Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([N:22]3[CH:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[N:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:36]1[CH:40]=[CH:39]N=N1.C([O-])([O-])=O.[K+].[K+].S1(CCCC1)(=O)=O>C(O)(=O)C.ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:16]([N:22]3[CH:26]=[C:25]([C:27]4[O:29][CH:39]=[CH:40][N:36]=4)[CH:24]=[N:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(C(=O)O)cn2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(-c3ncco3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 mL scintillation vial was charged with 1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (87 mg, 0.2 mmol), oxalyl chloride (2 mL, 1.0 M solution in dichloromethane), and dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours, the volatiles removed in vacuo, and the residue further dried at reduced pressure for 4 hours. The scintillation vial containing the crude acid chloride was subsequently charged with 1H-1,2,3-triazole (34 mg, 0.5 mmol), K2CO3 (138 mg, 1.0 mmol), and sulfolane (2 mL). The vial was sealed and stirred at 80° C. for 16 hours. The reaction solution was neutralized to pH=7 with glacial acetic acid. The mixture was extracted with ethyl acetate (2×10 mL) and the combined organics were concentrated in vacuo. The residue was purified via preparative HPLC to afford 4-tert-butyl-N-[5-chloro-2-(4-oxazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamide as a white powder: MS (ES) M+H expected 458.1, found 458.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.Cl.ClC1C=CC(NN)=CC=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][C:4]([CH3:13])=[C:3]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:2]3=[N:30]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnc(C)c(-c2ccccc2)c1Cl
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: COc1ccc(-n2nc3c(-c4ccccc4)c(C)[nH]cc-3c2=O)cc1
Yield: 4 %

Procedure:
Following a similar procedure to that described in Example 4, except using ethyl 4-chloro-2-methyl-3-phenyl-5-pyridinecarboxylate and 4-methoxyphenylhydrazine hydrochloride instead of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate and 4-chlorophenylhydrazine hydrochloride, the title compound was prepared, after further purification by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and recrystallization (CH2Cl2-MeOH-EtOAc), in 4% yield as a yellow solid; mp 300-310° C.; 1H NMR (360 MHz, DMSO-d6) δ2.25 (3H, s), 3.74 (3H, s), 6.93 (2H, d, J 9.2 Hz), 7.43 (1H, m), 7.47-7.51 (4H, m), 7.95 (21H, d, J 9.1 Hz), 8.50(1H, s), 12.34 (1H, br s); MS (ES+) m/z 332 [MH]+. Anal. found: C, 72.15; H, 4.84; N, 12.66. C20H17ClN3O2 requires: C, 72.49; H, 5.17; N, 12.68%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([SH:14])[CH2:12][CH3:13].Cl[C:16]1[N:30]=[C:29]([Cl:31])[C:28]([F:32])=[CH:27][C:17]=1[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19]>C1COCC1.CN(C=O)C>[Cl:31][C:29]1[C:28]([F:32])=[CH:27][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[C:16]([S:14][CH2:11][CH2:12][CH3:13])[N:30]=1
Reactant: CCCS
Reactant: O=C(NC1CCCCC1)c1cc(F)c(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide (8.24 mL, 8.24 mmol) in THF (1M) was added to a stirred solution of 1-propanethiol (0.622 mL, 6.87 mmol) in DMF (30 mL) at 5° C., over a period of 3 minutes under air. The resulting suspension was stirred at 20° C. for 15 minutes. 2,6-dichloro-N-cyclohexyl-5-fluoronicotinamide (2.0 g, 6.87 mmol) in DMF (10 mL) was added at room temperature.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: COc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 68, 1268 (1946)) and 3.0 mL of 4-chlorobenzylamine is stirred 1 h at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.39 g.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]2[N:25]([CH3:26])[N:24]=[CH:23][C:10]=2[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:13]=1.C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[O:47]1[CH2:50][CH:49]([NH2:51])[CH2:48]1>ClCCCl.CCOC(C)=O>[CH3:26][N:25]1[C:9]2[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])=[N:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:35]([NH:51][CH:49]4[CH2:50][O:47][CH2:48]4)=[O:37])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:23]=[N:24]1
Reactant: NC1COC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc([N+](=O)[O-])cc2)nc2cnn(C)c12
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3COC3)cc2)nc2cnn(C)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.6 %

Procedure:
To a stirred solution of (S)-3-methyl-4-(1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)morpholine (50.0 mg, 0.154 mmol) in anhydrous 1,2-dichoroethane (5.0 mL) was added triethylamine (0.071 mL, 0.51 mmol, 3.3 eq.). The reaction was cooled to 0° C. and triphosgene (45.7 mg, 0.154 mmol, 1.0 eq) was added in one portion. After stirring at 0° C. under N2 for 5 minutes, the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to RT, and 3-oxetanamine hydrochloride (84.4 mg, 0.77 mmol, 5.0 eq.) was then added. The reaction mixture was stirred at RT under N2 for 16 h and then diluted with EtOAc (25 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by column chromotagraphy (Si-PPC, gradient 50 to 100% EtOAc in heptane, followed by 0 to 30% methanol in dichloromethane). Trituration from methanol afforded the title compound (49.3 mg, 75.5%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.76 (s, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.97 (d, J=6.7 Hz, 1H), 4.85 to 4.69 (m, 3H), 4.44 (t, J=6.0 Hz, 2H), 4.23 to 4.12 (m, 4H), 3.96 to 3.81 (m, 2H), 3.72 (dd, J=14.7 Hz, 5.8 Hz, 1H), 3.69 to 3.58 (m, 2H), 3.50 (d, J=13.3 Hz, 1H), 1.26 (d, J=6.5 Hz, 3H); LC-MS m/z (method C1)=424.2 [M+H]+, RT=3.12 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH:13]2[CH2:14][CH2:15][CH2:16][C:11]([CH3:18])([CH3:10])[CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)CCCC(=O)C1
Reactant: Cc1c(N)cccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC1CCCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-2-methylaniline (1000 mg) and 3,3-dimethylcyclohexanone (780 mg) were added to dichloromethane (25 mL) and the mixture was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (1367 mg) was then added and the solution was stirred at room temperature for 16 hours. Additional 3,3-dimethylcyclohexanone (780 mg) and sodium triacetoxyborohydride (1367 mg) were added, and the mixture was stirred for another 16 hours. The mixture was then washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified on silica gel using 2.5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1>Cl.O1CCOCC1.CO>[NH2:32][CH2:31][CH2:30][C:24]1([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:21][CH2:20]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNC(=O)OC(C)(C)C)CCCCC3)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.9 %

Procedure:
tert-Butyl [2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate (0.4760 g) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution (10.0 mL) and methanol (5 mL). The solution was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give the title compound (0.5036 g).
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:20]1[CH2:21][CH2:22][CH2:2][C:24]1=[O:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1cccc(CBr)c1
Reactant: C1CCOC1
Agent: [Li+]
Product: O=C1CCCC1Cc1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Compound 1b (7.0 g) was added to a solution of LHMDS (1M, 50 mL) in THF (50 mL) at −78° C. The mixture was stirred for 30 mins at −78° C. and then 1-bromomethyl-3-fluoro-benzene Compound 1c (8.80 g, 46.55 mmol) in THF (10 mL) was added dropwise. The mixture was stirred for 24 hrs while warming to room temperature. The reaction mixture was quenched with 1N HCl (5 mL), diluted with H2O (100 mL) and EtOAc (500 mL) and the organic layer was washed with brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude oil. Purification by flash chromatography (10% EtOAc in Hexane) to provide 2-(3-fluoro-benzyl)-cyclopentanone Compound 1d (5.20 g, 27.05 mmol, 58% yield) as a yellow oil.
Reaction SMILES: C1(S([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:26]=4)[NH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C(F)(F)F.C1COCC1>[CH3:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:19]([C:12]4[C:13]5[C:14](=[CH:15][N:16]=[CH:17][CH:18]=5)[NH:10][CH:11]=4)=[CH:20][NH:21][C:22]3=[N:23][CH:24]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(-c2cnc3[nH]cc(-c4cn(S(=O)(=O)c5ccccc5)c5cnccc45)c3c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3[nH]cc(-c4c[nH]c5cnccc45)c3c2)cn1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A suspension of 112 mg (0.25 mmol) of 1-benzenesulfonyl-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrolo[2,3-c]pyridine (“A14”) and 261 mg (0.74 mmol) of caesium carbonate in 1 ml of trifluoroethanol and 2 ml of THF is stirred at 65° C. for 18 hours. The reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrolo[2,3-c]pyridine as colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])(=O)C.[Na+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:16](OC)=[O:17]>C(O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2)=[CH:21][CH:22]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2ccccc2SC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a suspension of 2-aminothiophenol (12.6 g) and sodium acetate (23.6 g) in ethanol (150 ml) is added methyl α-bromo-4-fluorophenylacetate (23.6 g), and the mixture is stirred at room temperature overnight. After the solvent is distilled off, water is added to the residue. The resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (21.7 g) as crystals. M.p. 216°-219° C.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:18])[NH:9][C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3].CN(C)C=O.[CH2:24](Br)[CH:25]=[CH2:26]>O>[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:18])[N:9]([CH2:26][CH:25]=[CH2:24])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(N)c2ccccc2[nH]c1=O
Reactant: C=CCBr
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c(C(=O)OCC)c(N)c2ccccc21

Procedure:
To a solution containing 7.6 g. (0.03 mole) of the sodium salt of 4-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid ethyl ester in 50 ml. of dimethylformamide was added 4.8 g. (0.04 mole) of allyl bromide. The reaction mixture was heated on a steam bath for 1/2 hour. The reaction mixture was cooled in ice and poured into 500 ml. of water. The resulting precipitate was collected on a filter and recrystallized from ethyl acetate-petroleum ether giving 4.6 g. of product, m.p. 132°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[CH:14][CH:15]=O.C(=O)(O)O.[NH2:21][NH:22][C:23]([NH2:25])=[NH:24].[C:26]([OH:29])(=[O:28])[CH3:27]>C(O)C>[C:26]([O-:29])(=[O:28])[CH3:27].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[CH:14][CH:15]=[N:21][NH:22][C:23]([NH2:25])=[NH2+:24]
Reactant: O=CC=Cc1cccn1-c1ccccc1Br
Reactant: N=C(N)NN
Reactant: CC(=O)O
Agent: O=C(O)O
Solvent: CCO
Product: CC(=O)[O-]
Product: NC(=[NH2+])NN=CC=Cc1cccn1-c1ccccc1Br
Yield: 31 %

Procedure:
0.9 g (3.26 mmol) 4b and 1.2 eqv. of aminoguanidine bicarbonate was mixed in 10 ml of ethanol and 2 ml of acetic acid and refluxed for 30 min. The solvent was evaporated and the oily residue was dissolved in acetonitrile and a few drops of diethyl ether was added. After three days in refrigerator a precipitate was formed that was filtered, washed with diethyl ether and dried. 340 mg (31%) of the final product 5b was obtained as white crystals (m.p. 166-168° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[N:14]=[C:15]([C:17]4[C:18]([CH3:26])=[N:19][N:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=45)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([C:17]4[C:18]([CH3:26])=[N:19][N:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=45)[S:16][C:12]=3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In a 500 mL round bottomed flask was placed 4-(4-chlorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4,5,6,7-tetrahydro-1,3-benzothiazol-4-ol prepared above. The material was suspended in 1,2-dichloroethane (50 mL) and the suspension was stirred for 60 min at 90° C. To the hot solution were added triethylsilane (2 mL, 10 mmol) and trifluoroacetic acid (3 mL, 40 mmol). The mixture Was stirred for 2 days at the same temperature. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and then washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography, eluting with 30% to 100% EtOAc/hexane to yield the title compound (622 mg; 91.8%) as a yellow crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ ppm 8.66 (dt, 1H), 7.95 (dt, 1H), 7.33-7.37 (m, 3H), 7.16 (d, 2H), 6.96 (td, 1H), 4.27 (t, 1H), 2.84-2.93 (m, 2H), 2.56 (s, 3H), 2.15-2.21 (m, 1H), 1.77-1.88 (m, 3H).
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:19])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: O=C(CCBr)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1

Procedure:
Compound 9d was synthesized by a procedure similar to that described for 9a using commercially available 3-bromopropiophenone (8d, 1.0 g, 0.0047 mol), TBDMSOTf (1.4 mL, 5.1 mmol), and Et3N (1.1 mL) in CH2Cl2 (10 mL). After workup, 1.15 g (75%) of crude 9d was isolated as colorless oil with a Z-E ratio of 94:6: 1H NMR (CDCl3) δ 7.64-7.58 (m, 1H), 7.41-7.34 (m, 2H), 7.17 (t, 1H, J=8.04 Hz), 5.25 (q, 1H, J=6.9 Hz), 1.75 (d, 3H, J=6.9 Hz), 1.02 (s, 9H), −0.03 (s, 6H); 13C NMR (CDCl3) δ 148.8, 141.9, 130.2, 129.5, 128.7, 124.1, 122.1, 25.8, 18.3, 11.8, −4.0. C15H23BrOSi.
Reaction SMILES: I.[PH2](O)=O.[CH3:5][C:6]1[NH:7][CH:8]=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)(=O)C.O>[CH3:5][C:6]1[NH:7][C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1c(C)[nH]c(Cc2ccccc2)c1C
Reaction time: 0.17 h

Procedure:
A solution of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of 50% hypophosphorous acid containing 548 mg of 2,4-dimethyl-3acetyl pyrrole was stirred magnetically while a solution of 0.6 ml of benzaldehyde in 5 ml of acetic anhydride was slowly added over 20 mins. The solution was stirred for 10 mins, then poured into water. The crude product which separated was recrystallized from acetone (thimble) as nearly colourless irregular plates (85%, m.p. 165.5°-167° C. after a partial change to prismatic rods above 165° C. Anal. Cal. for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.22; H, 7.50; N, 6.18.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:24])(C)[CH2:19]C(C)C)=[O:10].C(OC)(OC)OC.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[F:1])=[O:10])(=[O:24])[CH3:19]
Reactant: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)(O)CC(C)C
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(OC)OC
Product: CC(=O)c1ccccc1NC(=O)c1c(C)nn(C)c1F
Reaction time: 1 h

Procedure:
14 g (80% pure, 33.6 mmol) of 5-fluoro-N-[2-(1-hydroxy-1,3-dimethylbutyl)phenyl]-1,3-dimethyl-1H-pyrazole-4-carboxamide and 4.28 g (40.3 mmol) of trimethyl orthoformate are dissolved in 420 ml of toluene, and 5 drops of concentrated sulphuric acid are added. The solution is boiled for 1 h, treated with sodium sulphate and filtered off, and the filtrate is concentrated under reduced pressure. The residue is treated with 300 ml of heptane. This results in the N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide still present in the starting material precipitating out. The filtrate is concentrated using a rotary evaporator, giving 10.7 g of a yellow oil. Examination by GC/MS shows the following composition: 24% A, 25% B, 29% C and 7% of a methanol adduct.
Reaction SMILES: Br[CH:2]([C:5]([C:7]1[CH:8]=[N:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1)=O)[C:3]#[N:4].[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[NH2:24][C:22]1[S:23][C:2]([C:3]#[N:4])=[C:5]([C:7]2[CH:8]=[N:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]=2)[N:21]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Cn2cc(C(=O)C(Br)C#N)cn2)cc1
Solvent: CCO
Product: COc1ccc(Cn2cc(-c3nc(N)sc3C#N)cn2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
According to Scheme 7, Step 3: To a solution of 2-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (25.3 mmol, 8.44 g) in EtOH (120 mL) was added thiourea (26.5 mmol, 2.06 g). The resulting mixture was stirred at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by silica column on combi-flash EtOAc/PE (1:10 to ˜1:1) to give 2-amino-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-5-carbonitrile as a yellow solid (22.0 mmol, 6.83 g, 87%).
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].O>CC(O)C.C[O-].[Na+]>[OH:12][C@@H:11]1[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@H:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:2]1[OH:1]
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@@H]3O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g (20.5 mmol) of (8R,9R)-8-hydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 30 ml of 2-propanol and 2 ml of 0.3% strength methanolic sodium methoxide solution. 0.4 g (10.2 mmol) of sodium borohydride, dissolved in 5 ml of 0.3% methanolic sodium methoxide solution, is added dropwise at 10° C. in the course of 10 minutes. The reaction mixture (suspension) is stirred overnight at room temperature (a solution forms in the course of this). The reaction solution is added to 90 ml of water and extracted three times with 30 ml of ethyl acetate each time. The combined ethyl acetate phases are washed once with water and concentrated. The residue is chromatographed on silica gel (ethyl acetate/2-propanol 95:5). The product fractions are concentrated and crystallized using diethyl ether. The crystals are filtered off with suction and dried at 50° C. in a high vacuum. 4.3 g (71% of theory) of the title compound of m.p. 119° C. (decomposition) are obtained.