Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]([C:30]1[N:31]=[C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:33][C:34]=1[CH2:35]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([C:30]1[N:31]=[C:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:33][C:34]=1[CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCc1oc(-c2ccccc2)nc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(Cc2oc(-c3ccccc3)nc2Cc2ccccc2)CC1
Yield: 74 %

Procedure:
A suspension containing 2-methoxyphenylpiperazine (1.0 mmole), potassium carbonate (2.0 mmole), potassium iodide (0.5 mmole) and 4-benzyl-5-chloromethyl-2-phenyloxazole (1.0 mmole) from example 6, was stirred in acetone (15 ml) at ambient temperature for 16 hr. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (2×50 ml). The combined organics were washed with water (40 ml), brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as an off-white crystalline powder (0.74 mmole, 74% yield). This was transformed into its mono-fumarate salt, an off-white crystalline powder, using the procedure outlined in example 10 above. mp 175-175° C.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24]C)[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:26][C:9]1[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCC3CCCNC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
To a solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (35 mg, 0.097 mmol) in methanol (4 ml) was added 4M HCl in dioxane (1.5 ml, 6.00 mmol) and the mixture was allowed to stir at room temperature for 1.5 hours. The reaction was then dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. This was redissolved in methanol (˜5 mL) and passed down a 2 g aminopropyl (—NH2) SPE cartridge. The filtrate was dried under a stream of nitrogen in Radleys blowdown apparatus. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as an off-white solid (21.5 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: BrCC1CCCCO1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC2CCCCO2)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered K2CO3 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60° C. overnight. The mixture was taken up in water and ethyl acetate. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].IC.[CH3:34][Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:34])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
{2′-[(Acetyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.143 g, 0.33 mmol) and iodomethane (0.02 mL, 0.36 mmol) were combined in THF (1.5 mL) and cooled to −78° C. Sodium hexamethyldisilazide (1M in THF; 0.36 mL, 0.36 mmol) was added, and the mixture was stirred for 1 hour at −78° C. Once no starting material was seen by analytical LCMS, the mixture was quenched with aqueous 1N HCl and diluted with CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([CH2:18][C:19](=O)[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([C:18]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([Br:2])[CH:8]=2)[NH:9][C:19]=1[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccc(Br)cc2c1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 3. Thus, 4-bromophenylhydrazine, hydrochloride (4.694 g, 21 mmol) was reacted with benzylacetone (2.964 g, 20 mmol) in ethanol (60 ml) to give the product (3.199 g, 10.657 mmol, 51%) as a tan solid, mp 130-134° C. 1H NMR (DMSO-d6) δ 2.36 (s, 3H), 3.95 (s, 2H), 7.05 (dd, J=1.8, 8.4 Hz, 1H), 7.12 (t, J=7.2 Hz, 1H), 7.17-7.20 (m, 3H), 7.23 (t, J=7.8 Hz, 2H), 7.43 (d, J=1.7 Hz, 1H), 11.01 (s, 1H); [ESI(−)], m/z 298/300 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])=[CH:6][CH:5]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[N:3]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17]
Reactant: Nc1ccc(Nc2ccc(C(=O)c3c(F)cccc3F)c(N)n2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(Nc2ccc(NS(=O)(=O)c3ccccc3)cc2)ccc1C(=O)c1c(F)cccc1F
Yield: 73.5 %

Procedure:
A solution of Compound 17 (5.8 mg, 0.017 mmol), benzenesulfonyl chloride (2.38 μL, 0.019 mmol), triethylamine (2.9 μL, 0.021 mmol) in THF (0.2 mL) and methylene chloride (0.2 mL) was stirred at rt for about 2 hours. The resultant mixture was then separated by chromatography (on silica gel, eluting with 1:1 ethyl acetate:hexane) to give Compound 19 (6 mg, 73% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([OH:14])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH3:16])[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([O:14][C:23](=[O:25])[CH3:24])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)c2c1cc(C)c(O)c2C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc2c(c1C)C(C)CN2C(C)=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To an ice-cold solution of indoline 11a (219 mg, 1 mmol) dissolved in methylene chloride (5 mL) were added sequentially pyridine (1 mL) and acetic anhydride (0.12 mL, 1.1 mmol), and the resulting mixture was stirred over a range of 0° C. to room temperature for 18 h. The reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were washed with 5% aq. hydrochloric acid and brine then dried (MgSO4). Removal of solvents and chromatographic purification of the residue using 3:7 ethyl acetate:hexanes as eluent gave the acetate 12a (228 mg, 87% yield) as a pale yellow solid. This was recrystallized from hexanes-methylene chloride to afford a colorless solid, mp 128°-130° C. Spectral data: 1H NMR: δ 1.23 (d, 3H, J=7 Hz), 2.04 (s, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 2.31 (s, 3H), 3.61 (dd, 1H, J=10.2, 2.3 Hz), 4.13 (t, 1H, J=9.53 Hz), 7.96 (s, 1H); 13C NMR: δ 12.3, 16.7, 20.4, 20.7, 24.8, 33.9, 57.4, 116.4, 125.7, 129.3, 133.7, 139.5, 144.2, 168.5, 169.1; HRMS: calcd. for C15H20NO3 (M+H+) 262.1443, fnd. 262.1446.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:51][NH:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:52]([CH3:51])[CH2:53][C:54]6[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: CNCc1cccnc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N(C)Cc4cccnc4)cc3F)cn2)cc1
Yield: 100.6 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and N-methyl-N-(3-pyridylmethyl)amine (21.6 mg, 0.177 mmol) instead of 1-pyridine-3-yl-piperazine, the amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-N-methyl-N-pyridin-3-ylmethyl-benzamide as a yellow solid (92.8 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-318) as a yellow powder (38.0 mg, 59%).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C1C=CC=CC=1>[CH:13]1[C:14]2[CH:2]([O:1][C:22](=[O:25])[CH:23]=[CH2:24])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: OC1c2ccccc2-c2ccccc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1c2ccccc2-c2ccccc21
Temperature: 8 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a 250 mL round-bottomed flask was added 9-hydroxyfluorene (5 g, 27.4 mmol) and triethylamine (3.86 ml, 27.4 mmol) in benzene (150 mL) to give a colorless solution. The solution was cooled to 8° C. with an ice bath. Next, acryloyl chloride (2.229 mL, 27.4 mmol) was dissolved in 25 mL of benzene, placed in a dropping funnel, and added over 1 hour with vigorous stirring. The reaction formed a white precipitate. The ice bath was removed and the viscous sludge was stirred overnight at room temperature. The resulting cloudy white suspension was washed with 50 mL water, followed by 50 mL 5% NaOH solution, and 50 mL water. The benzene layer was collected and dried with MgSO4, filtered, and rotovapped to give the 9-fluorenylacrylate as a viscous beige oil which crystallized on cooling to 4° C. (4.73 g, 20.02 mmol, 73.0% yield).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:13]=1[C:14]([OH:16])=[O:15].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:24][C:17]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 28.0 g of p-phenetidine, 23.6 g of 2,6-dichloro-3-nitrobenzoic acid, and 80 ml of N,N-dimethylaniline was heated five hours on a steam bath. The resulting mixture was diluted with chloroform and extracted with 1N sodium hydroxide. Acidification of the aqueous extract yielded 6-chloro-2-[(4-ethoxyphenyl)amino]-3-nitrobenzoic acid as reddish brown crystals.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2.C(O)(=O)C.C1C=CC=CC=1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A mixture of 3.7 g of 6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 14), 10 ml of acetic acid, 30 ml of benzene and 0.75 ml of 10% w/v aqueous sulfuric acid was heated under reflux for 30 minutes. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give the title compound.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:13].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N:1]1[C:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[CH2:8][CH2:9][C:4]=2[S:3][C:2]=1[NH:13][S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: Nc1nc2c(s1)CCc1sccc1-2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1nc2c(s1)CCc1sccc1-2)c1ccccc1

Procedure:
The title compound was prepared from 4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-amine (106 mg, synthesized according to METHOD I from 4-keto-4,5,6,7-tetrahydrothianaphthene) and benzenesulfonyl chloride (93 mg) as described in the synthetic METHOD A to give a white solid (13 mg) with a purity >90%: MS-ES (neg) m/z 347.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1C(OC)=O.S(=O)(=O)(O)O.[O:30]1CCC[CH2:31]1>>[F:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([CH2:31][OH:30])=[CH:19][CH:20]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: C1CCOC1
Reactant: COC(=O)c1c(-c2ccccc2)ccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Product: OCc1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: -10 °C

Procedure:
Next, to a solution comprising 4 g of lithium aluminum hydride dissolved in 200 ml of tetrahydrofuran was added dropwise a solution comprising 30 g of the previously obtained methyl 3,4-difluorobiphenyl carboxylate and 100 ml of tetrahydrofuran with stirring at -10° C., and the mixture was stirred for one hour at the same temperature to proceed the reaction. After completion of the reaction, to the reaction mixture was added 30 g of sulfuric acid and the resulting mixture was extracted with toluene. The reaction mixture was washed with a saturated NaCl aqua, dried, and the solvent was removed under reduced pressure. The residue was purified by distillation under reduced pressure (165° C/1 mmHg) to obtain 28 g of 4-(3,4-difluorophenyl)benzyl alcohol.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.C([O:9][C:10](=O)[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](OCC)=[O:13])C>C(N(CCCC)CCCC)CCC>[C:17]1([C:11]2[C:10]([OH:9])=[N:6][C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:12]=2[OH:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(O)c1-c1ccccc1
Temperature: 185 °C
Reaction time: 8 h

Procedure:
A mixture of 1H-[1,2,4]Triazol-3-ylamine SM (500 mg, 5.95 mmol) and 2-Phenyl-malonic acid diethyl ester 3-1 (1.41 g, 5.95 mmol) in N,N-dibutylbutan-1-amine (5 mL) was stirred at 185° C. overnight. The mixture was partitioned with two layers after cooling to room temperature. The top layer was removed and the lower layer was washed with cold PE. The resulting solution was concentrated and extracted with a mixture of diethyl ether and 10% w/w NaOH solution. The organic layer was discarded and aqueous layer acidified with concentrated HCl. The precipitated product was collected by filtration to afford compound 3-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=NC=C(F)C=3)=CC([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)=[CH:12][C:11]([C:21]([N:46]3[CH2:44][CH2:47][NH:48][C:49](=[O:51])[CH2:50]3)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cncc(F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CCN1

Procedure:
100 mg (0.30 mmol) of the compound of Example 60A is reacted analogously to the synthesis of the compound of Example 98 with 33 mg (0.33 mmol) of 2-oxopiperazine. 92 mg (74% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][CH:61]1[CH2:66][CH2:65][CH:64]([NH2:67])[CH2:63][CH2:62]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:64]3[CH2:65][CH2:66][CH:61]([CH3:60])[CH2:62][CH2:63]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: CC1CCC(N)CC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 4-methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (192 mg). LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]([Mg]Cl)#[CH:13]>C1COCC1>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1)[C:12]#[CH:13]
Reactant: COc1ccc(C=O)cc1O
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OC)c(O)c1

Procedure:
3-Hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propyne was prepared according to Method B above from 3-hydroxy-4-methoxybenzaldehyde (0.304 g, 2 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 273 mg, 77%).
Reaction SMILES: [CH2:1]([N:5]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:34]O.C=O>C(O)(=O)C>[CH2:1]([N:5]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH:1]1([N:5]([CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:33])[CH:26]([N:31]([CH3:32])[CH3:34])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:24]2)[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Agent: C=O
Agent: CCCCN(C1CCN(C(=O)C(CC(C)C)NC)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CC(C)CC(C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 10 %

Procedure:
A mixture of (2S) N-cyclopropyl-N-[1-(4-methyl-2-methylamino-pentanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (see Example 10, 323 mg, 0.7 mmol), methanol (4 mL), paraformaldehyde (50 mg, 1.0 mmol), NaBH3(CN) (132 mg, 2 mmol), and acetic acid (0.01 mL) was shaken at room temperature for 20 hours. The solvents were removed under vacuum. The residue was dissolved in dichloromethane (15 mL), and treated with aqueous saturated K2CO3 (5 mL). The organic layer was separated, washed with brine, concentrated under vacuum, and purified by column (silica gel, EtOAc/hexane 3/7) to give the title compound (2S) N-cyclopropyl-N-[1-(2-dimethylamino-4-methylpentanoyl)piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide as white solid (30 mg, yield 10%). 1H NMR (CDCl3): δ 8.14 (s, 1H), 8.08 (d, 1H, J=7.9 Hz), 7.87 (d, 1H, J=7.7 Hz), 7.7 (dd, 1H, J=7.7 & 8.1 Hz), 4.7-4.76 (m, 1H), 4.18-4.24 (m, 1H), 4.06-4.12 (m, 1H), 3.34-3.4 (m, 1H), 2.94-3.06 (m, 1H), 2.44-2.54 (m, 1H), 2.26 (br, 6H), 1.35-1.98 (m, 8H), 0.94-1.02 (m, 2H), 0.86-0.95 (m, 6H), 0.74-0.78 (m, 2H). LC: 100%. MS (e/z), 490 (m+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:9]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:24]=2[F:23])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(N)cn1S(C)(=O)=O
Reactant: O=C(Cl)c1cccc(F)c1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(=O)c2cccc(F)c2F)cn1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of 4-amino-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid ethyl ester (1 g, 4.3 mmol) and triethylamine (650 mg, 6.4 mmol) in dry CH2Cl2 (20 mL) was added 2,3-difluoro-benzoyl chloride (760 mg, 4.3 mmol). The mixture was stirred at RT for 3 h and diluted with EtOAc (150 mL). After washing with 2N HCl (80 mL) and NaHCO3 (2×80 mL), the organic layer was dried over MgSO4, filtered, and evaporated to give a yellow solid (1.3 g, 81%). This solid was dried on the vacuum pump for 14 hrs and then was used for the next step directly. MS (ES+): m/e=373.2 (M+H); LC: 3.45 min.