Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:8]([CH3:9])[CH:7]=[N:6][C:5]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3]>CC(C)=O.[Mn]>[C:2]([C:4]1[N:8]([CH3:9])[CH:7]=[N:6][C:5]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1c(SCc2ccccc2)ncn1C
Agent: [Mn]
Solvent: CC(C)=O
Product: CC(=O)c1c(SCc2ccccc2)ncn1C
Yield: 21.1 %

Procedure:
5-(1-Hydroxyethyl)-1-methyl-4-(phenylmethyl)thioimidazole (6.2 g. 25 mmol) in acetone (310 ml) and active manganese IV oxide (62 g), under a calcium chloride drying tube, were mechanically stirred and refluxed for 4 hours. The reaction mixture was cooled, filtered, washed with dichloromethane and evaporated under reduced pressure to provide crude product. Purification by flash chromatography starting with dichloromethane followed by 1%, 2% and 10% methanol in dichloromethane provided 1.3 g of 5-acetyl-1-methyl-4-(phenylmethyl)thioimidazole (21%) and 3.6 g of starting material 5-(1-hydroxyethyl)-1-methyl-4-(phenylmethyl)thioimidazole (58%). The yield based on the starting material consumed is 50%; mp 62° C.; -H NMR(300 MHz, CDCl3) δ 2.49 (s, 3H, CH3CO), 3.86 (s, 3H, NCH3), 4.45 (3, 2H, SCH2), 7.26-7.37 (m, 5H, ArH), 7.49(s, 1H, 1m H-2); 13C NMR(75 MHz, CDCl3) δ 30.4, 35.6, 37.2, 127.2, 128.1, 128.5, 129.0, 137.8, 142.0, 145.4, 188.4 (C=O) ppm; IR (CCl14) 3060, 2960, 1665 (C=O), 1550, 1515, 1250, 825, 730 cm-1, LRMS (ei) m/z 246 (M+ -SH, 100), 155 (23), 91 (C7H7+ 95), 81 (29), 42 (23); HRMS (ei) calc. 246.0827 obsd. 246.0826.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH3:31])[C:25]=1[CH:32]=O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]3[N:21]=[C:32]([C:25]4[C:26]([O:30][CH3:31])=[N:27][CH:28]=[CH:29][C:24]=4[I:23])[NH:22][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1N
Reactant: COc1nccc(I)c1C=O
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(3,4-Diamino-5-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (44.6 mmol—assuming 100% conversion in previous step) in methanol (ca 2700 mL) at 0° C under a nitrogen atmosphere was slowly added (2 h) via addition funnel, a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (15.0 g, 57.1 mmol) in anhydrous methanol (225 mL). The resulting solution was then stirred at 0° C. for an additional 30 min, the cooling bath was removed, and the reaction mixture was allowed to stir at room temperature in the presence of air for 72 h. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane (1500 mL) and the solvent removed in vacuo (repeated 3×). The resulting dark foamy solid was dried under high vacuum. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, 1H, J=5.4 Hz), 7.50 (d, 1H, J=5.4 Hz), 6.98 (brs, 1H), 6.90 (brs, 1H), 4.05 (s, 3H), 3.67–3.58 (m, 4H), 3.18–3.09 (m, 4H), 2.63 (s, 3H), 1.49 (s, 9H); LCMS (M+H)+ m/z 550.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23]C)=[O:22])=[C:17]([CH3:27])[CH:16]=2)[O:11][CH:12]=1.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:17]([CH3:27])[CH:16]=2)[O:11][CH:12]=1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccccc3Cl)co2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2nc(-c3ccccc3Cl)co2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The solution of methyl 2-(4-((4-(2-chlorophenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetate from Step A is diluted with THF (1 mL), then a solution of 1 M LiOH in H2O (0.2 mL) is added and the mixture is stirred for 12 h at rt. The mixture is acidified with 1 M HCl (5 mL), and extracted into EtOAc (20 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound D1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=8.28 (s, 1H), 7.97 (dd, J=0.8, 8.0 Hz, 1H), 7.38 (dd, J=0.8, 7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.20 (dt, J=1.2, 7.6 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.73 (dd, J=2.8, 8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.10 (s, 2H), 4.57 (s, 2H), 2.21 (s, 3H). MS calcd. for C19H17ClNO5 (M+H+) 374.1. found 374.1.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][N:4]([C:6]#[N:7])[CH2:3]1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1>ClCCCl>[N:9]1([C:6]([N:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)=[NH:7])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: N#CN1CC(F)(F)C1
Solvent: ClCCCl
Product: N=C(N1CC(F)(F)C1)n1nnc2ccccc21
Temperature: 80 °C
Yield: 59.2 %

Procedure:
A mixture of 3,3-difluoroazetidine-1-carbonitrile (135 mg, 1.14 mmol) and benzotriazole (136 mg, 1.14 mmol) in 1,2-dichloroethane (0.2 mL) was heated to 80° C. under nitrogen for 30 min. A needle was inserted to facilitate evaporation of the solvent and the mixture was heated at 80° C. for 45 min. The resulting solids were washed with ether (2×3 mL) and dried under reduced pressure to give the title compound as an off-white solid (160 mg, 51%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([CH3:37])=[CH:35][CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: Cc1ccc(CBr)cc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccc(C)cc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 4-methylbenzyl bromide. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1>[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Agent: [Pd]
Product: Cc1ccc2nc(N)c(N)cc2c1
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
0.24 g of palladium on charcoal (10% Pd) is added to a solution of 1.32 g of 2-amino-3-nitro-6-methylquinoline (compound B2) in 100 ml of methanoltetrahydrofurane 1:1. After hydration for 1.5 h, the catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is chomatographed on silica gel (dichloromethane/methanol 8:1). 1.02 g of the title compound are obtained as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14].Br[CH:20](C1C(C(N)=O)C1(C)C)C(Br)(Cl)Cl.F[B-](F)(F)F.C[O+](C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13](=[NH:15])[O:14][CH3:20]
Reactant: CC1(C)C(C(N)=O)C1C(Br)C(Cl)(Cl)Br
Reactant: CC(C)C(C(N)=O)c1ccc(C(F)(F)F)cc1Cl
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC(=N)C(c1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
In like manner, each of 2-(2-chloro-4-trifluoromethylphenyl)-3-methylbutyramide and 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropaneamide is reacted with trimethyloxonium tetrafluoroborate, giving methyl 2-(2-chloro-4-trifluoromethylphenyl)-3-methylbutanimidate and methyl 2-(1.2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanimidate, respectively. Each of these imidates is then reacted with 3-phenoxybenzyl alcohol to yield, respectively, 3-phenoxybenzyl 2-(2-chloro-4-trifluoromethylphenyl)-3-methylbutanimidate and 3-phenoxybenzyl 2-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanimidate.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]#[CH:25])[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N+:27]=[N-:28].CN(C=O)C>>[CH3:1][O:2][C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][C:24]5[N:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[N:27]=[N:28][CH:25]=5)[C:14]=4[CH:15]=3)=[CH:10][N:5]2[N:4]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Solvent: CN(C)C=O
Product: COc1cc(OCc2cnnn2-c2ccccc2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 110 °C
Yield: 13.9 %

Procedure:
In a 5 mL microwave vial, was added 2-methoxy-6-(6-methoxy-4-(prop-2-yn-1-yloxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (Example 9A, 27 mgs, 0.076 mmol), azidobenzene (Example 9B, 30 mgs, 0.252 mmol), anhydrous DMF (2.5 mL, 32.3 mmol) and (Cp*RuCl)4 (12 mgs) under a nitrogen atmosphere. The vial was capped and heated at 110° C. for 20 min. in the microwave apparatus. The solvent was evaporated and the residue was purified by silica gel chromatography ISCO, concentrated and twice triturated with methanol (2×1 mL). To the solid was added acetonitrile (2 mL) and water (4 mL) and the mixture was freeze dried over the weekend to give the title material (5 mgs, 10.54 μmol, 14% yield). LC (Method F): 2.480 min. HRMS (ESI) calcd for C23H19N6O4S [M+H]+ m/z 475.1183, found 475.1234. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.35 (s, 1H), 8.12 (s, 1H), 7.66-7.73 (m, 2H), 7.53-7.63 (m, 3H), 6.84 (dd, J=2.0, 0.8 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 5.40 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1F)[C:11]#[N:12].[CH2:17]([OH:20])[CH2:18][OH:19]>>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:19][CH2:18][CH2:17][OH:20])[C:11]#[N:12]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1ccc(OCCO)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To potassium tert-butoxide (19.35 g) was added ethylene glycol (160 mL). The mixture was then heated to 50° C. At 50° C., 3,4-difluorobenzonitrile (20 g) was added and this was washed in with ethylene glycol (40 mL). The combined solution was heated to 80° C., and held at this temperature for two hours, before being cooled to 20° C. over one hour. The reaction mixture was filtered and washed with ethylene glycol (40 mL). To the filtrate was added water (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was concentrated in vacuo, to give the sub-title compound as a waxy white solid (26.1 g, 100% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:28]2[CH2:30][CH2:29]2)[C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:28]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[N:19][CH:18]=2)=[O:16])[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-n3ccnc3)nc2)C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cnc(-n2ccnc2)nc1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 4-[cyclopropyl-(2-imidazol-1-yl-pyrimidine-5-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester by treatment with trifluoroacetic acid in dichloromethane. LC (method 10): tR=0.68 min; Mass spectrum (ESI+): m/z=313 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.[NH2:19][NH2:20]>O>[C:1]1([C:7]2[C:8](=[O:9])[NH:19][NH:20][C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 115 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
46 g (264.1 mmol) 3-Phenyl-furan-2,5-dione were suspended in 1.56 L water. After addition of 34.4 g (264.1 mmol) hydrazine sulfate the reaction mixture was heated to reflux (bath temperature: 115° C.) and kept there for five hours. During the night the reaction mixture was kept at a bath temperature of 98° C. After cooling the precipitate was sucked off, washed with water (100 mL) and dried at 40° C. yielding 47.6 g (95.8%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH:11]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12]2)=[CH:8][C:7]=1[C:22]([O:24]C)=O)[CH2:2][CH2:3][CH3:4].[CH3:26][NH:27]C=O.C[O-].[Na+].CO.Cl>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH:11]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12]2)=[CH:8][C:7]=1[C:22]([NH:27][CH3:26])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CNC=O
Reactant: CCCCOc1cc2c(cc1C(=O)OC)CC(N(CCC)CCC)C2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCOc1cc2c(cc1C(=O)NC)CC(N(CCC)CCC)C2
Temperature: 25 °C

Procedure:
To a mixture of methyl 6-butoxy-2-(dipropylamino)-2,3-dihydro-1H-indene-5-carboxylate (75, 0.35 g, 1 mmol) and N-methylformamide (0.59 g, 10 mmol) in DMF (10 mL) at 100° C. and 25% was added sodium methoxide in methanol (0.22 mL, 1 mmol) dropwise over a period of 10 min. The resulting mixture is cooled to room temperature and quenched with water (100 mL). The resulting solid was purified by chromatography to give an oil that was converted into the HCl salt and crystallized from EtOAc/MeOH to yield the title compound 82 as a white solid (m.p.129-130° C.).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH2:18]([O:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29](B(O)O)=[C:28]([CH3:36])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH2:18]([O:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([Pb+3:17])=[C:28]([CH3:36])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [Pb+4]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Hg+2]
Product: Cc1cc(OCc2ccccc2)cc(C)c1[Pb+3]
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Lead tetraacetate (5.7 g, 0.013 mol) and mercury (II) acetate (0.2 g, 0.0006 mol) are stirred together and thoroughly flushed with nitrogen. Chloroform (20 ml) is added and the dark orange solution heated to 50° C., followed by the addition of 4-benzyloxy-2,6-dimethylphenyl boronic acid (3 g, 0.012 mol) in one portion. After further heating at 50° C. for 3 hours the reaction mixture is cooled to 0° C. and potassium carbonate added (1.9 g, 0.02 mol). The suspension is stirred for just 5 minutes before filtering and evaporation of the crude solution under reduced pressure. The crude product is then azeotroped with diethyl ether to afford 4-benzyloxy-2,6-dimethylphenyl lead triacetate as a pale solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=1)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:11]=[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[N:10][N:9]3[CH:13]=2)=[CH:21][CH:20]=1
Reactant: COCCOc1ccc(C(=O)CBr)cc1
Reactant: CCCOc1ccc(N)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41 %

Procedure:
A stirred mixture of 6-propoxypyridazin-3-amine (4.50 g, 29.4 mmol), 2-bromo-1-[4-(2-methoxyethoxy)phenyl]ethanone (8.03 g, 29.4 mmol) and ethanol (280 mL) was heated under reflux for 2.5 hours. The mixture was cooled and sodium bicarbonate (2.50 g, 30 mmol) added. The mixture was stirred at room temperature for 15 hours, heated under reflux for 1 hour, then cooled and evaporated. The residue was extracted with chloroform (150 mL) and the extract washed with saturated, aqueous, sodium chloride solution (50 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-2% methanol in dichloromethane afforded a green/brown solid. Treatment with decolourising charcoal in diethyl ether solution (three times) and recrystallization from cyclohexane gave Compound 63 (3.95 g, 41%) as pale green crystals. M.p. 82.5-84° C. 1H n.m.r. (CDCl3) δ 1.06, t, J=7.2 Hz, 3H; 1.75-1.94, m, 2H; 3.47, s, 3H; 3.74-3.81, m, 2H; 4.14-4.21, m, 2H; 4.27, t, J=6.6 Hz, 2H; 6.68, d, J=9.3 Hz, 1H; 7.00, d, J=8.8 Hz, 2H; 7.76-7.88, m, 3H; 7.94, s, 1H. Mass spectrum (APCI+) m/z 328 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO.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]>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:3][C:4]=1[O:12][CH3:13])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a degassed solution of methyl 4-bromo-2-methoxybenzoate (0.70 g, 2.86 mmol) in 1,4-dioxane (10 mL) and MeOH (2.5 mL) is added 4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl2 (0.233 g, 0.286 mmol) and K3PO4 (0.728 g, 3.43 mmol). The resulting suspension is heated to 80° C. and stirred for 3 hours. After this time, the reaction is cooled to room temperature and filtered through Celite™. The solids that form are collected and washed with additional MeOH before the filtrate is concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc; 6:1 to 4:1) to provide 0.615 g (78% yield) of the desired compound as orange crystals. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1H, d, J=8.0 Hz), 7.52-7.56 (2H, m), 7.44 (2H, d, J=8.7 Hz), 7.17 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=1.6 Hz), 3.99 (3H, s), 3.92 (3H, s). HPLC-MS: m/z 277 [M+H]+.
Reaction SMILES: C(ON=O)C(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22](N)[S:23][C:17]=2[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Br-:25]>CN(C=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([Br:25])[S:23][C:17]=2[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Suspended CuBr2 (905 mg, 4.05 mmol) in 5 mL of DMF and added i-butylnitrite (0.57 mL), 4.86 mmol). To this was added 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (860 mg, 3.36 mmol) and the mixture was stirred for 2 h at 60° C. LC-MS analysis indicated the desired bromide. Concentrated the mixture to a brown-red residue. Dissolved the residue in CH2Cl2 and purified via SiO2 chromatography (EtOAc/hexanes 0-20%) to give 650 mg of 2-bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[NH:19]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:20]([NH2:22])=[NH:21]>CC#N>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:22]=[C:20]([NH:19][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[CH2:26][NH:27][C:28](=[O:30])[CH3:29])[N:21]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: CC(=O)NCc1cccc(NC(=N)N)c1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CC(=O)NCc1cccc(Nc2nccc(-c3sc(C)nc3C)n2)c1

Procedure:
By treatment of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(3-guanidino-benzyl)-acetamide nitrate. Yellow solid. Mp 206-207° C. Anal. RP-HPLC: tR=13.6 min (0-60% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 1.99 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.68 (s, 3H, CH3), 4.38 (s, 2H, CH2), 6.94 (d, 1H, J=7.5 Hz, Ph-H), 7.01 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.26 (d, 1H, J=8.0 Hz, Ph-H), 7.56 (d, 1H, J=7.5 Hz, Ph-H), 7.70 (s, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 345.42 [M+H]+ (C18H19N5OS requires 353.44).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[Si:12]([O:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:21][CH:20]([O:19][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(C(C=O)O[Si](C)(C)C(C)(C)C)cc1
Reactant: CCOC(=O)c1[nH]ccc1N
Product: CCOC(=O)c1[nH]ccc1NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Yield: 29 %

Procedure:
The title compound (0.13 g, 19%) was prepared in accordance with general method A using 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.16 g, 1.07 mmol) and {[tert-butyl(dimethyl)silyl]oxy}(4-methoxyphenyl)acetaldehyde (0.3 g, 1.07 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1

Procedure:
tert-Butyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetate (2.50 g, 4.68 mmol) was dissolved in a mixture of TFA (11.3 mL) and water (1.3 mL). After a period of 18 h at room temperature the reaction mixture was evaporated followed by two co-evaporations with toluene. The yellow oil was dissolved in ethyl acetate (12.5 mL) and hexane (37.5 mL) was then added slowly. The resulting solid was filtered to provide (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetic acid.