 mL) and dried (Na2SO4). The solvent was evaporated, then the residue suspended in diethyl ether (10 mL) and filtered to give the title compound (730 mg, 76%). LCMS (Method 1): Rt 1.83 min, m/z 172 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(N)c2)c1C

Procedure:
The compound of Example 2 (1.8 g) was dissolved in ethanol then 0.2 g 5% Pd/C was added to the solution. The mixture was treated with hydrogen gas at 45 psi. Upon completion of the reaction, the solution was filtered through Celite, and the filtrate concentrated under vacuum. The named product slowly crystallized upon standing (m.p. 93° C.–95° C.).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[CH2:3][CH:4]=[CH2:5].[C:10]1([PH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:17]1([P:16]([CH2:5][CH2:4][CH2:3][Si:2]([CH2:6][CH2:7][CH2:8][P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH3:9])[CH3:1])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC[Si](C)(C)CC=C
Product: C[Si](C)(CCCP(c1ccccc1)c1ccccc1)CCCP(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 70 g (0.5 mole) dimethyl diallyl silane and 204.6 g (1.1 m mole, 10% excess over equivalent amounts) of diphenyl phosphine was reacted in the manner described in Example 1 at 40° C. The additionwas slow. After 24 hours, only about 10% of the diphenyl phosphine reacted.The irradiation of the reaction mixture was continued for a total of 160 hours. A subsequent fractional distillation provided 46 g of monoadduct, as a clear, slightly viscous liquid monoadduct of bp. 122°-134° C. at 0.05 mm and 113 g of the desired diadduct (Table 1) as a clear, light yellow, viscous liquid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[O:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:36][N:37]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:32][C:33]3[O:34][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[N:36][N:37]=3)=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1nnc(-c2ccccc2)o1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(OCc3nnc(-c4ccccc4)o3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Yield: 38 %

Procedure:
To a solution of N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.20 g, 0.58 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added cesium carbonate (0.32 g, 0.99 mmol) and catalytic amount of n-tetrabutylammonium iodide, followed by the addition of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (0.15 g, 0.76 mmol). The reaction mixture was heated at 80° C. for 20 hours and concentrated in vacuo, followed by the addition of dichloromethane (100 mL). The mixture was washed with water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexanes to afford the title compound as a colorless solid in 38% yield (0.11 g): 1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J=5.9 Hz, 1H), 8.69 (d, J=8.0 Hz, 1H), 8.04-8.01 (m, 2H), 7.69-7.57 (m, 3H), 7.37-7.29 (m, 4H), 7.27-7.21 (m, 1H), 6.50-6.43 (m, 2H), 5.64 (s, 2H), 4.42 (d, J=5.9 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 500.2 (M+1), 522.2 (M+23).