Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(Cc4ccccc4)CC3)CC2)cc2nc[nH]c12
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc2nc[nH]c12
Reaction time: 3 h

Procedure:
67 mg (0.08 mmol) (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and combined with 30 mg 10% Pd/C. The mixture was hydrogenated for 3 h in a Parr apparatus at 50° C. and 50 psi hydrogen pressure. Then the catalyst was filtered off and the filtrate was evaporated down i.vac. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)#[N:36]>CN(C1C=CN=CC=1)C>[C:35]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:45])=[O:44])=[CH:41][CH:42]=1)#[N:36]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Yield: 41.2 %

Procedure:
Following the general procedure of Example 11, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 4-cyanobenzenesulfonyl chloride (34 mg, 0.168 mmol) were reacted to give the title compound (28 mg, 41%).
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([CH3:11])[CH2:7][CH2:8][C:9]#[CH:10].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[O:14].[Cl-].[NH4+]>CCOCC>[OH:14][CH:13]([C:10]#[C:9][CH2:8][CH2:7][CH:6]([CH3:11])[CH3:5])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: C#CCCC(C)C
Reactant: CCCCOC(=O)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Product: CCCCOC(=O)C(O)C#CCCC(C)C
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A Grignard reagent was prepared under dry nitrogen by the addition, over a 1 hour period, of a solution comprising 10.9 grams (g) (0.10 mole) of ethyl bromide is 15 milliliters (ml) of anhydrous ether to a stirred suspension of 2.4 g (0.10 g atom) of clean magnesium metal turnings in 70 ml of dry ether. Stirring at 25° C. was continued for an additional hour and then a solution of 9.6 g (0.10 mole) of 5-methyl-1-hexyne in 15 ml of dry ether was added during 30 minutes with stirring. The resulting greyish solution was then heated at reflux for 2 hours and cooled to room temperature. The solution was transferred under dry nitrogen to a 200 ml addition funnel, followed by flushing with two 15 ml portions of dry ether. This solution was then added over a 45 minute period to a stirred solution of 13.0 g (0.10 mole) of n-butyl glyoxalate in 70 ml of dry ether cooled to -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm to room temperature overnight. The resulting yellow-orange solution was cautiously treated with 75 ml of saturated ammonium chloride solution and after stirring for 5 minutes, the two phases which formed were separated. The aqueous phase was extracted twice with 60 ml portions of ether and the combined organic phases were washed with three 75 ml portions of brine and dried over MgSO4. After filtration and concentration at the stripper, the residual reddish-orange oil (18.0 g.), was fractionated through a 15 cm Vigreux column to afford, after a small forerun, a single volatile fraction, boiling point (b.p.) 107.0°-117.0° C./0.20 millimeter (mm). Redistillation of this cut provided 10.3 g (41% yield) of n-butyl 2-hydroxy-7-methyl-3-octynoate as a light yellow, sweet smelling, mobile oil, b.p. 112.0°-115.0° C./0.20 mm.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].O=[CH:19][CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:19]/[CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=CCCNC(=O)OCc1ccccc1
Solvent: CCO
Product: CCCCCn1/c(=N/N=C\CCNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Yield: 97.9 %

Procedure:
A mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (2.3 g, 9.6 mmol) and benzyl (3-oxopropyl)carbamate (2.0 g, 9.6 mmol) in ethanol (30 mL) was refluxed overnight. The reaction mixture was concentrated to give the product (4.0 g, 58% yield), which was used for next step without further purification. LCMS calculated for C21H28N7O3 (M+H): 426.2. found: 426.1.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:10]1[CH2:29][CH3:30])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:29]([C@H:10]1[C@H:9]([OH:8])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=1)[CH3:30]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-ethyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-(trifluoromethyl)benzonitrile (433.7 mg) in tetrahydrofuran (6 mL)-methanol (12 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/2) to give the title compound as a colorless solid (yield: 266.1 mg, 83%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([OH:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:28][C:21]1[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[C:25]2[C:20]=1[O:19][C:18](=[O:29])[CH:17]=[C:16]2[NH:15][C:14]1[C:13]([Cl:30])=[CH:12][N:11]=[CH:10][C:9]=1[Cl:8]
Reactant: BrCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr

Procedure:
The title compound was prepared from 1,5-dibromopentane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.83 (s, 2H), 7.96 (d, 1H), 7.22 (d, 1H), 4.66 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.57 (t, 2H), 1.88 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H); MS (ESI): 500.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])=[O:18])[CH3:21]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCSc1ccccc1N
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To an ice bath cooled solution of 2-aminothiophenol (1.80 g) in N,N-dimethylformamide (35 ml) was added sodium hydride (60% in oil, 575 mg). After being stirred in an ice bath for 30 minutes, ethyl 6-bromohexanoate (3.21 g) was added and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate (100 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was purified by silica gel column (1% methanol in chloroform) to give 2-(5-ethoxycarbonylpent-1-yl)thioaniline (3.20 g) as a pale yellow amorphous.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][C:15](=[O:17])[CH3:16].[OH-].[K+].[CH3:20]S(C)=O.CI>O>[CH3:20][N:12]1[C:13]2[CH2:1][CH:2]([NH:14][C:15](=[O:17])[CH3:16])[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CS(C)=O
Reactant: CC(=O)NC1CCc2c([nH]c3ccccc23)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CC(=O)NC1CCc2c(n(C)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 mol of N-(1,3,4,9-tetrahydro-2H-carbazol-2-yl)acetamide, 0.15 mol of powdered KOH, and 75 ml of DMSO was stirred under nitrogen for 2 hr at room temperature. Methyl iodide (0.15 mol) was added in one portion, and, after brief cooling to moderate the exothermic reaction, the mixture was stirred at room temperature for 2 hr. The precipitate obtained by pouring the reaction mixture into excess water, was filtered, washed with water, and recrystallized from ethyl acetate to give the title compound, mp 171°-172°.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH:1]1([CH2:6][O:7][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of cyclopentan-methanol (2 g, 20 mmoles), CH2Cl2 (20 ml), triethylamine (5.85 ml, 42 mmoles) and p-toluen-sulphonyl chloride (4 g, 21 mmoles) was kept under stirring at room temperature for 1 night, then washed with water, 5% HCl and NaHCO3 and evaporated to give 5.09 g of the title compound (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:19][C:20]1[N:29]=[C:28](Cl)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1>CC(O)C>[Cl:19][C:20]1[N:29]=[C:28]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]#[N:32])[CH:26]=2)[N:21]=1
Reactant: N#Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: COc1ccc(CN)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(CNc2nc(Cl)nc3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Yield: 86.7 %

Procedure:
3.9 g of 3-chloro-4-methoxybenzylamine, 3.97 g of triethylamine and 200 ml of 2-propanol were added to 4 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes, cooled to room temperature and filtered to recover a crystalline precipitate. The precipitate was washed with water and chloroform successively to give 5.563 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28].O>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)[CH3:28]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Next, to a mixture of tert-butyl (7-hydroxy-1-naphthyl)carbamate (64.0 g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 mL anhydrous DMF was added iodoethane (42.3 g, 272 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hours. Water was added to the mixture, and the product was extracted with ethylacetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitate was collected and dried to afford tert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9 g, 67.5% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][N:17]=2)[N:14]=[CH:13][CH:12]=[C:11]3[N:18]2[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]2)[C:5]([N+:32]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[NH2:32][C:5]1[C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][N:17]=2)[N:14]=[CH:13][CH:12]=[C:11]3[N:18]2[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]2)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(-c4nc(Cl)ccc4[N+](=O)[O-])cc23)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(-c4nc(Cl)ccc4N)cc23)C1
Yield: 77 %

Procedure:
A heterogeneous solution of (S)-tert-butyl 1-(6-(6-chloro-3-nitropyridin-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 eq.) and iron (6.0 eq) in acetic acid, at a concentration of 0.4 M, was stirred vigorously for 14 hours. The mixture was then passed through a celite pad, eluting with MeOH. Upon removal of the volatiles in vacuo, the residue was dissolved in EtOAc, washed with Na2CO3(sat.), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding (S)-tert-butyl 1-(6-(3-amino-6-chloropyridin-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (77%). LCMS (m/z): 455.2 (MH+); LC Rt=3.10 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5](O)=[O:6].Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[C:40]1([NH2:44])[CH2:43][O:42][CH2:41]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:32][C:31]1[C:16]2[C:17]([C:27]([NH:28][CH3:29])=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:9]1[CH:8]=[C:4]([C:5](=[O:6])[NH:44][C:40]2([C:35]3[N:34]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:43][O:42][CH2:41]2)[CH:3]=[C:2]([F:1])[C:10]=1[CH3:11]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)c(F)c12
Reactant: NC1(c2ncccn2)COC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)COC4)cc(F)c3C)c(F)c12
Reaction time: 8 h

Procedure:
To a yellow solution mixture of 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (30 mg, 0.068 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (12.5 mg, 0.067 mmol) in DMF (1 ml) in a 25 mL round-bottomed flask was added PyBOP (50 mg, 0.096 mmol), followed by TEA (0.1 ml, 0.717 mmol), and the reaction mixture was stirred for overnight. Ice cooled water was added to the reaction mixture, which was then stirred for 10-15 min. at 0° C. Precipitation was observed. The solid was collected by filtration, washed with cold water, and then dissolved in dichloromethane. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield (10 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:18][NH2:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
In a sealed flask, a solution of 6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (750 mg, 2.6 mmol) in THF (20 mL) was cautiously added to well stirred BH3.THF complex (1.0 M solution in THF, 13 mL, 13.0 mmol) at 0° C. The reaction mixture was heated at 40° C. for 1 h and cooled to RT. MeOH (large excess) and Amberlyst 15 (35 g) were successively added and the resulting mixture was shaken at RT for 30 min. The resin was filtered, washed with MeOH (500 mL), and the desired compound was released with ammonia (1.0 M solution in MeOH, 1.2 L). The NH3-MeOH fraction was evaporated to yield the crude C-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-methylamine (778 mg) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[CH:8]12[O:13][CH:9]1[CH2:10][CH2:11][CH2:12]2>CCOCC.C1COCC1.[Cu]I>[CH2:2]([C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[OH:13])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: C1CC2OC2C1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC[C@@H]1CCC[C@H]1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A solution of 5-bromopent-1-ene (11.81 mL, 100 mmol) in Et2O (100 mL) was added to magnesium (2.43 g, 100 mmol) over 20 minutes. The resulting suspension was heated under reflux for 40 minutes, then cooled to 20° C., taken up in a syringe, and added dropwise at −5° C. to a stirred suspension of CuI (3.17 g, 16.6 mmol) in THF (160 mL). The resulting solution was stirred for 30 minutes at −5° C., then cooled to −20° C. Cyclopentene oxide (7.21 mL, 83 mmol) was added dropwise, and the resulting mixture was warmed to 20° C. over 2 hours, then stirred for 48 hours. The reaction was quenched by addition of NH4Cl(aq.); then the layers were separated, and the aqueous layer was extracted with Et2O. The combined organic phases were washed with H2O and brine, then dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography on SiO2 (gradient elution, 1-100% EtOAc/petroleum ether) to afford the title compound (7.92 g, 62%) as a liquid. 1H NMR (400 MHz, CDCl3) δ 5.88-5.76 (m, 1H), 5.01 (d, J=17.2 Hz, 1H), 4.95 (d, J=10.6 Hz, 1H), 3.83 (br s, 1H), 2.12-2.00 (m, 2H), 1.99-1.84 (m, 2H), 1.76-1.30 (m, 7H), 1.24-1.11 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:38]>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:37]([O:39][C:40]2[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=2)=[O:38])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][O:28][CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a well-stirred solution of 5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (12 g, 29 mmol) and pyridine (10 mL) in CH2Cl2 (100 mL) was added powdered 4-nitrophenyl chloroformate (8.69 g, 43 mmol) at 0° C. The reaction mixture was stirred for 12 h at room temperature and the solvent was evaporated from the filtrate and the residue was purified by column chromatography (SiO2, dichloromethane/hexane, 20%-50%) to give the product as a foam (14.2 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[CH:12][C:13]([O:15]C)=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:17].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:17]
Reactant: COC(=O)C=Cc1cc(F)cc2c(C)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(/C=C/C(=O)O)cc(F)cc12
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a stirred solution of methyl 3-(5-fluoro-3-methylindol-7-yl)acrylate (1.75 kg, 7.51 mole), prepared as described in Example 1, in 23.4 L THF/MeOH (1:1) at room temperature was added 2 M aqueous sodium hydroxide (16.35 L, 32.7 moles). Stirring was continued for 15 h, then the reaction mixture was concentrated in vacuo to remove the volatile organic solvents. The solution was diluted with 20 L water, then extracted with dichloromethane (3×10 L). The aqueous layer was acidified to a pH of 2-3 with 2 M HCl, which induced precipitation of the product. The product was collected via vacuum filtration, washed with water (2×2 L), and vacuum dried at 60° C. to afford 1.036 kg (91% yield) of the desired title compound: 1H NMR (400 MHz, DMSO-d6) δ 2.23 (d, 3H, J=0.8 Hz), 6.67 (d, 1H, J=16 Hz), 7.24 (br s, 1H), 7.34 (dd, 1H, J=9.2, 2.4 Hz), 7.41 (dd, 1H, J=10.4, 2.4 Hz), 8.06 (dd, 1H, J=16, 1.2 Hz), 11.35 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH:15](O)[CH3:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]([F:45])([F:44])[C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=3[C:35]([O:37]C)=[O:36])=[CH:27][CH:28]=[N:29]2)=[CH:24][CH:23]=1>>[F:45][C:21]([F:20])([F:44])[C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=3[C:35]([O:37][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=4)[CH2:10][CH2:11]3)=[O:36])=[CH:27][CH:28]=[N:29]2)=[CH:24][CH:23]=1
Reactant: CC(O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1cc(F)ccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Yield: 76.8 %

Procedure:
Using the procedure of Step B of Example 7, 6.57 g of 4-(3-trifluoromethylphenyl)-piperazin-1-yl-ethanol and 9.19 g of methyl 2-(7-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate were reacted to obtain 12.72 g of raw product which was chromatographed over silica gel. Elution with 95-5 methylene chloride-methanol mixture yielded 11.16 g of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(7-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate. The said product was dissolved in 25 ml of hot absolute ethanol and then 5.6 ml of an ethanol solution of 6.6 N hydrochloric acid was added thereto at 50° C. The mixture was stirred and 60 ml of anhydrous ether were added thereto in small amounts. The mixture was stirred overnight at room temperature and after the addition of 0.5 ml of the ethanolic hydrochloric acid solution, the mixture was stirred for one hour and was vacuum filtered. The recovered crystals were washed with a 1-3 anhydrous ethanol-ether mixture and then with ether to obtain 11.7 g of the dihydrochloride of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(7-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate melting at 200° C.