Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.25 g, 0.67 mmol) was dissolved in THF (10 ml). To this was added diisopropylethylamine (0.33 ml, 1.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.06 ml, 0.74 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 20% heptane, 80% ethyl acetate) to give the title compound (57 mg, 20% yield) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCO
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C2OCCO2)nc1
Yield: 29 %

Procedure:
A mixture of 2-pyridinecarboxaldehyde (267 g, 2.5 mol), ethylene glycol (310.35 g, 5 mol), and 118.8 g (0.62 mol) of p-toluenesulfonic acid in 1.5 L of toluene placed in a 3 L flask fitted with a Dean Stark trap was allowed to reflux until the removal of water was complete. The mixture was concentrated in vacuo and the residue was poured into 800 mL of ice/10% potassium carbonate solution. The above mixture was extracted with ether (2×500 mL), and the organic layer was dried over sodium sulfate, filtered through an active charcoal/supercel and concentrated in vacuo to yield an oil. The oil was distilled (0.15 mm/90° C.) to afford 109.7 g (29.3%) of 2-(1,3-dioxolan-2-yl)-pyridine, as a pale yellow liquid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:21])=O>>[ClH:21].[Cl:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(O)cnnc2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)cnnc2c1
Product: Cl
Yield: 97 %

Procedure:
The starting material 4-chloro-7-methoxycinnoline hydrochloride was obtained by heating a solution of 4-hydroxy-7-methoxycinnoline (352 mg, 2 mmol), (prepared as described in J. Chem. Soc. 1955, 2100), in thionyl chloride (3.5 ml) containing DMF (20 μl) at reflux, for 1 hour. After removing excess thionyl, chloride by evaporation and azeotroping with toluene. The residue was triturated with ether, filtered off and washed with ether to give 4-chloro-7-methoxycinnoline hydrochloride as a yellow solid (450 mg, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([N:33]1[CH2:34][CH2:35][N:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:31][CH2:32]1)=[O:23])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCN(c2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.6 %

Procedure:
12.3 g of N-benzyloxycarbonyltyrosine and 6.6 g of N-phenylpiperazine were dissolved in 150 ml of methylene chloride, and to the solution was added 8.4 g of DCC, and the mixture was stirred at a room temperature for 5 hours. Precipitated insoluble matter was filtered off and the filtrate was concentrated under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (1:1 to 1:2) to obtain 10.5 g of the title compound in a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]=O.Cl>C(OCC)(=O)C>[ClH:13].[CH3:11][CH:10]([CH2:20][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)=[O:12]
Reactant: CCC(=O)c1ccc(C)c(C)c1
Reactant: C1CCNCC1
Reactant: C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C(C)CN2CCCCC2)cc1C
Yield: 61.3 %

Procedure:
72.0 g of 3',4'-dimethylpropiophenone, 59.4 g of piperidine hydrochloride and 20.0 g of paraformaldehyde, 300 ml of ethyl acetate and 1 ml of concentrated hydrochloric acid were heated with stirring under reflux for 2.5 hours, while distilling off water generated through the reaction. After cooling, crystals precipitated were filtered and recrystallized froma mixture of alcohol-acetone, yielding white crystals of the object product. Each filtrate was collected, concentrated under reduced pressure to dryness, and dissolved in water. The solution was washed with ether, then adjusted to be alkaline with 5 N sodium hydroxide and extracted with ether. The extract was washed and then ether was removed after addition ofconcentrated hydrochloric acid, and the residue was recrystallized from a mixture of alcohol-acetone, yielding white crystals of 2,3',4'-trimethyl-3-piperidinopropiophenone hydrochloride (total yield 61.3%), m.p. 184°-185° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:29]2=O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]>O1CCCC1.CO>[CH2:1]([NH:8][C@H:29]1[C@H:28]([NH:27][C:25]([C:20]2[NH:21][C:22]([CH2:23][CH3:24])=[C:18]([Cl:17])[N:19]=2)=[O:26])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 41 %

Procedure:
Benzylamine (70 μL, 0.64 mmol), acetic acid (68.7 μL, 1.20 mmol) and sodium cyanoborohydride (42 mg, 0.667 mmol) were added to a mixed solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (99 mg, 0.267 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 26 mg of the cis isomer of the title compound (21%) as a colorless solid and 50 mg of the trans isomer of the title compound (41%) as a colorless solid.
Reaction SMILES: [N:1]1C=CC=CC=1.[F:7][C:8]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=1N.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[F:7][C:8]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH:9]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(F)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(F)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To a pyridine (20 ml) and DCM (40 ml) solution of 2-fluoro-5-methylaniline (purchased from ACROS, 3.5 g, 28 mmol), methanesulfonyl chloride (purchased from WAKO, 4.3 ml, 56 mmol) was added at room temperature and the mixture was stirred for 20 hours. The reaction was quenched with 2M sodium hydroxide aqueous solution and the aqueous layer was separated and washed with DCM. The layer was cooled to 0° C. and acidified to pH 2.0 using 2M HCl aqueous solution. The precipitates were collected, and the solvent evaporated in vacuo, to give the title compound (5.1 g, 90%). MS (ESI) m/z 202 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][CH3:11])C[NH:5]1.OC1CNC(C(O)=O)CC1>>[CH3:11][O:10][CH:7]1[NH:5][C@H:4]([C:3]([OH:2])=[O:12])[CH2:9][CH2:8]1.[CH3:1][O:2][C:3](=[O:12])[C@@H:4]1[CH2:9][CH2:8][CH2:7][NH:5]1
Reactant: COC(=O)C1CCC(OC)CN1
Agent: O=C(O)C1CCC(O)CN1
Product: COC(=O)[C@@H]1CCCN1
Product: COC1CC[C@@H](C(=O)O)N1

Procedure:
By substituting 5-methoxypipecolic acid methyl ester [preparing from 5-hydroxypipecolic acid by the procedure described in J. Chem. Soc. 429 (1945) for 5-methoxyproline] for the L-proline methyl ester in the procedure of Example 18, 2,3-dehydro-1-(3-acetylthio-1-oxopropyl)-5-methoxypipecolic acid is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:15])=[CH:4][N:3]=1.[CH2:16]([N:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)[CH3:17].Cl.O1CCOCC1>C(O)(C)C>[Cl:15][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:29][C:26]2[CH:27]=[CH:28][C:21]3[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:24][CH2:23][C:22]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)CCNc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCCC(=O)NC)n3)cc2CC1
Yield: 23.9 %

Procedure:
A solution of 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-propionamide (35 mg, 0.14 mmol) in isopropanol (3 mL) was treated 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (27 mg, 0.14 mmol) and 4N HCl/dioxane (0.035 mL, 0.14 mmol). The reaction was irradiated at 130° C. for a total of 20 minutes. A white precipitate formed in the reaction mixture, which was collected via vacuum filtration and triturated with acetonitrile (5 mL) to afford 3-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-propionamide (13.5 mg) as the HCl salt. LC/MS (ESI)=403.02 (M+H), MP=206.1° C. 1H NMR (400 MHz, DMSO, d6) δ 10.51 (m, 1H), 10.05 (m, 1H), 8.12 (s, 1H), 7.88 (m, 1H), 7.59 (s, 1H), 7.42 (m, 1H), 7.17 (d, 1H, J=8.34 Hz), 3.62 (m, 7H), 3.29 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 2.59 (s, 3H), 2.45 (m, 2H), 1.27 (m, 3H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25].C[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C1COCC1>[CH3:1][C:30]1[CH:29]=[CH:28][CH:33]=[CH:32][C:31]=1[N:34]1[CH2:35][CH2:36][N:37]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([OH:15])=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=2)[CH2:38][CH2:39]1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(Cc2ccc(O)c([N+](=O)[O-])c2)CC1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (1.8 g, 8.4 mmol) is added to a solution of 4-hydroxy-3-nitro-benzaldehyde (1.3 g, 8.0 mmol) and 1-(4-methyl-phenyl)-piperazine (2.8 g, 16.1 mmol) in 50 mL of THF at room temperature, and the mixture is stirred overnight. The reaction is quenched by pouring into 400 mL of water, and the precipitate which forms is collected by filtration. Yield=1.7 g (33%) of 4-[4-(methylphenyl)-piperazin-1-ylmethyl]-2-nitro-phenol oil.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:10]([NH2:11])=[C:9]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:8]=[C:7]([CH3:17])[N:6]=1.[CH2:18]([O:20][CH2:21][C:22](Cl)=[O:23])[CH3:19]>C(N(CC)CC)C>[Cl:4][C:5]1[C:10]([NH:11][C:22](=[O:23])[CH2:21][O:20][CH2:18][CH3:19])=[C:9]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH:8]=[C:7]([CH3:17])[N:6]=1
Reactant: CCOCC(=O)Cl
Reactant: Cc1cc(NCC(C)C)c(N)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1c(NCC(C)C)cc(C)nc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Anhydrous dichloromethane (300 ml), 2-chloro-N4-(2-methylpropyl)-6-methyl pyridin-3,4-diamine (4.14 g) from Part B and triethylamine (2.93 ml) were combined and cooled to 0° C. To the resulting mixture was added dropwise ethoxyacetyl chloride (2.49 g). After 1 hour the resulting reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction, monitored by HPLC, was complete, and the solvent was removed under reduced pressure. The resulting yellow oil was dissolved in ethyl acetate, and the resulting solution was washed with water. The organic layer was dried with magnesium sulfate and concentrated to a yellow oil under reduced pressure. The yellow oil was put through a column of silica gel using 20/80 ethyl acetate/hexane. NMR analysis of the oil obtained after removal of the solvent under reduce pressure indicated desired product (3.64 g) of good purity for use in the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:29]([C:37]([OH:39])=O)[C:28](=[O:40])[N:27]1[CH3:41].[F:42][C:43]1[CH:44]=[C:45]([NH2:62])[CH:46]=[CH:47][C:48]=1[O:49][C:50]1[C:59]2[C:54](=[CH:55][C:56]([O:60][CH3:61])=[CH:57][CH:58]=2)[N:53]=[CH:52][CH:51]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:42][C:43]1[CH:44]=[C:45]([NH:62][C:37]([C:29]2[C:28](=[O:40])[N:27]([CH3:41])[N:26]([CH3:25])[C:30]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:39])[CH:46]=[CH:47][C:48]=1[O:49][C:50]1[C:59]2[C:54](=[CH:55][C:56]([O:60][CH3:61])=[CH:57][CH:58]=2)[N:53]=[CH:52][CH:51]=1
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cn1c(-c2ccccc2)c(C(=O)O)c(=O)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(-c5ccccc5)n(C)n(C)c4=O)cc3F)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of HATU (458 mg, 1206 μmol), 1,2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (140 mg, 603 μmol), 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (258 mg, 908 μmol), and Triethylamine (254 μL, 1809 mmol) in DMF (2 mL) was stirred at 60° C. overnight. The mixture was diluted with EtOAc (10 mL). The mixture was transferred to a separatory funnel with EtOAc (20 mL) and was washed with NaOH (1N, 10 mL), H2O (2×10 mL), NaHCO3 (sat), NaCl (sat), and dried over Na2SO4. The residue after concentration was purified on silica gel and the product was triturated with EtOAc-hexane (1:2) to afford a pink solid (106 mg, 35%). Calc'd for C28H23FN4O4: 498; MS (ESI pos. ion) m/z: 499 (MH+). 1HNMR (CDCl3, 400 MHz): 11.04 (1H, s), 8.56 (1H, d, J 5.3), 7.88 (1H, d, J 14.7), 7.55-7.40 (5H, m), 7.47 (1H, s), 7.35 (1H, d), 7.22 (1H, d, J9.1), 7.13 (1H, t, J 8.8), 6.36 (1H, d, J 5.3), 3.96 (3H, s), 3.62 (3H, s), 3.41 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[S-:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[K+]>CN1CCCC1=O.O>[C:10]1([S:9][C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [S-]c1ccccc1
Reactant: O=c1ccc(Br)c[nH]1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1ccc(Sc2ccccc2)c[nH]1

Procedure:
A solution of 5-bromo-2-pyridone (17.3 g 0.1 mole) in N-methylpyrrolidinone (250 ml.) and potassium thiophenoxide (18.1 g, 0.12 mole) is heated at reflux for 12 hours under a nitrogen atmosphere. The reaction mixture is cooled and diluted with water. The product is collected by filtration, washed with water and dried to yeild 5-(phenylthio)-2-pyridone.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].NCC[CH2:9][CH2:10][CH2:11][CH2:12]N>C(O)CCCCO>[CH3:9][CH2:10][CH2:11][CH2:12][NH:4][C:3]([NH2:5])=[N:2][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: N=C(N)N
Reactant: NCCCCCCN
Agent: Cl
Agent: OCCCCCO
Product: CCCCN=C(N)NCCCC
Temperature: 80 °C

Procedure:
Guanidine hydrochloride (200 parts) and hexamethylene diamine (292 parts) were heated to 120° C. for 4 hours under a nitrogen atmosphere. The temperature of the reaction mixture was then raised to 150–170° C. for a further 10 hours. The product was cooled to 80° C. and 1,5-pentanediol (400 parts) was added while the temperature was maintained at 80° C. until dissolution occurred. The mixture was then cooled to give a solution of polyhexamethyleneguanidine (prepolymer 3) in 1,5-pentanediol.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH3:6])[CH3:3].[CH2:7]([O:14][NH:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][N:15]([CH:2]([CH3:3])[CH2:4][CH2:5][CH3:6])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Reactant: CCCC(C)Br
Product: CCCC(C)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 67.8 %

Procedure:
Using the general method of Compound 42 Part B, 2-bromopentane (2.7 mL, 21.7 mmole) was reacted with 1-benzyloxy-3-phenylurea (4.9 g, 20.1 mmole) to provide 4.26 g of 1-benzyloxy-1-(1-methylbutyl)-3-phenylurea as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH3:26])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([C:17]1[C:18]([CH3:26])=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:16]=1[O:15][CH3:14])=[O:9]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COc1ccc(Br)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6B (24 g, 10 mmol), 3,4,5-trimethoxytoluene (1.82 g; 10 mmol), P2O5 (10.0 g) and dichloromethane (150 ml) is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by column chromatography (petrol ether: ethyl acetate, 8:2 v/v) and recrystallized from diisopropylether. The solid material is collected by vacuum filtration, washed with cold petrol ethers:diisopropylether (1:1 v/v) and dried, yielding white crystals, 2.2 g (54% ), mp 89-91° C.
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][N:4]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:10]=[CH:9][C:8]=2[C:7]2[N:20](COCC[Si](C)(C)C)[N:21]=[CH:22][C:6]=2[C:5]1=[O:31].FC(F)CN1C2C=C(C3C=CN=CC=3)C=CC=2C2NN(COCC[Si](C)(C)C)CC=2C1=O.[ClH:65].O1CCOCC1>C(Cl)Cl.C(O)(C)C>[ClH:65].[F:32][CH:2]([F:1])[CH2:3][N:4]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:10]=[CH:9][C:8]=2[C:7]2[NH:20][N:21]=[CH:22][C:6]=2[C:5]1=[O:31]
Reactant: C[Si](C)(C)CCOCn1ncc2c(=O)n(CC(F)F)c3cc(-c4ccncc4)ccc3c21
Agent: C[Si](C)(C)CCOCN1Cc2c(c3ccc(-c4ccncc4)cc3n(CC(F)F)c2=O)N1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1c2cn[nH]c2c2ccc(-c3ccncc3)cc2n1CC(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg, 0.22 mmol) in 2 mL of DCM is added a 4M solution of anhydrous hydrogen chloride in dioxane (1.10 mL, 4.38 mmol) at room temperature. After stirring at room temperature for 24 hours, the mixture is filtered. The solid obtained is taken up in isopropanol, filtered off and dried under vacuum to give 74 mg of a white powder (hydrochloride, yield: 94%).
Reaction SMILES: [CH2:1]([O:4]C(=O)NC1CC(=O)OC1OC1CCCC1)[CH:2]=C.[O:20]=[C:21]1[O:25][CH:24]([O:26][CH2:27][CH2:28][C:29]2C=CC=[CH:31][CH:30]=2)[CH:23]([NH:35][C:36]([CH:38]2[CH2:42][CH2:41][CH2:40][N:39]2[C:43](=[O:57])[CH:44]([NH:46][C:47](=[O:56])[C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]([Cl:55])[CH:49]=2)[CH3:45])=[O:37])[CH2:22]1>>[CH:27]1([O:26][CH:24]2[CH:23]([NH:35][C:36]([CH:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43](=[O:57])[CH:44]([NH:46][C:47](=[O:56])[C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:1](=[O:4])[CH3:2])=[C:50]([Cl:55])[CH:49]=3)[CH3:45])=[O:37])[CH2:22][C:21](=[O:20])[O:25]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OC2CCCC2)cc1Cl
Yield: 69 %

Procedure:
Prepared from 97b and (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 215 mg of title compound (69% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.35-1.90 (m, 1H), 1.90-2.35 (m, 4H), 2.24 (s, 3H), 2.40-3.10 (m, 2H), 3.50-3.95 (m, 3H), 4.15-4.90 (m, 3H), 5.44 (s, 0.55H), 5.56 (s, 0.15H), 5.64 (d, 0.22H), 5.71 (d, 0.08H), 7.70-8.25 (m, 3H). Analytical HPLC: 12.13 min. LC-MS (ES+): m/e=549.2 (M+H+).
Reaction SMILES: [C:1](S)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH:9](Br)([CH3:11])[CH3:10].O[O:14][S:15]([O-:17])=O.[K+]>CS(C)=O.CO.O>[CH:9]([S:15]([C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:17])=[O:14])([CH3:11])[CH3:10]
Reactant: CC(C)Br
Reactant: O=S([O-])OO
Reactant: CC(C)(C)S
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: CC(C)S(=O)(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
To a solution of tert-butyl thiol XXIIa(i) (1.50 mL, 13.2 mmol) in DMSO (8 mL) was added NaOMe (802 mg, 14.7 mmol) and isopropylbromide (0.62 mL, 6.54 mmol) at rt. The resulting cloudy solution was heated to 90° C. and stirred for 5 hrs at the same temperature. The reaction was quenched with water, extracted by ether, dried over MgSO4. The organic phase was concentrated to afford the crude sulfide. This sulfide was directly used for the next step. To a solution of the above crude sulfide in MeOH (30 mL) was added a solution of oxone (6.8 g, 11.0 mmol) in water (30 mL) at 0° C. The resulting cloudy solution was warmed to rt, then stirred for 5 hrs. The reaction mixture was concentrated using rotary evaporator, diluted with water, extracted with EtOAc. The organic layer was separated, dried over MgSO4, concentrated to afford the crude sulfone which was purified by flash chromatography (EtOAc:Hex=1:3 to 1:2) to give 594 mg (56% for 2 steps) of tert-butyl isopropyl sulfone XXIc(i)). Rf 0.36 (1:2-EtOAc:Hex); 1H NMR (400 MHz, CDCl3) δ 3.40 (m, 1H), 1.44 (s, 9H), 1.42 (d, J=6.8 Hz, 6H).