Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9](Br)=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:13]([Cu])#[N:14].[OH-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: COc1ccc(Br)c2[nH]ccc12
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c2[nH]ccc12
Temperature: 165 °C
Reaction time: 0.17 h

Procedure:
To an oven dried 500 ml round bottom flask at rt. was charged with 4-methoxy-7-bromo-indole intermediate 5 (12.8 g, 56.6 mmol) and dry DMF (120 ml), followed by CuCN (25.3 g, 283 mmol). The reaction mixture was refluxed at 165° C. for 16 hr. After cooling to rt., the mixture was slowly added ammonium hydroxide (100 ml), stirred for 10 min, concentrated in vacuo to ˜50 ml and diluted with CHCl3 (250 ml). The organic mixture was washed with H2O (250 ml), and the aqueous layer back extracted with CHCl3 (2×200 ml). The combined organic extracts were filtered through a filter paper to remove some solids, and washed again with H2O (100 ml) and brine (100 ml), and then dried (MgSO4). After evaporation in vacuo, the residue was purified by flash column chromatography (10% EtOAc/Hexane (250 ml), then 25% EtOAc/Hexanes (1250 ml)) to afford 4-methoxy-7-cyanoindole intermediate 35 (8.0 g, 82%) as yellow solids. 1H NMR: (CDCl3) δ 8.73 (b s, 1H), 7.50 (d, J=8.3 Hz), 7.22 (app t, J=2.8 Hz, 1H), 6.73 (dd, J=2.3, 3.2 Hz, 1H), 6.58 (d, J=8.3 Hz, 1H), 4.01 (s, 3H); LC/MS: (ES+) m/z (M+H)+=173, HPLC (YMC C18 S7 3×50 mm, Flow Rate 4 ml/min, Gradient Time 3 min) Rt=1.700.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1.O.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1:1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by methanesulfonyl chloride (0.50 mL, 6.44 mmol) in 5 mL of ether were added, and stirred at 0° C. for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL×3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacuo to yield 1.314 g of N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine in 93% yield. MS m/z M+NH4 =282. H1 -NMR (in CDCl3) δ=1.48 (s, 9H, Boc), 2.79 (s, 3H, S-CH3), 3.18 (t, 4H, piperazine), 3.55 (t, 4H, piperazine). The obtained N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine (1.3 g, 4.97 mmol) was dissolved in 10 mL of 20% trifluoroacetic acid in methylene chloride and stirred at room temperature for 30 minutes. Solvent and trifluoroacetic acid were removed to obtain N-methanesulfonylpiperazine trifluoroacetic acid salt in quantitative yield. MS m/z M+H=165, H1 -NMR (in MeOH-d4) δ=2.95 (s, 3H, S-CH3), 3.35 (m, 4H, piperazine), 3.5 (m, 4H, piperazine). The obtained N-methanesulfonyl trifluoroacetic acid salt (2.2 g) was dissolved in 30 mL of acetonitrile and cooled in an ice bath. Solid sodium bicarbonate was added to the acetonitrile solution and stirred for 2 hours. Solid was filtered off and the filtrate was concentrated in vacuo to yield N-methanesulfonylpiperazine in quantitative yield. MS m/z M+H =165, M+NH4 =182; H1 -NMR (in MeOH-d4) δ=2.85 (s, 3H, S-CH3), 2.95 (t, 4H, piperazine), 3.22 (t, 4H, piperazine).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:18][CH:17]=1.Cl>CCCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:28]2([OH:31])[CH2:27][CH2:26][N:25]([CH2:24]/[CH:23]=[CH:22]/[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: O=C1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution of n-buthyllithium in hexane (47.0 ml of a 1.6 M solution) was added dropwise to a solution of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (6.35 g) in dry THF (100 ml) at −5° C. under a N2 atmosphere over 15 min. The resulting solution was stirred at 0° C. for 2 hours, and then a solution of 1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-one (7.49 g) in THF (15 ml) was added dropwise to the above solution of the dianion at 0° C. over a 1 hour period. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at r.t. The solution was then poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford the title product (6.2 g). M.p. 177-179° C.; Retention Time HPLC 2.19 min; MS (ES+) 461 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][N:19]([CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:18](=[O:22])[CH:17]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccn3c(-c4ccccc4)cnc3c2)cc[nH]1
Reactant: ClCCCN1CCCCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccn3c(-c4ccccc4)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 40 °C

Procedure:
To a solution of 4-(3-phenylimidazo[1,2-a]pyridin-7-yl)pyridin-2(1H)-one (0.050 g, 0.173 mmol) in 1.0 mL of anhydrous DMF was added sodium iodide (0.038 g, 0.260 mmol), cesium carbonate (0.140 g, 0.430 mmol), and 1-(3-chloropropyl)piperidine (0.0420 g, 0.25 mmol). Reaction was refluxed at 40° C. overnight. Poured reaction into saturated sodium bicarbonate solution and extracted with methylene chloride. Dried organic over sodium sulfate. Removed solvent under reduced pressure. Purified by silica chromatography (10% MeOH/CH2Cl2). 1H NMR (CDCl3) δ 8.40 (d, 1H, J=6.59 Hz), 7.92 (s, 1H), 7.78 (s, 1H), 7.62–7.52 (m, 4H), 7.50 (d, 1H, J=7.09 Hz), 7.45 (t, 1H, J=7.33 Hz), 7.06 (dd, 1H, J=7.08, 1.71 Hz), 6.84 (s, 1H), 6.50 (dd, 1H, J=7.08, 2.20 Hz), 4.08 (t, 2H, J=6.84 Hz), 2.40 (bs, 2H), 2.02 (bs, 2H), 1.62 (bs, 8H), 1.46 (bs, 2H). HRMS m/z (M+1) Calc: 413.2, found: 413.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=O)[CH2:3]1.O.[NH2:20][NH2:21].CC(O)=O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2/[C:4](=[N:20]/[NH2:21])/[CH2:3]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)C/C(=N\N)c2sc(N3CCOCC3)nc2C1
Yield: 35.7 %

Procedure:
To a stirred solution of Example 48 (0.27 g, 1.00 mmol) in EtOH (10 mL) was added hydrazine monohydrate (0.05 g, 0.05 mL, 1.00 mmol) and a catalytic amount of AcOH. The reaction mixture was then heated to reflux for 8 h. Upon cooling, the reaction mixture was poured into aqueous sat. NaHCO3 (50 mL) and extracted with DCM (2×50 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a white solid (0.10 g, 35%). δH (DMSO-d6) 5.93 (2H, br. s), 3.68 (4H, t, J 4.9 Hz), 3.36 (4H, t, J 4.9 Hz), 2.42 (2H, s), 2.22 (2H, s), 1.00 (6H, s). LCMS (ES+) 281.2 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][O:16][C:14]([C:8]1([CH2:7][C:6]([OH:18])=[O:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:15]
Reactant: COC(=O)C1(CC(=O)OC(C)(C)C)CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CC(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
To a solution of methyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.1 g, 4.26 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL) and the resulting solution was stirred at rt for 5 h. The mixture was concentrated under reduced pressure to afford [4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (900 mg, 94%), which was used in the next step without further purification. LC-MS ret. time 0.93 min, m/z 202.9 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.68 (s, 2H), 3.62-3.71 (m, 2H), 3.72 (s, 3H), 3.79-3.86 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:16][CH:15]=4)[CH:13]=[C:5]3[C:4]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2].Cl.[NH+]1C=CC=CC=1.O.C(=O)([O-])O.[Na+]>CO.ClCCl>[CH2:1]([C:3]1[C:11]2[N:6]3[C:7](=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)=[CH:18][CH:19]=4)[CH:13]=[C:5]3[C:4]=1[C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)[CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(-c3ccc(OCCN4CCCCC4)cc3)c3cccc1n32
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCc1c(-c2ccc(O)cc2)c2cc(-c3ccc(OCCN4CCCCC4)cc3)c3cccc1n32
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.6 %

Procedure:
1-Ethyl-2-(4-methoxyphenyl)-4-[4-(2-piperidinoethoxy)phenyl]pyrrolo[2,1,5-cd]indolizine (190 mg, 0.4 mmol) and pyridinium hydrochloride (462 mg, 4.0 mmol) was melted together at 170° C., and stirring was continued for 24 hours at 170° C. The mixture was cooled to room temperature and dissolved in 10 ml of methanol and 50 ml of dichloromethane. 100 ml of water and solid sodium hydrogen carbonate was added until pH=8. The aqueous layer was extracted with 10% of methanol in dichloromethane (2×50 ml), and the combined organic layers were washed with brine, dried oversodium sulfate and evaporated. The crude product was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent. The crude product was recrystallized from methanol, dichloromethane and petroleum ether to afford 55 mg (29%) of 1-ethyl-2-(4-hydroxyphenyl)-4-[4-(2-piperidinoethoxy)phenyl]pyrrolo[2,1,5-cd]indolizine. MS(SP): m/z 464 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.31-1.58 (m,9 H); 2.39-2.49 (m, 4 H); 2.68 (t, 2 H); 3.22 (q, 2 H); 4.12 (t, 2 H); 7.00 (d, 2 H); 7.07 (d, 2 H); 7.66-7.79 (m, 3 H); 7.83-7.98 (m, 3 H); 8.11 (d, 1 H); 8.29 (d, 1 H); 9.83 (br s, 1 H).
Reaction SMILES: FC1C=CC2C(C3CCNCC3)=NOC=2C=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)(=O)=O>C(#N)C>[CH3:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1COc2ccccc2O1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-]-piperidinyl]methyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p.=86°-87° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[NH:8][C:7]1=O)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:11]2[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]2[CH2:4][OH:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1C(=O)NC(=O)C[C@H]1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1CNCC[C@H]1c1ccc(F)cc1
Yield: 22 %

Procedure:
Compound E1 (±)-trans-3-ethoxycarbonyl-4(4'-fluorophenyl)piperidin-2,6-dione (2.0 g) was reduced with lithium aluminium hydride (0.58 g) in refluxing tetrahydrofuran (50 ml) for 4 hours. Work up as described in Example 5 gave the title compound as a solid (0.28 g, 22%).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)=[CH:32][CH:31]=1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (80 mg, 0.41 mmol) and Et3N (58 μL, 0.41 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (70 mg, 0.29 mmol) and DMAP (5 mg, 0.04 mmol) and stir the resulting solution for 10 min. Add 4-Amino-benzoic acid methyl ester (77) (42 mg, 0.27 mmol) and stir the reaction solution 2d at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine, dry with Na2SO4 and filtrate it through a short pad of silica gel using EtOAc to obtain 4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acid methyl ester (78) (91 mg, 88%) as a white solid. No further purification. 1H NMR (400 MHz, CDCl3): 2.60 (t, 2H, J=7.6 Hz); 2.91 (t, 2H, J=7.6 Hz); 3.70 (s, 6H); 3.76 (s, 3H); 3.83 (s, 3H); 6.35 (s, 2H); 7.55 (d, 2H, J=8.3 Hz); 7.91 (d, 2H, J=8.6 Hz); 8.09 (s, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:34][N:35]1[C:39]([CH2:40][CH2:41][C:42](O)=O)=[N:38][C:37]([N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[N:36]1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:63][N:64]1[C:69](=[NH2+:70])[C:68]([CH3:71])=[CH:67][N:66]=[C:65]1[CH2:72][CH3:73]>CN(C)C=O>[CH2:72]([C:65]1[N:64]2[N:63]=[C:42]([CH2:41][CH2:40][C:39]3[N:35]([CH3:34])[N:36]=[C:37]([N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[N:38]=3)[N:70]=[C:69]2[C:68]([CH3:71])=[CH:67][N:66]=1)[CH3:73]
Reactant: CCc1ncc(C)c(=[NH2+])n1N
Reactant: Cn1nc(N2CCCC2)nc1CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncc(C)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
HATU (40.5 mg, 106 μmol, Eq: 1.5) and N,N-diisopropylethylamine (27.5 mg, 37.2 μL, 213 μmol, Eq: 3) were added to 3-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)propanoic acid in dimethylformamide (1 ml). The mixture was stirred for 10 min at room temperature. 3-Amino-2-ethyl-5-methylpyrimidin-4(3H)-iminium 2,4,6-trimethylbenzenesulfonate was added, and the mixture was stirred at 100° C. for 1 h. The product (2.7 mg, 100%) was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([NH:11]C(=O)OCC2C=CC=CC=2)[N:8]([CH3:22])[N:7]=1>CO.[Pd]>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH3:22])[N:7]=1
Reactant: CN(C)CCOc1cc(NC(=O)OCc2ccccc2)n(C)n1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1cc(N)n(C)n1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of benzyl (3-(2-(dimethylamino)ethoxy)-1-methyl-1H-pyrazol-5-yl)carbamate (1.42 g, 4.46 mmol) and 10% Pd/C (0.2 g) in MeOH (40 mL) was hydrogenated with fully inflated H2 balloon at rt overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.65 g, 79% yield) as a pale solid. 1H NMR (400 MHz, CDCl3) δ ppm 5.04 (s, 1H), 4.19-4.16 (t, 2H), 3.51 (s, 3H), 3.45 (bs, 2H), 2.67-2.64 (t, 2H), 2.32 (s, 6H). m/z for C8H16N4O 185.14 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3O)[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2].[SiH](CC)(CC)CC.FC(F)(F)C(O)=[O:44]>C(Cl)CCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:44])[CH:23]=3)[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4cccc(O)c4)n3)C2SC1
Yield: 96 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8m (157 mg, 0.240 mmol), Et3SiH (0.383 mL, 2.40 mmol), and trifluoroacetic acid (0.739 mL, 9.59 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9m (113 mg, 96%) as a white solid after crystallization from THF/CH2Cl2 /hexane. mp 140° C. (dec); IR (KBr) 3600-2650 (br), 3286, 1782, 1738, 1671, 1230 cm-1 ; 1H NMR (DMSO-d6) δ1.98 (3H, s, CH3), 3.44 (1H, d, J=18.1 Hz), 3.59 (1H, d, J=18.1 Hz), 3.72 (2H, s, CH2), 4.64 (1H, d, J=12.8 Hz), 4.96 (1H, d, J=12.8 Hz), 5.07 (1H, d, J=4.8 Hz), 5.69 (1H, dd, J=8.2 and 4.8 Hz), 6.82 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.28 (1H, d, J=7.8 Hz), 7.29 (1H, s), 7.39 (1H, s), 9.06 (1H, d, J=8.2 Hz, NH), 9.68 (1H, br s, OH), 13.62 (1H, br s, CO2H); FDMS m/z 490 (M+ +1); Anal. Calcd for C21H19N3O7S2.(C4H8O) 0.25: C, 52.06; H, 4.17; N, 8.28. Found: C, 51.95; H, 3.94; N, 8.04
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methoxy-phenyl)-propionic acid (500 mg, 2.0 mmol) in methylene chloride (20.1 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.1 mL, 2.21 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min then at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (444 mg, 4.42 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) in tetrahydrofuran (10.1 mL). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (638 mg, 95.8%) as a pale yellow solid: mp 166-167° C.; EI-HRMS m/e calcd for C18H22N2O2S (M+) 330.1402 found 330.1398.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C#N)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 729 mg (2.56 mmol) 6-amino-4-[(3-cyanophenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and cooled to 0° C. under N2. Added 392 μl (2.81 mmol) triethylamine and 234 μl (2.81 mmol) acryloyl chloride. Removed ice bath after 15 minutes and stripped solvent at 2 hours. Washed residue with water and collected solids. Recrystallized from ethyl acetate and dried in vacuo, giving 318 mg of yellow solid: mass spectrum (electrospray m/e): M+H=340.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I-:46]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][I:46])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To the solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (80 mg, 0.253 mmol) in DCM (2.5 ml), was added Ph3P (133 mg, 0.505 mmol), imidazole (34.4 mg, 0.505 mmol) and iodide (128 mg, 0.505 mmol) at 0° C., The mixture was stirred at 0° C. for 10 min, then at room temperature for 1 h. The reaction was quenched with sat. Na2SO3 solution. The aqueous phase was extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified via flash chromatography to afford the title compound (50 mg, 46.4% yield) as colorless oil. LCMS: rt=4.47 min
Reaction SMILES: C(OCC)C.Br[C:7]1[C:11](OC)([CH3:12])[CH2:10][CH2:9][C:8]=1[CH3:15].C([Li])CCC.[CH:21](=[C:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)[CH2:22][CH2:23][CH3:24]>O>[C:25]1([CH:21]([C:7]2[C:11]([CH3:12])=[CH:10][CH2:9][C:8]=2[CH3:15])[CH2:22][CH2:23][CH3:24])[CH:26]=[CH:27][CH2:28][CH:29]=1
Reactant: COC1(C)CCC(C)=C1Br
Reactant: CCCC=C1C=CC=C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCCC(C1=CCC=C1)C1=C(C)CC=C1C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
15 ml of diethylether was added to 2-bromo-3-methoxy-1,3-dimethyl-cyclopentene (2 g, 9.75 mmol), and the result was cooled to −30° C. Then, n-butyllithium (2.7 g, 9.75 mmol) was added and the reactant solution was incubated at an elevated temperature for 15 minutes and again cooled to −30° C. Then, 1 eq. (1.3 g) of the 5-butylidene-cyclopenta-1,3-diene prepared in (1-1) was added, and the result was incubated for 3 hours. Then, 15 ml of diethylether and 15 ml of water were added, and the resultant solution was washed with 30 ml of 1 N HCl for 3 minutes and neutralized with 30 ml of an aqueous saturated sodium bicarbonate solution. An organic layer was separated, dried over magnesium sulfate to remove water and then subjected to solvent removal in a rotary evaporator. The resultant residue was purified through silica-based column chromatography (hexane) to give 2-(1-cyclopenta-1,4-dienylbutyl)-1,3-dimethylcyclopenta-1,3-diene (yield: 65%).