Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]1([CH2:41][OH:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.[H-].[Na+]>CN(C=O)C.O>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28]([O:42][CH2:41][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: OCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(OCc3cccc4ccccc34)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (0.200 g, 0.423 mmol) and 1-naphthalenemethanol (0.140 g, 0.888 mmol) in DMF (1 mL) was added sodium hydride (0.0355 g, 0.888 mmol) and stirred for 3 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0 to 20% EtOAc/hexanes) to afford the title compound (0.139 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[N:23])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:7]2.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1.C(Cl)Cl>[C:24]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:22]#[N:23])=[CH:3][C:2]=2[Cl:1])[CH2:7][CH:8]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2C(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of compound 163A (164 mg, 0.472 mmol) in pyridine (1 mL) and CH2Cl2 (1 my) at RT was added benzoyl chloride (82 μL, 0.71 mmol), and the mixture was then stirred at 50° C. for 16 h. After cooling to RT, the reaction was concentrated in vacuo and the resultant residue was taken into MeOH (4 mL), and Et3N (1 mL) added. The reaction was stirred at 70° C. for 1 h. After cooling to RT, the reaction was concentrated. The residue was diluted with 10% aqueous citric acid, then extracted with EtOAc (3×15 mL). The combined EtOAc extracts were concentrated. The resulting residue was purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (50-80%) in H2O for 8 min, and then 80% MeOH in H2O for 7 min to give the title compound (60 mg, 28%) as a white solid. HPLC: 99% at 6.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A 90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 452 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]3=[O:26])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[Cl-].[Na+].[CH3:29]O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:29][CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]3=[O:26])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: CO
Reactant: N=C(N)c1ccc(-c2ccc(N3CCN(CCC(=O)O)C3=O)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Product: N=C(N)c1ccc(-c2ccc(N3CCCN(CCC(=O)O)C3=O)cc2)cc1

Procedure:
Rf value: 0.54 (Reversed Phase Plate RP8; 1 0% sodium chloride solution/methanol=4:6)
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: C=CCOc1ccc(-c2nc(CNC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 373 and allyl bromide, white powdery N-[2-(4-allyloxy-3-difluoromethoxyphenyl) oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 98.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NCCN1CCOCC1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-morpholin-4-yl-ethylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, CDCl3) δ 2.33-2.43(m, 6 H), 3.25-3.31(m, 6 H), 3.65-3.71(m, 4H), 3.84-3.89(m, 4 H), 5.54(s, 1 H), 6.08-6.10(m, 1 H), 6.77-6.80(m, 1 H), 7.09(d, J=8.0 Hz, 1 H), 7.27-7.33(m, 2 H), 7.50-7.57(m, 2 H), 7.92-7.97(m, 2 H), 8.13-8.17(m, 2 H).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=C(CNC)[CH:36]=[CH:37][CH:38]=1>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15](=[O:16])[N:17]([CH2:21][C:20]2[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=2)[CH3:18])=[CH:7][CH:8]=1
Reactant: CNCc1cccc(F)c1
Reactant: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc(F)c1)C(=O)/N=C1\SCCN1c1ccc(Cl)cc1

Procedure:
To a solution of 1-({[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (94 mg, 0.209 mmol, Example 25B) in dry acetonitrile (3 mL) were added diisopropylethylamine (0.040 mL, 0.230 mmol) and 1-(3-fluorophenyl)-N-methylmethanamine (0.032 mL, 0.230 mmol). The mixture was heated for 2 hours, and then cooled and concentrated under reduced pressure. The residue was purified by chromatography over silica using dichloromethane:methanol 95:5 as eluent to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)[CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCOc1cccc(C2=NNC(=O)CC2)c1
Product: O=C1CCC(c2cccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][O:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:32](O)(=[O:36])[C:33]#[C:34][CH3:35]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:31][O:30][CH2:29][CH2:28][N:27]3[C:32](=[O:36])[C:33]#[C:34][CH3:35])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:24][CH:25]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3COCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: CC#CC(=O)N1CCOC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 14.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (R)-4-(8-amino-3-(morpholin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 47) and 2-butynoic acid, to afford the title compound (4.9 mg, 14.1%). Data: UPLC(C) Rt: 1.38 min; m/z 482.3 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-methylphenyl)-5-(pent-1-enyl)pyridine (Example 129) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.77 (t, J=7.0 Hz, 3 H), 1.10-1.40 (m, 19 H), 2.27 (m, 2 H), 2.42 (s, 3 H), 3.22 (m, 1 H), 3.41 (m, 1 H), 4.34 (d, J=6.0 Hz, 2 H), 7.10 (d, J=8.0 Hz, 2 H), 7.20 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C24H35NO 354; found 354 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 92-94° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[C:16]([C@@H:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][C@H:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step C and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+29.5°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>CC(C)=O.O>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g), and thereto is added p-nitrobenzoyl chloride (40 g) under ice-cooling and the mixture is stirred at room temperature overnight. To the reaction mixture is added a suitable amount of water. The precipitated crystal is collected by filtration and dried to give 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (40.8 g) as white powder, m.p. 86°-88° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]=1[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][CH2:3][CH3:4].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([NH2:39])=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:7]=1[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)O)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(N)=O)cc12
Yield: 85.3 %

Procedure:
A solution of (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.34 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.29 g, 87.9%) as crystals.
Reaction SMILES: Br[C:2]1[C:3]2[S:17][CH:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:7]=1.C(OC(=O)[NH:24][C:25]1[S:26][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:29]=1)(C)(C)C>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:25]1[S:26][C:27]([C:2]2[C:3]3[S:17][CH:16]=[CH:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=3)[N:7]=2)=[CH:28][N:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: Oc1cccc(-c2nc(Br)c3sccc3n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Nc1ncc(-c2nc(-c3cccc(O)c3)nc3ccsc23)s1
Temperature: 150 °C
Yield: 21.9 %

Procedure:
A suspension of 3-(4-bromo-thieno[3,2-d]pyrimidin-2-yl)-phenol (128 mg, 0.42 mmol), (5-tributylstannyl-thiazol-2-yl)-carbamic acid tert-butyl ester (306 mg, 0.63 mmol), and Pd(PPh3)4 (25 mg, 0.021 mmol) in anhydrous DMA (4 ml) was heated in a microwave at 150° C. for 15 mins. The reaction was absorbed onto silica and purified using 10% methanol in ethyl acetate as the eluent to give the title compound as an off-white solid (30 mg, 22%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:16](#[N:19])[CH:17]=[CH2:18]>CN(C)C=O>[C:16]([CH2:17][CH2:18][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)#[N:19]
Reactant: C=CC#N
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCn1cnc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
4-Nitroimidazole (6.87 g, 60 mmol), triethylamine (18.2 g, 180 mmol) and acrylonitrile (9.55 g, 180 mmol) were dissolved in N,N-dimethylformamide (100 ml), and the solution was stirred at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and chloroform was added to the concentrate. Solids deposited were collected by filtration and dried to obtain 9.2 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28]O)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2].[NH2:39][N:40]1[C:44]([N:45]2[CH:49]=[CH:48][CH:47]=[N:46]2)=[N:43][N:42]=[C:41]1[SH:50].O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[C:21]([C:25]([OH:27])=[O:26])=[C:20]([CH2:28][S:50][C:41]4[N:40]([NH2:39])[C:44]([N:45]5[CH:49]=[CH:48][CH:47]=[N:46]5)=[N:43][N:42]=4)[CH2:19][S:18][C@H:17]23)=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2]
Reactant: Nn1c(S)nnc1-n1cccn1
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CO)CSC23)c2ccc(O)cc2)C(=O)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(-n5cccn5)n4N)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 294.78 mg. of 7-[2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 3-acetate and 136.6 mg. of 4-amino-5-(1-pyrazolyl)-4H-1,2,4-triazole-3-thiol in 10 ml. of water is adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate. A 5 ml. portion of acetone is added producing solution. This solution is stirred at 60°-63° C. for 5 hours, then stripped free of acetone under reduced pressure, cooled to room temperature and filtered. The filtrate is acidified to pH 2.0 with 2 N hydrochloric acid. The resulting solid is filtered and dried giving 192 mg. of the desired product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>CO>[NH2:21][C:20]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:11])([F:12])[F:1])[N:10]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccccc1C(F)(F)F
Solvent: CO
Product: N#Cc1cnn(-c2ccccc2C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(2-(Trifluoromethyl)phenyl)hydrazine (CAS no. 365-34-4) (10.0 g, 56.77 mmol) was dissolved in MeOH (150 mL) under nitrogen at 0° C. 2-(ethoxymethylene)malononitrile (6.93 g, 56.77 mmol) added portionwise over 2 mins and the mixture stirred at ˜0° C. for 0.5 hours. The reaction was heated at reflux for 2 hours. Further methanol (15 mL) was added to aid mobility. The mixture was allowed to cool and was evaporated to give the product (14.3 g, 100%) which was used without further purification. 1H NMR (400 MHz, DMSO) δ 6.63 (2H, s), 7.53 (1H, d), 7.73 (1H, s), 7.74-7.77 (1H, m), 7.82-7.86 (1H, m), 7.91-7.94 (1H, m); m/z (ESI+) (M+H)+=253; HPLC tR=1.60 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:28]3[CH2:29][CH2:30][CH2:31][CH:26]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:20][CH:21]=4)[C:27]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (131.2 mg, 0.5 mmol) and of 2-bromo-6-phenyl-cyclohexanone (139.2 mg, 0.55 mmol) in ethanol (5 mL) was stirred at room temperature over the weekend. A clear yellow solution was obtained which was heated over night to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (110 mg, 53%) as a white solid. MS ISP (m/e): 417.5 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.19 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.27 (t, 2H), 7.11-7.18 (m, 4H), 6.95 (s, 1H), 6.71 (d, 1H), 3.98 (m, 1H), 3.34 (s, 3H), 2.73 (m, 2.14 (m, 1H), 2.10 (s, 3H), 1.70-1.91 (m, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncn(Cc3ccc4nc(Nc5ccccc5)sc4c3)c2cc1OC
Temperature: 120 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (60 mg, 0.148 mmol) from Step 4 of Example 2 in aniline (0.6 mL) was added DIEA (23 mg, 0.178 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. for 48 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine (31 mg, 50%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.53 (br s, 1H), 8.18 (s, 1H), 7.71-7.82 (m, 3H), 7.56 (d, J=8.3 Hz, 1H), 7.26-7.42 (m, 3H), 7.19 (d, J=3.2 Hz, 2H), 7.01 (t, J=7.3 Hz, 1H), 5.48 (s, 2H), 3.77 (s, 6H). LCMS (ESI) m/z 417 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[O:9][C:10]([Cl:12])=[CH:11][C:3]=12.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[O:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)c2cc(Cl)oc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2cc(Cl)oc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A 0.2 M solution of 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol (143 mg, 0.6 mmol) and K2CO3 (200 mg, 1.45 mmol) in DMF stirred at 0° C. under an atmosphere of nitrogen was treated with MeI (99 mg, 0.7 mmol). The ice bath was removed; the mixture was stirred at rt overnight. The reaction mixture was treated water (15 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (113 mg, 85%) as a white solid. LCMS (M+H)+=263.