Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][CH2:2][CH:3]([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(C#N)cc1
Yield: 92.5 %

Procedure:
A solution of tert-butyl (3-amino-2-methylpropyl)carbamate (200 mg, 1.06 mmol), 4-cyanobenzoic acid (156 mg, 1.06 mmol), HATU (525 mg, 1.38 mmol) and TEA (0.444 mL, 3.19 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanobenzamido)-2-methylpropyl)carbamate (311 mg, 0.980 mmol, 92%) as a white powder.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH2:19]>>[F:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C)ccc1F
Yield: 62.6 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2-fluoro-5-methylaniline (2.43 g, 19.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (3.80 g, 50%) was obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[C:20](F)=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:20]1[C:10]([F:9])=[CH:11][C:12]([N+:22]([O-:24])=[O:23])=[C:13]([CH:19]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
8.25 g of Verkade base are added to a solution of 2.61 g of benzyl alcohol in 20 ml of THF. The mixture is stirred for 10 minutes at room temperature, and a solution of 5.3 g of ethyl 4,5-difluoro-2-nitrobenzoate and 2.55 g of Et3N in 150 ml of THF is added to this solution. The mixture is stirred for 1 hour at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in DCM and washed three times with aqueous 1N HCl solution, and then with water. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/DCM mixture from (100/0, v/v) to (0/100, v/v) to give 4.5 g of the expected product.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18]>>[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[O:18][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
The sub-title compound was prepared by the method of Example 2 step a) using methyl bromoacetate and 2-bromo-4-(trifluoromethyl)phenol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]#[N:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[BH4-].[Na+].[H][H]>CO>[CH3:1][O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(C#N)CC12CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CN)CC12CCCC2
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.45 g, 19.3 mmol) in methanol (240 mL) was added CoCl2-6H2O (9.16 g, 38.5 mmol) to give a deep purple colored solution. Sodium borohydride (7.30 g, 193 mmol) was added portionwise over 10 minutes with caution to control the evolution of hydrogen and the exothermic reaction that ensued to give a black solution. The reaction mixture was stirred for 30 minutes under nitrogen after the addition was completed. The reaction was quenched carefully by the addition of 0.5N HCl (1.3 L). The solution was made alkaline (pH˜9) by the addition of concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 3.07 g (87%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.74 (br d, 1H), 1.4-1.7 (m, 10H), 1.9 (m, 1H), 2.58 (d, J=13.8 Hz, 1H), 3.16 (d, J=13.8 Hz, 1H), 3.48 (s, 3H); MS (APCI) m/z 184 [M+H]+.
Reaction SMILES: O.[O:2]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Ca+2].O(C1C=C(C(C)C([O-])=O)C=CC=1)[C:22]1C=CC=CC=1.OS(O)(=O)=O>CO>[CH3:22][O:17][C:16](=[O:18])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=1)[CH3:19]
Reactant: CC(C(=O)[O-])c1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)c1cccc(Oc2ccccc2)c1

Procedure:
To a suspension of calcium 2-(3-phenoxy-phenyl)-propionate hydrate (5.00 g, 9.57 mmol) in methanol (150 mL) was added conc. H2SO4 (1.1 mL) and the gelatinous solution heated to reflux for 4 hrs. After cooling, the solution was filtered and evaporated to dryness, the residue dissolved in EtOAc, washed with satd. aq. NaHCO3 soln., dried (MgSO4) and evaporated to yield methyl-2-(3-phenoxy-phenyl)-propionate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.34 (2H, m), 7.26 (1H, m), 7.11 (1H, m), 6.99-7.02 (4H, m), 6.87 (1H, m), 3.70 (1H, q, J=7.2 Hz), 3.67 (3H, s), 1.58 (3H, d, J=7.2 Hz)
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([NH2:15])=[O:13]
Reactant: O=C(O)c1sc2cnccc2c1Br
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1sc2cnccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) mixture of 3-bromothieno[2,3-c]pyridine-2-carboxylic acid (50 mg, 0.19 mmol), DCM (1 mL) and DMF (10 μL, 0.1 mmol) was added oxalyl chloride (29 μL, 0.34 mmol). The ice bath was removed and the mixture was stirred at room temperature for 1 h. Oxalyl chloride (29 μL, 0.34 mmol) was added again and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and THF (1 mL) was added. Ammonium hydroxide (0.7 mL, 20 mmol) was added to the mixture and stirred at room temperature for 1 h. The precipitate was filtered and washed with DCM and used without further purification. 1H NMR (400 MHz, CD3OD): δ 9.20-9.27 (m, 1 H), 8.61 (d, J=5.8 Hz, 1 H), 7.89 (dd, J=5.7, 0.9 Hz, 1 H); MS (ESI): 257.33, 259.35 [M+H]+; HPLC tR=0.52 min (HPLC: Analytical—2 min).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[S:30][C:29]([S:31]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:32])=[CH:28][CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.00 g, 4.25 mmol) in dichloromethane (50 ml) was treated with morpholinomethyl-polystyrene HL resin (2.10 g, 4.0 mmol/g loading, 8.50 mmol) followed by 5-bromo-2-thiophenesulfonyl chloride (1.33 g, 5.09 mmol). The resulting solution was stirred at room temperature overnight and was then filtered and the solvent evaporated. The residue was then chromatographed over silica gel (Flashmaster (II)) eluting with 0 to 10% methanol in dichloromethane 90% for 5 mins, 0-10% 20 mins and 10% 10 mins). The compound was then purified by mass directed autoprep HPLC and the residue further purified by SCX, eluting with methanol first and then NH4OH/methanol. (E122). MS (ES+) m/e 460/462 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].C(N(CC)C(C)C)(C)C.[CH3:59][CH:60]1[CH2:62][CH:61]1[C:63](O)=O>CN(C=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:63]([CH:61]5[CH2:62][CH:60]5[CH3:59])[N:48]([CH3:49])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:45][CH:44]=1
Reactant: CC1CC1C(=O)O
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC1c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (235 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (200 mg), N,N-diisopropylethylamine (0.308 ml) and 2-methylcyclopropanecarboxylic acid (0.057 ml) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and concentrated in vacuo. The resulting solid was recrystallized from THF to give the title compound as a white solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C@@H:17]2[CH2:21][O:20][C@@H:19]3[C@H](O)[CH2:23][O:24][C@H:18]23)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1C=CC=CC=1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C@@H:17]2[CH2:21][O:20][C@@H:19]3[C@@H:1]([Br:5])[CH2:23][O:24][C@H:18]23)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 65 °C
Yield: 42.7 %

Procedure:
A solution of carbon tetrabromide (18.12 g, 54.63 mmol) in pyridine (100 mL) was added to a solution of monotosylate (50) (14.9 g, 49.66 mmol) and triphenylphosphine (26.1 g, 99.32 mmol) in pyridine (150 mL) over 30 minutes, then the mixture heated at 65° C. for 1.5 hours under an atmosphere of argon. Water (200 mL) was added then the aqueous phase extracted with dichloromethane (5×100 mL). The organic phase was washed with brine (50 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue which was azeotroped with toluene (5×50 mL). Flash chromatography over silica, eluting with diethyl ether:heptane mixtures 0:100 to 100:0 gave bromotosylate (46) (7.70 g, 43%) as a white solid. [α]D17+68.60 (c=0.51, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Br:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1Cl
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCCCBr)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred and refluxing mixture of 122 parts of 4-chloro-3-methylphenol, 214.1 parts of 1,3-dibromopropane and 850 parts of water added dropwise, during a one hour-period, a solution of 34 parts of sodium hydroxide in 213 parts of water. Upon completion, stirring at reflux is continued overnight. The reaction mixture is cooled to room temperature and the product is extracted with 765 parts of benzene. The extract is washed with a sodium hydroxide solution 10%, dried, filtered and evaporated. The residue is distilled twice, yielding 114 parts of 4-(3-bromopropoxy)-1-chloro-2-methylbenzene; bp. 119° C. at 0.6 mm. pressure.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cccc(-c2ccc(-c3cccnc3N)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 35.5 mg) in THF (dry) (5 mL) was added 2-chloroethanesulfonyl chloride (0.056 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(3′-methoxybiphenyl-4-yl)pyridin-2-amine (49 mg) in THF (dry) (5 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with EtOAc and dried in vacuo to give the title compound (18 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C(O)C.Cl>[Fe].O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([NH2:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)ccc1C=O
Temperature: 85 °C
Yield: 82.8 %

Procedure:
To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, NC. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85° C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83%) as a yellow solid. 1H NMR (CDCl3)δ 7.58 (dd, 1H, J=2.1, 8.7 Hz), 7.89 (d, 1H, J=8.7 Hz), 8.17 (s, 1H), 8.83 (d, 1H, J=1.7 Hz), 9.45 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(pyridin-2-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH2:27])[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=1.C(O[K])(C)(C)C>CS(C)=O>[O:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:27][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1ccc(-c2nc3cccc(N)c3nc2-c2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: COc1ccc(-c2nc3cccc(Nc4ccc(N)cc4)c3nc2-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
While agitating 5.0 g (14.0 mmol) of 2,3-di(4-methoxylphenyl)-5-aminoquinoxaline, 2.4 g (17.0 mmol) of 4-fluoronitrobenzene and 120 ml of dimethylsulfoxide, 5.7 g (50.8 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 8 hours. After completion of the reaction, 100 ml of water was added while cooling, and an organic phase was extracted by use of a chloroform solvent, followed by concentration to obtain the intended product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:24]([F:25])=[CH:23][C:15]([O:16][CH2:17][C:18](OCC)=[O:19])=[C:14]([N+:26]([O-])=O)[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[C:24]([F:25])=[CH:23][C:15]3[O:16][CH2:17][C:18](=[O:19])[NH:26][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc3c(cc2F)OCC(=O)N3)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
A solution of 4.5 g (0.0106 mole) (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)-acetic acid, ethyl ester in 75 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 1.8 g (0.033 mole) iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 3 hours. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was recrystallized from methylcyclohexane/ethyl acetate to give 2.95 g (80%) of 6-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-2H-1,4-benzoxazin-3-(4H)-one as a white solid, mp 207° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[C:15]1([C:21]2[N:22]=[C:23]3[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][N:24]3[CH:30]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:29][C:27]1[CH:26]=[CH:25][N:24]2[CH:30]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:22]=[C:23]2[N:28]=1)=[O:5])[CH3:2]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
5-Chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.60 g, assumed purity 60%, 10 mmol) was added slowly to a cooled (0° C.) solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 2.52 g, 12 mmol) and triethylamine (2.02 g, 20 mmol) in dichloromethane (50 ml), and the suspension was stirred overnight at RT. The mixture was taken up in dichloromethane, and washed with water. The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The title compound (2.75 g, 71%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=391.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]2[CH3:20].[CH3:26][NH:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:27]([CH3:28])[CH3:26])=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]2[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(CCl)cc3)cc2n1C
Reactant: CNC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(CN(C)C)cc3)cc2n1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
A mixture of 1.34 g (3.53 mmol) of ethyl 4-chloro-6-[4-(chloromethyl)phenoxy]-1-methyl-2-indolecarboxylate, 8.0 g of dimethylamine and 80 ml of dimethylformamide was stirred at 0° C. for 3 hours. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.29 g (21.2%) of ethyl 4-chloro-6-[4-(dimethylaminomethyl)phenoxy]-1-methyl-2-indolecarboxylate.
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]1[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=1)#[CH:6].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)#[CH:6]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C#Cc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Glacial acetic acid (0.2 mL) was added to a mixture of 4-ethynylbenzaldehyde (1 g, 7.5 mmol), pyrrolidine (1.2 mL, 15 mmol) and NaBH(OAc)3 (2.5 g, 11.5 mmol) in DCE (35 mL). The resulting mixture was stirred for 2 h at rt. The reaction was quenched with saturated aqueous NaHCO3 (50 mL). The product was extracted into CH2Cl2 (2×100 mL), and the combined organic layer was washed with brine (25 mL), dried (MgSO4) and evaporated in vacuo to give 1-(4-ethynylphenyl)pyrrolidine in quantitative yield. 1H NMR (CDCl3) δ: 7.45 (d, J=7.8 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 3.62 (s, 2H), 3.06 (s, 1H), 2.51 (bs, 4H), 1.80 (bs, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:7]([N:20]=[N+]=[N-])[CH2:6]1)=[O:4].[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>O=[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C@@H:7]([NH:20][C:29]([C:27]2[S:28][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:30])[CH2:6]1)=[O:4]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)[C@H]1CC(N=[N+]=[N-])[C@@H](OCCOC2CCCCO2)C1
Agent: O=[Pt]=O
Product: COC(=O)C1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OCCOC2CCCCO2)C1

Procedure:
In analogy to example 10A and example 1B, (S,4S)-3-azido-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-cyclopentanecarboxylic acid methyl ester was hydrogenated in the presence of PtO2 and coupled with 5-chloro-2-thiophenecarboxylic acid to give (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-cyclopentanecarboxylic acid methyl ester. Brown gum. MS 432.2 ([M+H]+).