Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH:16](OS(C)(=O)=O)[C:17]([F:20])([F:19])[F:18])[N:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1.C(O)C>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:16][C:17]([F:18])([F:19])[F:20])[N:13]([CH3:15])[CH:14]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(OS(C)(=O)=O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cn1cc(O)c(=O)cc1CC(F)(F)F
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In a 500-mL reaction vessel was placed methanesulfonic acid 1-(5-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (1.80 g, 4.60 mmol), and ethanol (120 mL). The mixture was sonicated to give a clear solution. To the solution was added 1.80 g of Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W). Hydrogenation was carried out under a hydrogen atmosphere set at a pressure of 50 psi. The reaction was completed within 90 min. The reaction mixture was diluted with methanol (120 mL), and the resulting mixture was sonicated for 10 min. The reaction mixture was then filtered through a short hydrochloric acid pre-treated CELITE™ bed. The filtrate was collected, and concentrated in vacuo to a volume of about 100 mL. To the resulting solution was added morpholine polymer-bound beads (1% cross-linked w/DVB, 200-400 mesh, 2.5-4.0 mmol N/g, 5.2 g), and the mixture was vortexed for 3 h. The morpholine beads were removed by filtration. Upon partial concentration in vacuo, a solid separated and the first crop of the title compound was obtained as the free base (0.74 g, 77% yield, HPLC Method 1 (Example 24); RT=8.2 min, HPLC purity (peak percent area): 98.7% at x=280 nm). 1H NMR (CD3OD) δ ppm: 7.55 (s, 1H), 6.52 (s, 1H), 3.77 (q, J=10 Hz, 2H), 3.78 (s, 3H); MS-ESI (m/z): 208.2 ([M+1]+, 100%), 188.2, 139.2.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl.Cl.[NH2:21][C:22]1[CH:54]=[CH:53][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:34]=[C:33]([CH2:35][O:36][C:37]4[CH:50]=[CH:49][C:40]([CH2:41][CH:42]5[S:46][C:45](=[O:47])[NH:44][C:43]5=[O:48])=[CH:39][CH:38]=4)[N:32]([CH3:51])[C:31]=3[CH:52]=2)=[CH:24][CH:23]=1>CN(C)C=O>[F:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:34]=[C:33]([CH2:35][O:36][C:37]4[CH:38]=[CH:39][C:40]([CH2:41][CH:42]5[S:46][C:45](=[O:47])[NH:44][C:43]5=[O:48])=[CH:49][CH:50]=4)[N:32]([CH3:51])[C:31]=3[CH:52]=2)=[CH:53][CH:54]=1)=[O:12]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc21

Procedure:
A reaction was conducted by a similar procedure to that described in Example 52 using triethylamine (0.32 ml), 2,4-difluorobenzoyl chloride (0.10 ml), 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and anhydrous N,N-dimethylformamide (8 ml). The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1 to afford the title compound (251 mg, white powder, mp 172-174° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:26][O:27][CH2:28][CH:29]=[CH:30]B(O)O.C([O-])([O-])=O.[K+].[K+]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:30]=[CH:29][CH2:28][O:27][CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: COCC=CB(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CCOC)Cc2ccccc2C1

Procedure:
To a solution of 2-(2-Iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.89 mmol) and 3-methoxy-1-propenylboronic acid (206 mg, 1.78 mmol) in 10 mL EtOH/10 mL dioxane is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 195 mg, 0.089 mmol) and 2M aqueous solution of K2SO4 (1.78 mL, 3.56 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 4 h. After concentration in vacuo, the residue is purified by HPLC to give the product (220) as pale yellow oil.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].[CH2:53]([C:55]1[CH:56]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:57][C:58](=[O:60])[CH:59]=1)[CH3:54].CC(O)(C)C.C([C@@H]1C[C@H](O)C[C@@H]1C(OCC)=O)C>C1(C)C=CC=CC=1.[Cu]Cl>[CH2:53]([CH:55]1[CH2:59][CH:58]([OH:60])[CH2:57][CH:56]1[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH3:54]
Reactant: CCOC(=O)C1CC(=O)C=C1CC
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)[C@H]1C[C@@H](O)C[C@H]1CC
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(O)CC1CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of copper (I) chloride (0.136 g, 1.37 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.854 g, 1.37 mmol), and NaOt-Bu (0.132 g, 1.37 mmol) in toluene (50 mL) was stirred at ambient temperature for about 15 min then cooled to about 5° C. and polymethylhydrosiloxane (12 mL, 55 mmol) was added. The reaction mixture was stirred for about 40 min at about 5° C. then cooled to about −12° C. A solution of ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (5.00 g, 27.4 mmol) and t-BuOH (14 mL, 148 mmol) in toluene (50 mL) was added in one portion and the reaction mixture was stirred for about 16 h at about −12° C. The reaction mixture was quenched by the addition of MeOH (50 mL). The solvents were removed under reduced pressure. The residue was dissolved in MeOH (35 mL) and filtered through a pad of Celite®. The filtrate was concd under reduced pressure and the residue was triturated with EtOAc (100 mL) and filtered. The filtrate was concd under reduced pressure and the residue was purified using silica gel chromatography (280 g) eluting with a gradient of 0-10% EtOAc in heptane to give a scalemic mixture enriched with (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 22%): 1H NMR (CDCl3) δ 4.30 (m, 1H), 4.24-4.08 (m, 2H), 2.88 (td, J=2.1, 7.1 Hz, 1H), 2.40 (dt, J=7.8, 14.0 Hz, 1H), 2.08-1.91 (m, 3H), 1.52-1.31 (m, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: C([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH:38]([C:40]1[O:41][C:42](=[O:56])[C:43]2[C:48]([C:49]=1[C:50]1[CH2:51][CH2:52][O:53][CH2:54][CH:55]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:39].[H-].[Na+]>CN(C=O)C>[N:24]1[C:25]([NH:29][CH:38]([C:40]2[O:41][C:42](=[O:56])[C:43]3[C:48]([C:49]=2[C:50]2[CH2:51][CH2:52][O:53][CH2:54][CH:55]=2)=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:39])=[C:26]2[C:21]([NH:20][CH:28]=[N:27]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1C1=CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1C1=CCOCC1
Yield: 5.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 21, from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (214 mg, 0.449 mmol) and 3-(1-bromoethyl)-4-(3,6-dihydro-2H-pyran-4-yl)-1H-isochromen-1-one (intermediate C19, 94 mg, 0.280 mmol) and 50% dispersion in mineral oil NaH (18 mg, 0.34 mmol) in DMF. This was purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%). Fractions containing the required product were collected, 1 M HClaqueous (5 ml) was added and concentrated under reduced pressure to give the title compound (6.3 mg, 5.8%) as colourless solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Trifluoromethylpyridin-2-yl)methanol (760 mg, 4.3 mmol) was dissolved in CH2Cl2 and thionyl chloride was added slowly at room temperature. The reaction mixture was stirred at room temperature for 4 h. Solvent was removed under the reduced pressure, the pH was adjusted to 5, and the product was extracted with EtOAc. Purification by flash column (5% EtOAc-Hexane) gave 2-chloromethyl-6-trifluoromethylpyridine (200 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][CH:33]=1.ClC1C=CC(C2N=C(C)N3C(=O)N(CC4C=CC(C(F)(F)F)=CC=4)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[N:16]([CH2:27][C:28]4[CH:33]=[N:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)[N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12

Procedure:
The title compound was prepared by coupling 7,8-bis(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one with 5-(chloromethyl)-2-(trifluoromethyl)pyridine in a manner analogous to that in which 7,8-bis(4-chlorophenyl)-5-methyl-2-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one was prepared. HPLC/MS: retention time=4.188 min, [M+H]30 =530.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc3ccccc3s2)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
Prepared as described in the Demethylation section above using 2-(2-methoxy-4-nitrophenyl)benzothiazole (0.5 g, 1.75 mmol) in dry DCM (30 ml) was added dropwise at room temperature and BBr3 (1.0 M solution in DCM, 8.8 ml, 8.8 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched by addition of MeOH (5 ml) and extracted with 8% w/v NaOH (5×35 ml). The combined aqueous extracts were acidified with 6 M HCl and extracted with EtOAc (3×70 ml). The combined organic extracts were washed with brine (40 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give a solid which was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.47 g, 99%) as a pale yellow solid after work-up and flash chromatography (1:1 Hexane/EtOAc).
Reaction SMILES: O[C:2]([C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:5][CH3:6])[CH2:3][CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl.C(OCC)C>[CH3:13][C:9]1([CH3:12])[N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@@H:7]([C:2]([CH2:5][CH3:6])=[CH:3][CH3:4])[CH2:11][O:10]1
Reactant: CCC(O)(CC)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC=C(CC)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a solution of (R)-tert-butyl 4-(3-hydroxypentan-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 200, 26.4 g, 91.86 mmol) in dichloromethane (350 mL) at 0° C. was added triethylamine (128 mL, 918.60 mmol) and then slowly added methanesulfonyl chloride (35.8 mL, 459.30 mmol). The yellow reaction mixture was warmed to room temperature and stirred overnight for ˜16 h. The reaction mixture was diluted with diethyl ether and poured into water. The organic layer was washed with 10% citric acid, saturated sodium bicarbonate, saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. Purification by flash column chromatography (0-20% ethyl acetate/hexanes) afforded the title compound (17.70 g, 71.5%) as very pale yellow oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:14][N:13]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22])=[N:19][CH:20]=2)[CH2:12]1)#[N:9].Br[C:45]1[C:46]([CH2:50][CH3:51])=[N:47][NH:48][CH:49]=1>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:30]2[CH:34]=[C:33]([C:45]3[C:46]([CH2:50][CH3:51])=[N:47][NH:48][CH:49]=3)[CH:32]=[N:31]2)[CH2:14][N:13]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[O:22])=[N:19][CH:20]=2)[CH2:12]1)#[N:9]
Reactant: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1)C(F)(F)F
Reactant: CCc1n[nH]cc1Br
Solvent: O=C(O)C(F)(F)F
Product: CCc1n[nH]cc1-c1cnn(C2(CC#N)CN(c3cnc(C(=O)N[C@@H](C)C(F)(F)F)cn3)C2)c1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (Example 1, Step 5) and 4-bromo-3-ethyl-1H-pyrazole. LCMS calculated for C21H23F3N9O (M+1)+: m/z=474.2. Found: 474.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13]C(O)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C([N:23](CC)C(C)C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][N:23]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(CC(=O)O)CC(=O)c1ccc2c(c1)OCO2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)CN=C(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.2 %

Procedure:
To a solution of 5-(1,3-benzodioxol-5-yl)-3,3-dimethyl-5-oxopentanoic acid (444 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.292 mL, 1.68 mmol) in chloroform, add diphenylphosphorylazide (0.364 mL, 1.68 mmol). Stir at room temperature for 2 days, then treat with 2N NaOH. After 1 h, dilute the reaction with chloroform and water, then separate the organic layer and dry with magnesium sulfate, filter, and concentrate under reduced pressure to obtain 132 mg (36%) of the title compound. MS: 218 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1H), 7.20-7.24 (m, 1H), 6.78-6.81 (m, 1H), 6.00 (s, 2H), 3.75-3.74 (m, 2H), 2.72-2.71 (m, 2H) and 1.16 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:18][NH:19][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(SCc1ccc(Cl)cc1)C(C)=O
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(C)c1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of crude 3-(4-chloro-benzylsulfanyl)-pentane-2,4-dione [prepared as described above from 3-chloro-pentan-2,3-dione (1.03 g, 7.63 mmol) and 4-chlorobenzyl mercaptan (1.21 g, 7.63 mmol)] in ethanol (60 mL) was added hydrazine hydrate (0.713 mL, 22.9 mmol) and p-toluenesulfonic acid monohydrate (ca. 25 mg). The solution was heated to reflux and stirred for 15 hours. The reaction mixture was allowed to cool to room temperature, and water (300 mL) was added. The precipitate that formed was removed by filtration, washed with water, and dried to provide 1.38 g (72%) of the product as a white solid: 1H NMR (CDCl3) δ 7.17 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 3.57 (s, 2H), and 2.02 (s, 6H) ppm. 13C NMR (CDCl3) δ 137.2, 132.7, 130.3, 128.3, 105.2, 39.9, 10.7 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2- naphthalenyl)ethynyl]benzoate (Compound 15a) and 8.5 mg (0.20 mmol) of LiOH—H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. PMR (d6-DMSO): δ 1.29 (6H, s), 2.42 (2H, d, J=4.6 Hz), 6.68 (1H, t, J=4.6 Hz), 7.51 (2H, m), 7.62 (2H, d, J=8.2 Hz), 7.77 (IH, d, J=3.3 Hz), 7.93 (2H, d, J=8.2 Hz), 7.98 (1H, d, J=3.3 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:26][C:27](N)=[O:28])=[O:25].O>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([NH:26][C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])=[O:28])[CH2:7][CH2:6]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: NC(=O)NC(=O)c1ccco1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccco1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Yield: 17.5 %

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.2 g, 0.005 m) and 2-furoylurea (0.7 g) in pyridine (5 ml) was refluxed for 6 hours, then cooled. Water was added and the precipitate collected by filtration. The solid was dissolved in chloroform with a little methanol and filtered. The solvent was removed under reduced pressure and the residue was purified by medium pressure liquid chromatography on silica using CHCl3 : MeOH (9:1 v/v) as eluent. The isolated product (1st component eluted) was dissolved in ethyl acetate and acidified with ethanolic HCl to give a precipitate. This was filtered and dried to give 0.3 g of the title compound as the HCl, 3/4 H2O salt, mp. 157°-159° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C:10]2[CH:11]=[CH:12][C:13]([C:18](OCC)=[O:19])=[N:14][C:15]=2[O:16][CH3:17])[CH2:9][CH2:8]1.[Cl-].[NH4+]>O1CCCC1>[CH:7]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:18][OH:19])=[N:14][C:15]=2[O:16][CH3:17])[CH2:9][CH2:8]1
Reactant: CCOC(=O)c1ccc(C2CC2)c(OC)n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1nc(CO)ccc1C1CC1
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Lithium aluminum hydride (4.44 g) was added in small portions to a solution of ethyl 5-cyclopropyl-6-methoxypyridine-2-carboxylate (17.3 g) in tetrahydrofuran (300 mL) under ice-cooling, and the mixture was stirred at the same temperature for one hour. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure to give (5-cyclopropyl-6-methoxypyridin-2-yl)methanol (14.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25]N(CC(O)=O)[CH2:23][CH2:22]2)[C:3]=1[Br:31].C[Si](C)(C)CCOC[N:38](COCC[Si](C)(C)C)[C:39]1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCC(CC#N)C2)[CH:40]=1.NC1N2N=CC(C3C=NC4C(C=3)=CC=CC=4)=C2N=C(C2CCN(CC(OC(C)(C)C)=O)CC2)C=1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][CH:23]([CH2:40][C:39]#[N:38])[CH2:22]2)[C:3]=1[Br:31]
Reactant: Nc1c(Br)c(C2CCN(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: CC(C)(C)OC(=O)CN1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Product: N#CCC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)C1

Procedure:
2-(3-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile was synthesized in a manner similar to the synthesis of 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetic acid, but with 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile substituted for tert-butyl 2-(4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate. The reaction was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield 2-(3-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile as a yellow solid. (m+H=447.22, retention time=3.99 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+](=[CH2:21])=[N-]>>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH3:21])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1
Product: COC(=O)C(C)c1ccc(-c2ccccc2)c(O)c1

Procedure:
An ethereal solution of 2-(2-hydroxy-4-biphenylyl) propionic acid was treated with excess diazomethane and the resulting mixture evaporated to dryness under reduced pressure. The resulting product was triturated with light petroleum, b.p. 40° - 60°C., collected by filtration and dried. The product was recrystallised twice from light petroleum (b.p. 80° - 100°C.) to give methyl 2-(2-hydroxy-4-biphenylyl)propionate, m.p. 105.5° - 107.5°C.