Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.B([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:24]=[CH:23][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccccc3C(=O)O)cnc2N)nc2cnccc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 8.9 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-boronobenzoic acid (0.033 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes at 250° C. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0032 g of the title compound.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:30](=[O:42])[NH:31][C@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O.COC(C)(C)C>C1COCC1>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH3:18])[C:11]([CH3:13])([CH3:14])[CH3:12])[C@H:6]([C:30](=[O:42])[NH:31][C@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[CH2:5]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 3 (1.7 g, 2.9 mmol) in 10.6 mL dry THF was added Ph3P (765 mg, 2.9 mmol) at room temperature. Water (78.3 μL, 4.35 mmol) was added drop wise and the reaction mixture was allowed to stir for 16 hours at room temperature. A 1:1 mixture of water/MeOtBu was added to quench the reaction. The two phases were separated. The aqueous phase was extracted by EtOAc twice, and then the combined organic phase was washed by brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc, the 5% to 15% MeOH/methylene chloride to give the title compound as a white foam-like solid. 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)C.O.[NH2:19][NH2:20].O>CO>[NH2:11][C:9]1[S:10][C:6]([C:4]([NH:19][NH2:20])=[O:3])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1
Reactant: NN
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Solvent: CO
Solvent: O
Product: NNC(=O)c1sc(N)nc1-c1ccccc1
Yield: 70 %

Procedure:
2-Amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (5.0 g, 20 mmol) was suspended in methanol. Hydrazine monohydrate (5 mL, 100 mmol) was added and heated to reflux for 2 h. Hydrazine monohydrate (10 mL) was added and heated to reflux for 48 h. Water (100 mL) was added to the reaction mixture and the methanol was removed by evaporation in vacuo. The product precipitates and the solid product is collected by filtration. Yield: 70%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 58d (0.30 g, 0.74 mmol) was hydrolyzed with LiOH using the procedure described in Example 54, Step E to obtain the title compound 76 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 13.00 (br, 1H), 8.14-8.11 (m, 3H), 7.81 (d, J=8.1 Hz, 2H), 7.60-7.49 (m, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 6.43 (d, J=5.7 Hz, 1H), 4.07-4.02 (m, 4H), 3.85-3.83 (m, 4H), 2.78-2.73 (m, 4H), 1.80-1.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H27N5O3: 482.2 (M+H). Found: 482.1.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:15]([CH:17]([CH2:23][C:24]([O:26][CH2:27]C)=[O:25])[C:18](OCC)=O)=[O:16].C[O-].[Na+].C(O)(=O)C>CO.O>[OH:16][C:15]1[C:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][N:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:14]=1
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 2-(4-nitrophenyl)ethanimidamide hydrochloride (6.06 g, 28.12 mmol) and diethyl 2-formylsuccinate (6.54 g, 32.34 mmol) in methanol (100 mL) was added sodium methoxide (28% in methanol, 11.2 mL, 56.25 mmol) at room temperature, and the reaction mixture was stirred at 90° C. overnight. After the cooling to room temperature, the reaction was quenched with acetic acid (3.38 mL, 59.06 mmol) and water (100 mL) was added to. The resulting precipitates were collected by filtration and washed with water and acetone/diisopropyl ether (3/2) to give methyl [4-hydroxy-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (5.41 g, 64%) as brown solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][C@@H:16]2[C@@H:14]([CH2:15]2)[NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([C:21]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31](O)=[O:32])[N:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][C@@H:16]2[C@@H:14]([CH2:15]2)[N:13]1[C:31](=[O:32])[CH2:30][N:23]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:18](=[O:20])[CH3:19])=[N:22]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester hydrochloride (2.98 g, 9.06 mmol), (3-acetyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (prepared as described in Part A, 3.2 g, 9.06 mmol) and HBTU (5.15 g, 13.59 mmol) in DMF (30.2 mL) was added DIPEA (4.75 mL, 27.2 mmol). The reaction mixture was stirred for 16 h at RT under a nitrogen atmosphere. DMF was evaporated. The residue was diluted in EtOAc and washed with aq. HCl 1N then with NaHCO3 (5% in water). The organic layer was dried (Phase separator) and concentrated. The residual oil was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 0:10) to give the title compound. TLC, Rf (EtOAc)=0.33; MS (UPLC-MS): 419 [M+H]+; tR (HPLC conditions d): 2.97 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][CH:30]([CH2:32][O:33][P:34](=[O:45])([O:40]C(C)(C)C)[O:35]C(C)(C)C)[O:29][C:28]2=[O:46])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([O:14][CH:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[CH:12][CH:13]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][CH:30]([CH2:32][O:33][P:34](=[O:35])([OH:45])[OH:40])[O:29][C:28]2=[O:46])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([O:14][CH:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OP(=O)(OCC1CN(c2ccc(-c3ccc(OC4COc5nc([N+](=O)[O-])cn5C4)nc3)c(F)c2)C(=O)O1)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(COP(=O)(O)O)CN1c1ccc(-c2ccc(OC3COc4nc([N+](=O)[O-])cn4C3)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Phosphoric acid mono-(3-{3-fluoro-4-[6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl) ester was prepared according to the scheme shown in FIG. 17. Phosphoric acid di-tert-butyl ester 3-{3-fluoro-4-[6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl ester (13 mg) was dissolved with 1 mL TFA/CH2Cl2 (v/v, ½). The resulting solution was stirred at room temperature for 1 hour before all the solvent was removed. The residue was washed with 3 mL CH2Cl2, 3 mL EtOAc and 3 mL MeOH consequently. The residue was dried in vacuo to give the titled compound (8 mg) as white solid. ESI MS m/z 552 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:12][C:13]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O.O.[Na+].[K+].C(C(C(C([O-])=O)O)O)([O-])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)c(Cl)c2)c(CCCO)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Methyl 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate (0.67 g) was dissolved in toluene (5 ml). To the obtained solution was added dropwise a mixture of a 70% toluene solution (0.81 g) of sodium dihydrobis(2-methoxyethoxy)aluminate, and toluene (5 ml) at 0° C., which was stirred at 0° C. for 1 hour. To the reaction mixture was carefully added a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate (50 ml), which was stirred at room temperature for 1 hour. The precipitated crystals were filtered, washed in sequence with a 10% aqueous solution of (+)-sodium potassium tartrate sesquihydrate, pure water, and isopropyl ether, and air-dried to give crystals of 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (0.46 g, 74%). Recrystallization from acetone-hexane gave pale yellow prisms. Melting point 140-141° C.
Reaction SMILES: C[C:2]1(C)C2[C:5](=CC=CC=2)[NH:4][C:3]1=O.COCCO[AlH2-]OCCOC.[Na+].[C:25]1([CH3:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:2][CH:3]1[CH2:31][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]1[CH3:5]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: CC1Cc2ccccc2N1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A solution of dimethyl oxindole (220 mg, 1.4 mmol) in toluene (5 mL) was treated with 65% Red-Al solution in toluene (0.64 mL, 2.05 mmol) at 80° C. After stirring at 100° C. for 4 h, the reaction mixture was quenched with 1N sodium hydroxide solution. The organic layer was separated, washed with water and brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 25% EtOAc in hexanes) to give dimethyl indoline as a light blue oil (121 mg, 60%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][C:5](=[O:27])[NH:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1.O>CO.Cl.[Pd]>[NH2:1][C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(NC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(C(NC(=O)CC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Yield: 85 %

Procedure:
A suspension of 107.3 g Z-Gln(Mtt)OH (200 mM) in 800 ml methanol and 200 ml IN hydrochloric acid is hydrogenated at room temperature and normal pressure in the presence of 0.4 g palladium on carbon (10%) catalyst. On completion of the hydrogen uptake the catalyst is filtered off, washed with methanol and the filtrate, after addition of 27.9 ml triethylamine (200 mM) and 200 ml water, concentrated to a volume of about 600 ml. The formed crystalline precipitate is filtered off and washed with water until the washings are chloride-free. The obtained H-Gln(Mtt)OH contains 0.5-1 mole water and decomposes slowly above 231° C. Yield 85%.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[C:20]([C:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>C(O)C>[C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:28][C:22]1([C:20]#[CH:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:2]
Reactant: C#CC1(N)CCCCC1
Reactant: CC(C)C(=O)Nc1ccc(OCC2CO2)c(C#N)c1
Solvent: CCO
Product: C#CC1(NCC(O)COc2ccc(NC(=O)C(C)C)cc2C#N)CCCCC1

Procedure:
7.8 gm (0.03 mol) of 1-[2-cyano-4-(isobutyroyl-amino)-phenoxy]-2,3-epoxy-propane were dissolved in 80 ml of ethanol, and after addition of 7.5 gm (0.06 mol) of 1-ethinyl-cyclohexyl-amine the mixture was refluxed for one hour. The solvent was then distilled off, and the residue was acidified with dilute HCl. After extraction with ethyl acetate the aqueous phase was made alkaline by addition of NaOH, whereby basic components precipitated in oily form. They were taken up in ethyl acetate, the organic phase was washed with water, dried over MgSO4, evaporated and the solid residue was recrystallized twice from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]=4[O:23][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:22][CH2:21][N:20]([C:24](=[O:26])[CH3:25])[CH2:19][C:18]=4[O:23][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(c1cccc(Cl)c1)c1ccc2c3c(oc2c1)CNCC3
Product: CC(=O)N1CCc2c(oc3cc(S(=O)(=O)c4cccc(Cl)c4)ccc23)C1

Procedure:
Prepared as described for Example 612 using 7-[(3-chlorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine (Example 344) and acetic anhydride. MS m/z 390 [M+H]+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[Cl-].[NH4+]>C1COCC1>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[C:16]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33])[S:15][C:14]=23)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)c2ncn3ccsc23)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)c3ccc(C)cc3)c2s1
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
A solution of 669 mg of 7-p-toluenesulfonylimidazo[5,1-b]thiazole in 65 ml of THF was cooled to −60° C. in an argon atmosphere. A 1.6 N n-butyllithium/n-hexane solution (2.5 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 20 min. A solution of 1.25 g of tri-n-butylstannyl chloride in 10 ml of THF was added thereto, and the mixture was stirred at the same temperature for 40 min. A semisaturated aqueous ammonium chloride solution (150 ml) was added thereto, followed by extraction with 250 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1). The title compound (590 mg) was obtained from the fraction of Rf=0.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Na+].[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C([O-])c1cnccn1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cnccn1
Reaction time: 6 h
Yield: 72.2 %

Procedure:
A four-necked flask was charged with 14.6 g (0.10 mole) of sodium pyrazinecarboxylate, 15.1 g (0.10 mole) of chloromethyl pivalate and 1.0 g (0.01 mole) of triethylamine and the charge was maintained under stirring at 98°-100° C. for 6 hours. The reaction mixture was then cooled and 100 ml of toluene was added. The solids (sodium chloride) were filtered off. From the filtrate thus obtained the toluene was distilled off and the filtrate was subjected to distillation under reduced pressure to give 17.2 g of pivaloyloxymethyl pyrazinecarboxylate. Yield: 72%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[O:22])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
A mixture of 3-(4-chlorophenyl)-5-(piperazin-1-yl)-1,2,4-thiadiazole (539 mg, 1.92 mmol), 2-bromo-4′-methoxyacetophenone (440 mg, 1.92 mmol) and DIPEA (744 mg, 1.01 ml, 5.76 mmol) in 10 mL EtOH was stirred for 2 h at RT. Another portion 2-bromo-4′-methoxyacetophenone (220 mg, 960 μmol) was added and stirring continued for 2 h. The reaction was filtered off and washed with MeOH (4×5 mL) and Et2O (2×5 mL). The filter cake was dried in vacuo at 50° C. to yield 526 mg (64%) of the title compound as white solid. MS (m/e): 429.2 (MH+).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=3)=[CH:14][C:13]([C:25]([O:27]CC)=[O:26])=[N:12]2)[CH:8]=[CH:9][CH:10]=1.Cl>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=3)=[CH:14][C:13]([C:25]([OH:27])=[O:26])=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.0 ml of water and 453 mg (18.9 mmol) of lithium hydroxide are added to 700 mg (1.89 mmol) of the carboxylic ester of Example 130A in 60.0 ml of THF. The mixture is stirred at RT overnight and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 712 mg (89% of theory) of the title compound are obtained in 81% purity.
Reaction SMILES: Cl.FC(F)(F)CC[N:6]1[CH2:15][CH2:14][C:13]2[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7]1.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:21]1[CH2:22][CH2:23][O:24][C:19]2[CH:18]=[C:17]([NH:16][C:12]3[C:13]4[CH2:14][CH2:15][N:6]([C:31]5[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=5)[CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:26]=[CH:25][C:20]1=2
Reactant: FC(F)(F)CCN1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine from Example 7 (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4A moleculer seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: [OH-].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:22]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:27]=1[O:33][CH3:34])=[N+]=[N-]>C1COCC1.O>[Br:32][C:28]1[C:27]([O:33][CH3:34])=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH2:22]
Reactant: COc1c(Br)cccc1CN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Br)cccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phosphine (Ph3P) were added to a solution of 1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL of water. The mixture was stirred overnight at room temperature. The mixture was quenched with aqueous concentrated hydrochloride. After standard acid/base aqueous work up, 3.9 g of crude 3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps).