Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[S:16][C:17]([C:27]#[N:28])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[C:7]=2[CH:6]=[CH:5]1>O.CCO>[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[S:16][C:17]([C:27]([NH2:28])=[O:1])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[C:7]=2[CH:6]=[CH:5]1
Reactant: Cc1cccc(Nc2c(C#N)sc3c2ccc(=O)n3-c2ccccc2)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2c(C(N)=O)sc3c2ccc(=O)n3-c2ccccc2)c1
Yield: 141.3 %

Procedure:
A solution of KOH (12.69 g, 85+%) in water (230 ml) was added to a suspension of Example 23 (114 g) in EtOH (345 ml). The resulting mixture was heated at reflux for 70 minutes, by which time the reaction had gone to completion. It was cooled and water (285 ml) added. The suspension was filtered and washed with water (200 ml). The product was dried under vacuum to give the title compound as a yellow solid (120 g). δH (CDCl3) 8.90 (1H, s), 7.55-7.65 (3H, m), 7.40 (2H, m), 7.20-7.30 (2H, m), 6.90 (3H, m), 6.35 (1H, d, J 9 Hz), 5.40 (2H, br s), 3.70 (2H, q, EtOH), 2.35 (3H, s), 1.25 (3H, t, EtOH). LCMS (ES+) RT 3.1 minutes, 376 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:17][SiH](C)C>C(Cl)Cl.CO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: Cc1cccc(NC(=O)CCC(=O)O)c1C
Reactant: C[SiH](C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 4-((2,3-dimethylphenyl)amino)-4-oxobutanoic acid (0.5 g, 2.26 mmol) in DCM (9 mL) and MeOH (2 mL) at room temperature was added 2.0 M diazomethyl)trimethylsilane (1.36 mL, 2.71 mmol) dropwise. The reaction was stirred at room temperature for 30 min and quenched with a solution of 20% AcOH in DCM). The mixture was concentrated and purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound as a white solid (0.52 g, 98% yield). LCMS, [M+H]+=236.4.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: Cc1ccc(Br)c2c1NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4c(Br)ccc(C)c43)c2cc1OC
Yield: 70 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 70% yield from 4-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 223°-225° C.; LC-MS: 400, 402 (MH+); anal. RP18-HPLC RT: 5.23 min.).
Reaction SMILES: Cl[C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:17])[C:5]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]3[CH:10]=[N:9][N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]2[N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:19][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(Cl)n1-c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=c1c2cnn(-c3ccccc3)c2nc(N2CCN(c3ccccc3)CC2)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one from step C (20.0 mg, 0.056 mmol) in DCM (1.0 mL) are added 1-phenylpiperazine (17.1 μL, 0.112 mmol) and TEA (15.6 μL, 0.112 mmol). The mixture is stirred at room temperature overnight. After removal of the solvent, the residue is purified by preparative LCMS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 8.11 (d, 2H), 7.52 (m, 4H), 7.38-7.29 (m, 5H), 7.00 (m, 3H), 3.44 (t, 4H), 3.07 (t, 4H); HPLC-MS calculated for C27H23ClN6O (M+H+) 483.2. Found: 483.2.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:24]([CH3:26])[CH3:25])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 42.1 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (1.24 g, 3.23 mmol) (obtained as described in Reference Example 59(3)) in methylene chloride (62 ml) were added methanesulfonyl chloride (0.30 ml, 3.88 mmol) and triethylamine (0.54 ml, 3.88 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (649 mg, yield 42%) as a pale yellow solid.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1[C:13](=[O:27])[N:14]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
A mixture of 3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (4.1 g, 11 mmol), as prepared in the preceding step, and 10% Pd/C (400 mg) in ethanol (100 mL) was hydrogenated under hydrogen (balloon) for 1.5 h. The catalyst was removed by filtration through Celite and the filtrate concentrated to give the title compound as white solid (2.55 g, 97%). 1H-NMR (300 MHz, CDCl3) δ 6.49 (d, J=7.3 Hz, 1H), 5.92 (d, J=7.3 Hz, 1H), 4.75 (s, 2H), 2.19 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][O:11][N:12]([CH3:16])[C:13](Cl)=[O:14]>>[CH3:10][O:11][N:12]([CH3:16])[C:13](=[O:14])[O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9]
Reactant: CON(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Product: CON(C)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino N-methoxy-N-methylcarbamate is prepared from tert-butyl N-hydroxycarbamate and N-Methoxy-N-methylcarbamoyl chloride according to Scheme 1. (2.48 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.83 (1H, s), 3.76 (3H, s), 3.23 (3H, s), 1.48 (9H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3cccnc3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccnc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a solution of 7—(3-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4—(N-methyl-N-(tetra-hydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (0.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7—(3-pyridyl)-N-(4—((N-tetrahydropyran-4-yl-N-methylamino)-methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 146) (0.06 g) as colorless crystals.
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[Si:17]([O:16][C@H:12]1[CH2:11][C@H:10]2[CH2:15][C@@H:13]1[CH2:14][C@@H:9]2[OH:8])([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Palladium (10 wt. % on activated carbon, 1.50 g) was added to a solution of ((1R,2S,4R,5S)-5-(benzyloxy)bicyclo[2.2.1]heptan-2-yloxy)(tert-butyl)diphenylsilane (8.47 g, 18.5 mmol) in methanol (50 mL). The mixture was placed under a balloon of hydrogen. After stirring at ambient temperature for 24 h, the mixture was filtered through a pad of Celite. Solvents were removed in vacuo to give the title compound as a colorless viscous oil.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[CH2:14]([N:18]=[C:19]=[S:20])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][C:19](=[S:20])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[C:6]([O:12][CH3:13])[CH:7]=1)[CH2:15][CH2:16][CH3:17]
Reactant: COc1cc(N)ccc1NNC=O
Reactant: CCCCN=C=S
Product: CCCCNC(=S)Nc1ccc(NNC=O)c(OC)c1

Procedure:
Procedure (12.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.2 g, 0.0066 mole) and butyl isothiocyanate (0.76 g, 0.006 mole). Yield 0.90 g (46%), m.p. 130°-132° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[NH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1>C(O)C>[OH:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([N:16]1[CH2:14][CH2:13][N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[CH2:3][CH2:2]1)[CH2:26][CH2:25]2
Reactant: NC1CCc2cc(O)ccc2C1
Reactant: COc1ccccc1N(CCCl)CCCl
Solvent: CCO
Product: COc1ccccc1N1CCN(C2CCc3cc(O)ccc3C2)CC1

Procedure:
2.48 g of N,N-Di(2-chloroethyl)-2-methoxyaniline are dissolved together with 1.63 g of 2-amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene in 100 ml of ethanol and finally refluxed for 20 hours. The solvent is evaporated off and the residue recrystallized from methanol/ether to yield the title compound. M.P. 282°-286° [Hydrochloride salt form].
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].O[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc(OCc3ccc(B(O)O)cc3)cc2s1
Temperature: 60 °C
Reaction time: 0.79 h
Yield: 94.2 %

Procedure:
2-Cyano-6-hydroxybenzothiazole (2) (150 mg, 0.85 mmol, 1.1 equiv.) and 4-(hydroxymethyl)benzeneboronic acid (5) (166 mg, 0.77 mmol, 1 equiv.) were dissolved in 15 mL dry dimethylformamide (DMF) prior to the addition of cesium carbonate (277 mg, 0.85 mmol, 1 equiv.). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with DI H2O. The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 EtOAc:methanol, dry loaded) to give 225 mg (94%) of the pure product. 1H NMR (400 MHz, d6-Acetone): δ 5.33 (2H, s), 7.23 (2H, s), 7.45 (1H, dd, J=9.0, 2.6 Hz), 7.52 (2H, d, J=8.0 Hz), 7.93 (3H, m), 8.16 (1H, d, J=8.8 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(C)(C)C.[NH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])N(C)OC)=[CH:19][N:18]2[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1>[NH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[F:8])=[CH:19][N:18]2[C:29]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Fc1ccccc1Br
Reactant: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2ccc(C(=O)c3ccccc3F)cn2c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 50.7 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (191 mL, 1.75mmol) in dry THF (2 mL) under an argon atmosphere was added t-butyl lithium dropwise. After stirring for 50 minutes at −78° C., a solution of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (148 mg, 0.5 mmol) in dry THF (3 mL) was added. The resulting red-orange solution was stirred at the same temperature for another 50 minutes and then allowed to warm to RT. The solution was poured into H2O (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with H2O, dried (Na2SO4), and removed in vacuo to give a brown solid. The crude solid was purified by column chromatography (CH2Cl2/CH3CN 2.5/1) to give 84.0 mg (50.6%) of product as a yellow solid. MS(FAB) m/z 332.2 (M++1, 51.99), NMR (200 MHz, CDCl3) d 4.27 (bs, 2H, NH), 7.12-7.58 (m, 11H, ArH+H7+H8), 8.71 (s, H5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1N(Cc1cccnc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 10 g. portion of 3-(2-methylphenylaminomethyl)pyridine was dissolved in 100 ml. of dichloromethane, and 10 g. of potassium carbonate and 8 g. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for 3 days, and was then diluted with 200 ml. of dichloromethane and extracted twice with 100 ml. portions of water. The organic phase was dried over magnesium sulfate and evaporated to an oil, which was chromatographed over silica gel with 1:4 acetone:toluene. The product-containing fractions were combined and evaporated, and the residue solidified upon standing and was recrystallized from hot diethyl ether to obtain 2.9 g. of the desired product, m.p. 97°-98°.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH3:30]C1N=C(NCCC)N=C(C(O)=O)C=1>>[CH3:27][C:25]1[CH:26]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:29])[N:5]=[C:4]([NH:3][CH2:1][CH2:2][CH3:30])[N:9]=3)[O:14][N:13]=2)[CH:16]=[C:17]([CH3:28])[C:18]=1[O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: CCCNc1nc(C)cc(C(=O)O)n1
Product: CCCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{2,6-Dimethyl-4-[5-(6-methyl-2-propylamino-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 6-methyl-2-propylamino-pyrimidine-4-carboxylic acid; LC-MS: tR=0.85 min*; [M+H]+=414.15.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[S:5])[NH:3][C:2]=1[Cl:9].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]Cl)[CH:14]=1>C(O)C>[CH:18]1[C:13]([Cl:12])=[CH:14][C:15]([CH2:19][S:5][C:4]2[N:3]=[C:2]([Cl:9])[CH:1]=[C:7]([NH2:8])[N:6]=2)=[N:16][CH:17]=1
Reactant: Nc1cc(Cl)[nH]c(=S)n1
Reactant: ClCc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Cl)nc(SCc2cc(Cl)ccn2)n1
Temperature: 50 °C

Procedure:
4-Amino-6-chloro-2-thio-pyrimidine (Cpd #110; 614 mg, 2.38 mmol) in ethanol (1.5 ml) is treated with 3.25 M NaOH (1.47 ml, 4.8 mmol) and the mixture is warmed to 50° C. 4-chloro-2-chloromethyl pyridine is added and the solution is stirred warm for 1 hour. The reaction mixture is cooled and concentrated in vacuo, and the resultant solid is filtered and washed with water followed by cold ethanol, mp 195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([C:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]=3[O:27][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1=C(OC(=O)C(C)(C)C)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.077 g, 0.20 mmol) dissolved in anhydrous dichloromethane (3 ml) is added triethylamine (0.031 ml, 0.22 mmol) then pivaloyl chloride (0.027 ml, 0.22 mmol). This mixture is stirred at room temperature for 3 hours, then diluted with dichloromethane (15 ml) and washed with distilled water (2×10 ml). Organic fractions are combined, dried over magnesium sulphate, then concentrated to give a crude oil which is purified by flash chromatography (100% hexane to hexane/ethyl acetate 9:1 ratio) to afford 2,2-dimethylpropionic acid 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-5-oxo-5,6-dihydro-2H-pyran-3-yl ester (0.090 g) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2ccccn2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (prepared by reaction of 1-methyl-4-piperidone with phenyl lithium; 3.83 g, 20 mM) in dry DMSO (50 ml) was treated with sodium hydride (960 mg of 50% dispersion in oil, 20 mM), stirred for 1 hour then treated with 2-fluoro-pyridine (1.94 g, 20 mM). After 48 hours the reaction was poured on to water (200 ml) and extracted with ether (3×200 ml). The organic extract was washed with brine, dried and the solvent removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (2.0 g,) m.p. 95°-6° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 41B was treated with 2-(4-chlorophenyl)acetyl chloride using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59 (s, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.11 (ddd, J=8.0, 1.3, 0.7 Hz, 1H), 7.99 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.91 (ddd, J=7.8, 7.2, 1.3 Hz, 1H), 7.33-7.48 (m, 5H), 4.42-4.46 (m, 2H), 3.67 (s, 2H), 1.37 (s, 9H); MS (APCI+) M/Z 343 (M−CO2tBu+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([CH:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 6 h
Yield: 75.7 %

Procedure:
To a stirred solution of 42 mg (0.30 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 126 mg (0.33 mmol) HATU and 0.066 ml (0.60 mmol) N-methylmorpholine and stirring continued at 50° C. for 6 h. 40 mg (0.15 mmol) 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 44 mg (75%) 4-fluoro-N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 388 (M+H+, 100).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[S:30][C:14]3[N:15]=[C:16]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[N:17]([CH3:18])[C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[S:30][C:14]3[N:15]=[C:16]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[N:17]([CH3:18])[C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1cc2c(nc(CNc3ccc(C(=N)N)cc3)n2C)s1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2sc(C(=O)N(CCC(=O)O)c3ccccc3)cc21
Yield: 85 %

Procedure:
Prepared analogously to Example 2 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]thieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 85% of theory, C24H24N6O3S (476.56); Rf value: 0.36 (Reversed Phase silica gel RP-8; methanol+5% saline solution); EKA mass spectrum: (M+H)+=477; (M+Na)+=499; (M+2Na)++=250.