Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=3[N:7]=[CH:6]2)[CH2:2]1.C=O.[BH3-][C:18]#N.[Na+]>CO.CC(O)=O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][N:5]([CH:3]3[CH2:4][N:1]([CH3:18])[CH2:2]3)[C:9]=2[CH:10]=1
Reactant: [BH3-]C#N
Reactant: Brc1ccc2ncn(C3CNC3)c2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(azetidin-3-yl)-6-bromo-1H-benzo[d]imidazole (100 mg, 0.396 mmol) in MeOH (10 mL) was added HCHO (300 mg, 3.96 mmol) and AcOH (two drops). The reaction mixture was stirred at room temperature for 30 min. NaCNBH3 (29.7 mg, 0.476 mmol) was then added and the reaction mixture stirred at room temperature for 2 h. The solvents were then removed by concentration and the residue was used for next step without purification. ESI-MS (m/z): 266.1 [M+1]
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]2[CH2:6][CH2:7][C:4]=2[CH:3]=1.C([Li])(C)(C)C.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][C:2]1[CH:9]=[CH:8][C:5]2[CH2:6][CH2:7][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CC2
Reactant: BrCCCCBr
Agent: [Li]C(C)(C)C
Product: BrCCCCc1ccc2c(c1)CC2
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a clean and dry 1000 ml round bottom flask equipped with a 250 ml addition funnel, low temperature thermometer and magnetic stir bar was transferred anhydrous tetrahydrofuran (500.0 ml) under nitrogen. 4-bromobenzocyclobutane (25.0 g, 0.1370 mol) was added to this flask by syringe. The reaction vessel was placed into a dry ice/acetone bath until a temperature of <−70° C. was achieved. The reaction mixture was then allowed to stir for 45 minutes at a stirring speed of 550 rpm in order to verify the integrity of the stirring apparatus at this temperature. Tert-butyllithium solution (161 ml, 0.2730 mol) was transferred to the addition funnel by cannula, then added dropwise to the reaction never allowing the temperature to rise above −65° C. Following addition, the reaction was allowed to stir for a period of 30 minutes. The vessel was then removed from the dry ice/acetone bath and allowed to warm to a temperature of −20° C. The vessel was then again placed into the dry ice/acetone bath until a temperature of <−70° was achieved. 1,4-dibromobutane (64.7 ml, 0.5460 mol) was added to the reaction dropwise via syringe, maintaining the current temperature. The reaction was allowed to stir for 30 minutes at this temperature following addition. The reaction was slowly warmed to room temperature over the following 12 hours. Reaction completion was confirmed by GC-MS. After warming, the reaction was quenched by the addition of isopropanol (25.0 ml) via syringe.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH:19]=[CH:20][C:21]=2[CH:22]=[O:23])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>CCOC(C)=O>[C:4]([O:8][C:9]([N:11]1[CH2:12][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH:19]=[CH:20][C:21]=2[C:22]([OH:42])=[O:23])[CH2:14]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C(=O)O)C1
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a CH2Cl2 (6 mL) solution of the title compound of Step A (0.236 g, 0.560 mmol) was added m-CPBA (77 wt %, 0.189 g, 0.840 mmol). After 15 h, 10% Na2S2O5 was added and the solution allowed to stir until the aqueous was Kl paper negative and extracted with CH2Cl2 (2×). The combined organic layers were dried and treated with MeOH (10 mL) and 1N NaOH (10 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M HCl (220 mL) then extracted with EtOAc (2×). The combined organic layers were dried and concentrated. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.091 g (37% yield) of the title compound. (MS (ESI): mass calcd. for C22H22F3NO5, 437.15. m/z found, 382.1 [M-56]+, 460.1 [M+Na]+. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 1.9 Hz, 1H), 6.52 (d, J=1.0 Hz, 1H), 4.97-4.88 (m, 1H), 4.30 (dd, J=9.8, 6.4 Hz, 2H), 4.05 (dd, J=9.9, 3.7 Hz, 2H), 1.45 (s, 9H)) and 0.091 g (39% yield) of 3-(4-Hydroxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (MS (ESI): mass calcd. for C21H22F3NO4, 409.15. m/z found, 354.1 [M-56]+, 432.1 [M+Na]+. 1H NMR (CDCl3): 8.19 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.12 (dd, J=8.0, 1.3 Hz, 1H), 6.63 (s, 1H), 5.11-5.00 (m, 1H), 4.36 (dd, J=10.1, 6.4 Hz, 2H), 4.12 (dd, J=10.6, 3.6 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][O:5][C@@H:4]([CH2:7][OH:8])[CH2:3]1.[NH2:9][C:10]1[C:11]([Cl:17])=[N:12][CH:13]=[N:14][C:15]=1Cl.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:9][C:10]1[C:15]([NH:1][C@H:2]2[CH2:6][O:5][C@@H:4]([CH2:7][OH:8])[CH2:3]2)=[N:14][CH:13]=[N:12][C:11]=1[Cl:17]
Reactant: N[C@H]1CO[C@@H](CO)C1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1N[C@H]1CO[C@@H](CO)C1
Yield: 58 %

Procedure:
To a 50 mL round bottom flask fitted with a reflux condenser was added (2R-cis)-4-aminotetrahydro-2-furanmethanol, Compound IV(f), (184 mg, 1.57 mmole), 5-amino-4,6-dichloro-pyrimidine (770 mg, 4.70 mmole), triethylamine (0.44 mL, 3.16 mmole) and t-butyl alcohol (16 mL). The reaction mixture was heated to reflux temperature under an atmosphere of argon for 72 hours, at which time the volatile materials were removed by rotary evaporation. The residue was dissolved in 100 mL EtOAc, washed with saturated NaHCO3 solution (50 mL) and saturated NaCL solution (50 mL), then dried over MgSO4. After filtration and evaporation, the product was purified by flash column chromatography (50% EtOAc/50% Hexane) to yield 220 mg (58%) of Compound IX.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC(N(C)C)=O.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:20][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCOc1ccc(C(=O)O)o1
Reaction time: 42 h

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 75.4 g (0.471 mole) of decanol and 1000 ml of dried dimethyl acetamide is stirred at room temperature after which 15.0 g (0.628 mole) of sodium hydride is added. The mixture is refluxed with stirring for 42 hours after which the mixture is poured into a water-ice mixture, acidified with acetic acid and extracted with ether. The ether layer is washed several times with water and salt water, then dried over sodium sulfate, filtered and evaporated on a steam bath replacing the ether with hexane and allowing the mixture to crystallize. The solid obtained is recrystallized from methanol to give 5-decyloxy-2-furoic acid, M.P. 124°-126° C.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:10]=1)=[O:5])C.CC(OC([NH:27][CH2:28][CH2:29]O)=O)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[O:13]([CH:11]([C:9]1[CH:10]=[C:6]2[C:4](=[O:5])[NH:27][CH2:28][CH2:29][N:7]2[N:8]=1)[CH3:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOC(=O)c1cc(C(C)Oc2ccccc2)n[nH]1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC(Oc1ccccc1)c1cc2n(n1)CCNC2=O

Procedure:
The compound was prepared from (rac)-5-(1-phenoxy-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester and tert-butyl n-(2-hydroxyethyl)carbamate using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[NH2:15]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:15][NH:14][C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 6-bromo-1H-indole-2,3-dione(Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381-4) and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 7.05 (s, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 11.2 (s, 1H), 12.7 (s, 1H); APCI−MS m/z 395 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:26])([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].I[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36].O>CS(C)=O>[CH2:36]([C:5]([CH2:4][CH2:3][C:2]([F:26])([F:1])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:21])([F:20])[F:19])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30]
Reactant: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-malonate prepared in Step 1 of Example 2 (1.2 g, 3.0 mmol) was slowly added dropwise to a suspension of 60% sodium hydride (288 mg, 12 mmol) in anhydrous dimethyl sulfoxide (20 ml) at 0° C., followed by stirring for 1 hour at room temperature. After 7-iodohept-1-ene (795 mg, 2.5 mmol) was slowly added dropwise, the reaction mixture was stirred for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(6-heptenyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (1.08 g, Yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20](=[O:25])[CH2:21][C:22]([NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([F:1])[CH:3]=1)=[O:23]
Reactant: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(F)c1
Yield: 65 %

Procedure:
The title compound is prepared in analogy to example 1 from 3-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 65%. Light yellow solid. MS: m/e=336.2 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccccc2Cl)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of o-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-chlorophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 152°-155° C.
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Cl[CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].O>C1COCC1>[C:1]([N:8]([CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of di-Boc-hydrazine (2.0 g, 8.6 mmol) in THF (30 mL) was slowly added sodium hydride (210 mg, 8.6 mmol). After stirring at 0° C. for 5 minutes and then at room temperature for 30 minutes, the mixture was added to a solution of 3-chloro-1-phenylpropan-1-one (1.50 g, 8.6 mmol) in THF (10 mL). After stirring at room temperature for 30 minutes, water was added, and the mixture was partitioned between brine and ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (15% ethyl acetate in hexanes) to provide the crude product.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:10][C:9]=1[F:24])=[O:6].[OH-].[NH4+:27]>>[F:24][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:12]([F:14])=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:27])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 56 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and and ammonium hydroxide. Yield=56%. Colorless solid. MS: m/e=339.3 (M++H).
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24]C(C)(C)[O:26][C:27](=O)[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3([C:19]#[N:20])[CH2:18][CH2:17]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]4([C:19]#[N:20])[CH2:18][CH2:17]4)=[C:11]([F:21])[CH:10]=3)[CH2:22][C:23](=[O:24])[CH2:28][C:27](=[O:26])[O:32]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2cc(F)c(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: N#CC1(c2c(F)cc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1

Procedure:
The desired product was prepared analogously to step of example A (97), substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluorophenyl}-cyclopropanecarbonitrile (1.0 g, 2.66 mmol) from Step 2 below in place of 2{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. Yield: 0.43 g, 42%. δ: 1H NMR (CDCl3) δ: 1.35 (t, J=2.8 Hz, 2H), 1.56–1.73 (m, 10H), 1.92 (t, J=4.45 Hz, 2H), 2.21–2.30 (m, 1H), 2.65–2.79 (m, 4H), 3.44 (d, J=5.6 Hz, 2H), 6.71(d, J=8.6 Hz, 2H). MS (ESI): 386 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:12]2[C:11]3[C:16](=[CH:17][N:18]=[C:9]([C:3]4[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:37]5[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=5)[N:4]=4)[CH:10]=3)[N:15]=[CH:14][CH:13]=2)[CH2:20]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(-c4nc(Cl)ccc4N)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1ccc(-c2ccc(F)cc2)nc1-c1cc2c(N3CCC[C@H](N)C3)ccnc2cn1
Yield: 61 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(3-amino-6-chloropyridin-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 4-fluorophenylboronic acid (3.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.15 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-2-(4-(3-aminopiperidin-1-yl)-1,7-naphthyridin-6-yl)-6-(4-fluorophenyl)pyridin-3-amine (61%). LC/MS=415.2 (M+H), LC=2.32 min.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[S:1]1[C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2c(s1)CCCC2
Temperature: 0 °C

Procedure:
4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid (1.0 g, 5.50 mmol) is dissolved in dichloromethane [DCM] (25 mL) that contains 5 drops of N,N-dimethylformamide [DMF] under nitrogen and cooled to 0° C. Oxalyl chloride (13.7 mL of a 2.0M solution in DCM) is added via syringe and allowed to warm to RT over 1 hour. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual oxalyl chloride. The residue is then dissolved in ethyl acetate and washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) as an off-white solid (1.03 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:22]1[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]1[OH:33])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][C:42]#[CH:43])([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(NCC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][C:42]#[C:43][C:19]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@@H:22]2[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]2[OH:33])=[C:12]([NH:11][C@H:8]([CH2:9][OH:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:20]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)NCC#Cc1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C

Procedure:
N-{(1S,2R,3S,4R)-4-[6-((S)-1-Benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate GC) (1 eq.), prop-2-ynyl-carbamic acid tert-butyl ester (10 eq.), CuI (0.25 eq.), bis(triphenylphosphine)-palladium(II) chloride (0.25 eq.) and triphenylphosphine (0.5 eq.) are dissolved in diethylamine and DMF. The reaction mixture is heated in a microwave for 1 hour at 120° C. The title compound is obtained by column chromatography.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].O=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[N:16]1[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:18]=[C:17]1[C:26]([O:28]CC)=O>C(O)(=O)C>[O:28]=[C:26]1[NH:5][C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][C:8]=2[N:16]2[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:18]=[C:17]12
Reactant: CCOC(=O)c1cn(C2Cc3ccccc3C2=O)c(C(=O)OCC)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3
Yield: 37.7 %

Procedure:
51.2 g of ammonium acetate are added in small portions to a solution of 2 g of diethyl 1-(1-oxoindan-2-yl)imidazole-2,4-dicarboxylate in 80 ml of acetic acid and the mixture is heated to reflux for 2 hours. After cooling to a temperature close to 20° C. the precipitate formed is filtered off and rinsed with distilled water and then with methyl ethyl ketone (2×10 ml) to give 0.65 g of ethyl 4,5-dihydro-4-oxo-10H-imidazol[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in the form of a beige solid melting above 260° C. (analysis % calculated C: 65.08, H: 4.44, N: 14.23; % found C: 65.2, H: 4.3, N: 13.8).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C:36]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[C:37]=1[C:38]([NH2:40])=[O:39]>CC(N(C)C)=O.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:40][C:38](=[O:39])[C:37]4[C:36](=[CH:44][C:43]([O:45][CH3:46])=[CH:42][C:41]=4[O:47][CH3:48])[N:35]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(C)N1CCN(Cc2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCN(C(C)C)CC4)cc3)nc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A mixture of 4-((4-isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 0.97 mmol), NaHSO3 (0.155 g, 1.50 mmol), and p-TsOH (0.019 g, 0.10 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97 mmol) in DMA (7 mL). The reaction was stirred at 130° C. overnight. Then, the mixture was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.122 g, 30%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.51 (s, 2H), 2.54-2.71 (m, 1H), 2.27-2.44 (m, 8H), 0.95 (d, J=6.4 Hz, 6H). ESI MS m/z 423 [M+H]+.