Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH3:12][O-:13].[Na+].CO>O>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
100 g (0.445 mol) of 4-(trifluoromethyl)bromobenzene, 120 g (2.22 mol) of sodium methoxide, and 300 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150° C. under tight sealing. The resulting reaction mixture was poured into water, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 49 g (0.278 mol) of 4-(trifluoromethyl)anisole (yield: 62.6%).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:19]3[C:11](=[N:12][NH:13][C:14]=3[N:15]=[C:16]([S:20][CH3:21])[N:17]=2)[CH:10]([C:22](O)=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:25]([NH:32][C:22]([CH:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:18]2[C:19]3[C:11]1=[N:12][NH:13][C:14]=3[N:15]=[C:16]([S:20][CH3:21])[N:17]=2)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc2c3c(n[nH]c3n1)C(C(=O)O)CN2Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
5-Benzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxlic acid (0.71 g, 2.1 mmol) and DMF (20 ml) were placed in a round-bottomed flask. To the stirring mixture was slowly added benzylamine (0.34 mL, 3.2 mmol), HBTU (1.03 g, 3.4 mmol), diisopropylethyl amine (1.1 mL, 6.3 mmol) and the solution was allowed to stir at room temperature for 16 h. The reaction was quenched by addition of EtOAc (200 mL) and washing with water (2×500 mL). The organic layer was combined, dried over MgSO4, and concentrated under reduced pressure to yield a yellow solid (0.84 g, 2.0 mmol). 1H-NMR (DMSO-d6): 8.56 (t, J=2.0 Hz, 1H), 7.40-7.22 (m, 10H), 4.36 (dd, J=8.1 & 21.2 Hz, 3H), 4.38-4.21 (m, 3H), 4.19 (t, J=5.2 Hz, 2H), 3.86-3.76 (m, 3H), 3.17 (d, J=5.2 Hz, 1H). LC: Rt=1.42 min. MS 431.53 [M+H].
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][C:14]([CH3:28])=[CH:15][CH2:16][CH2:17]/[C:18](/[CH3:27])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:26])=[CH:23]/[CH:24]=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1>[OH:25][CH:24](/[CH:23]=[C:22](\[CH3:26])/[CH2:21][CH2:20]/[CH:19]=[C:18](\[CH3:27])/[CH2:17][CH2:16][CH:15]=[C:14]([CH3:28])[CH3:13])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(CC(O)/C=C(\C)CC/C=C(\C)CCC=C(C)C)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (0.698 ml of a 2.5M solution in hexanes, 1.75 mmol) was added to a stirred solution of dimethyl methylphosphonate (0.189 ml, 1.75 mmol) in THF (4 ml), under argon at -78° C. The resulting colorless solution was stirred at this temperature for 20 min. Farnesal (350 mg, 1.59 mmol) in THF (4 ml) was added over 5 min and the resulting mixture stirred a further 30 min and then treated with saturated sodium bicarbonate solution (5 ml) and allowed to warm to r.t. The THF was evaporated in vacuo and the aqueous extracted twice with ethylacetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethylacetate to afford the title compound as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.[NH2:14][CH:15]1[C:20](=[O:21])[N:19]2[CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][CH:18]2[N:17]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[Cl:48])(=[O:40])=[O:39])[CH2:16]1>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:22]2[N:19]3[C:20](=[O:21])[CH:15]([NH:14][C:11]([C:3]4[CH:2]=[N:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:13])[CH2:16][N:17]([S:38]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=4[Cl:48])(=[O:40])=[O:39])[CH:18]3[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[C:23]2=[O:29])=[CH:32][CH:33]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: O=C(O)c1cnc2ccccc2c1
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cnc4ccccc4c3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 29e using 3-quinolinecarboxylic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=713.10 (calculated, monoisotopic); measured value (M+H)+:714
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=O)[CH:6]=[CH:5]2.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH:6]=[CH:5]2
Reactant: O=Cc1ccc2cc(O)ccc2c1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A mixture of 4 Å molecular sieves, 6-hydroxy-2-naphthaldehyde (1.0 g, 5.81 mmol), ethyl piperidine-4-carboxylate (0.91 g, 5.81 mmol), NaBH(OAc)3 (3.76 g, 17.43 mmol) and TsOH (0.1 g, 0.581 mmol) was stirred at rt for 2 h and then quenched with water (5 mL). The mixture was extracted with DCM (20 mL*2). The combined organics were washed with saturated brine (20 mL*3) and then concentrated. The white precipitates were filtered and dissolved in water (10 mL) and EtOAc (10 mL), NaHCO3 was added to adjust pH=8-9. The mixture was extracted with EtOAc (20 mL*2). The combined organics were washed with saturated brine (20 ml*2), dried over Na2SO4, concentrated and recystallized with EtOAc to give ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate as a white solid (0.83 g, yield: 41%), ESI-MS: 314.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.61-7.63 (m, 2H), 7.32-7.35 (m, 1H), 7.03-7.08 (m, 2H), 4.02-4.03 (q, J=7.2 Hz, 2H), 3.52 (s, 2H), 2.72-2.75 (m, 2H), 2.25-2.32 (m, 2H), 1.98-2.03 (m, 1H), 1.77-1.79 (m, 2H), 1.51-1.61 (m, 2H), 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][C@H:13]([CH3:17])[O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (3.53 g, 14.7 mmol), p-fluoro-phenyl-boronic acid (16.2 mmol), copper(II) acetate (2.94 g, 16.2 mmol), triethylamine (10.3 ml, 73.5 mmol) and freshly activated 4 A molecular sieves (17.7 g) in dichloromethane was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, and the dichloromethane was removed in vacuo. The residual oil was partitioned between ethyl acetate and 2 mol/l hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried over Na2SO4 and evaporated to give a residue, which was purified by column chromatograph on silica gel (20-60% ethyl acetate in iso-hexane, gradient) to give the desired ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](N1CCOCC1)(=[O:23])[CH3:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: CC(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 2 h

Procedure:
0.65 g (2.9 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 105A) is introduced into 10 ml of THF and cooled to −50° C. 4.5 ml (7.2 mmol) of butyllithium (1.6 M) are added dropwise. After the dropwise addition is complete, the reaction is slowly warmed to −10° C. and kept at 0° C. for 2 h. It is then cooled to −40° C. again, and 740 mg (5.7 mmol) of N-acetylmorpholine dissolved in 4 ml of THF are added. The reaction solution is stirred at −40° C. for 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution and extracted. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 2:1). 218 mg (28% of theory) of the product are obtained as an oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])=[CH:16][CH:15]=[C:14]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:13]=2.C(N(CC)CC)C>ClCCl>[CH2:33]([O:32][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]([CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:8][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Ethoxyacetyl chloride (1.82 mL, 16.60 mmol) was added to a chilled (0° C.) solution of tert-butyl [2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (6.04 g, 13.8 mmol) and triethylamine (3.86 mL, 27.68 mmol) in 150 mL of anhydrous dichloromethane. After stirring for 30 minutes, the cooling bath was removed and the reaction was stirred for 24 hours at ambient temperature. The volatiles were removed under reduced pressure and the resulting residue was dissolved in ethanol, followed by the addition of 3.86 mL of trietylamine. The reaction was heated at reflux for 2.5 days and then cooled to ambient temperature. The solvent was removed under reduced pressure and dichloromethane was added. The solution was sequentially washed with aqueous sodium bicarbonate followed by brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified using flash column chromatography on silica gel, eluting with 5% methanol in dichloromethane. Clean fractions were concentrated; while fractions containing both the product and the starting material were resubmitted to the reaction conditions and repurified as described above. The combined lots provided a total of 5.07 g of tert-butyl [2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate was obtained as an orange foam.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41](O)=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 18-[2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (12, 54 mg, 0.083 mmol) and carbonyldiimidazole (20 mg, 0.125 mmol, 1.5 eq) in dry THF (4 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (15 mg, 0.125 mmol) and DBU (19 mg, 0.125 mmol) were added. This solution was heated at 50° C. for 16 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography (gradient of EtOAc (0 to 50%) in DCM) afforded 45 mg (72%) of the title product which was recrystallized from water to give 12 mg of the desired product as a slightly yellow powder. m/z=751 (M+H)+. 1H NMR (CDCl3): 0.8-1.9 (m, 21H), 2.17 (m, 1H), 2.28-2.56 (m, 4H), 2.65 (m, 1H), 2.86, (m, 1H), 3.55 (m, 1H), 3.87 (m, 4H), 4.10 (m, 1H), 4.57 (m, 1H), 4.94 (t, J=9.5 Hz, 1H), 5.43 (m, 2H), 5.64 (m, 1H), 6.92 (broad s, 1H), 6.98 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.28 (m, 2H), 7.37 (s, 1H), 7.80 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Oc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Oc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenoxy-pyridine.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: C1CCNC1
Product: O=C(O)c1ccc(C(F)(F)F)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (purchased from APOLLO, 5.0 g, 22.2 mmol) and pyrrolidine (40 ml, 562 mmol) was stirred for 24 hours at room temperature according to J. Med. Chem., 2005, 48, 71-90). Then the reaction mixture was evaporated in vacuo to give the title compound (5.5 g, 95%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:13]=1)=[N:8][CH:9]=[CH:10][C:11]=2[CH3:12])[CH2:2][CH3:3].[C:14]1([C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23]=[N:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[C:46]1([C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:21]2[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]3[CH:37]=[CH:36][C:35]([CH2:38][N:13]4[C:7]5=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]5[N:5]=[C:4]4[CH2:1][CH2:2][CH3:3])=[CH:34][CH:33]=3)=[N:24][N:23]=[N:22]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
3-[2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 2-propyl-7-methylimidazo[4,5-b]pyridine (991 mg, 5.66 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (3.0 g, 5.39 mmol), and NaH (6.47 mmol). Yield: 1.11 g (32%) thick oil; Rf: 0.80 (SiO2 tlc, 1:1 EtOAc-hexanes); 1H NMR (300 MHz, CDCl3) δ 8.20 (d, 1H, J=5 Hz), 7.89 (d, 1H, J=8 Hz), 7.51-7.39 (m, 2H), 7.38-7.20 (m, 10 H), 7.10-7.03 (m, 3H), 6.95-6.88, (m, 8H), 5.49 (s, 2H), 2.78-2.68 (m, 2H), 2.69 (s, 3H), 1.83-1.60 (m, 2H), 0.91 (t, 3H, J=5.5 Hz).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH:12]([NH:14][NH2:15])=[O:13]>C(O)C.Cl>[CH:12]([NH:14][N:15]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: NNC=O
Reactant: O=C1CCc2ccccc2C1
Agent: Cl
Solvent: CCO
Product: O=CNN=C1CCCc2ccccc21
Temperature: 70 °C
Yield: 36.3 %

Procedure:
A mixture of 1,2,3,4-tetrahydronaphthalen-2-one (3.5 g, 24.0 mmol) and formic hydrazide (1.56 g, 26.0 mmol) in 25 mL of ethanol and 1 drop of concentrated hydrochloric acid was heated at 70° C. for 1 hour. The mixture was cooled to room temperature giving a crystalline material. The material was isolated by filtration and washed with ethanol. Drying gave 2-formylhydrazono-1,2,3,4-tetrahydronaphthalene (3.5 g, 8.7 mmol).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH-].[Na+].I[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][CH:9]=1>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:2]1([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:1]1
Reactant: O=C(O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: C#CCBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2ccc(C3CC3)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of (9-BBN)2 (1.96 g, 8.7 mmol) in 10 mL THF was added propargyl bromide (0.53 g, 4.4 mmol). After heating for 2 h and cooling to room temperature, NaOH (0.52 g, 13 mmol) in 4.3 mL of H2O was added and the reaction was stirred for 1 h. In a separate flask under argon was added the title product of Example 146 Step 1 in 5 mL of THF and Pd(PPh3)4. The reaction from the original flask was transferred to the second flask via cannula. After refluxing for 18 h and cooling to room temperature, 25 mL of H2O was added. The organic solvent was removed from the reaction under vacuum. The aqueous layer was extracted three times with 70 mL EtOAc. The combined organic extractions were washed one time with 50 mL of 1 N HCl and one time with 50 mL of saturated brine. Following drying over MgSO4 and concentrating under vacuum, the product was purified by flash column chromatography and reverse phase chromatography on YMC ODS-AQ in MeOH/H2O to yield desired product (0.40 g, 40%).
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6]O)[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:31])C=C.O>C(#N)C>[CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6][Br:31])[O:2]1
Reactant: OCCCC1(c2ccccc2)OCCO1
Reactant: C=CCBr
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Product: BrCCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.2 g of the alcohol compound obtained in 20 ml of acetonitrile were added 1.2 g of 1,1'-carbonyldiimidazole and 2.5 ml of allyl bromide. The mixture was stirred for 2 hours at room temperature and then heated under reflux for 1.5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.1 g of 4,4-ethylenedioxy-4-phenylbutyl bromide as colorless crystals.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:3][C:4]1[C:8]([NH:9][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:19])([F:30])[F:31])=[S:29])=[CH:7][S:6][CH:5]=1
Reactant: Nc1cscc1N
Reactant: FC(F)(F)c1ccccc1N=C=S
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cscc1NC(=S)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.8 g of 3,4-diaminothiophene dihydrobromide was added to a mixture of 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of anhydrous THF, and the mixture was stirred at room temperature for 10 minutes, and then admixed with 0.58 g of 2-trifluoromethylphenyl isothiocyanate. The mixture was stirred at room temperature for 3 hours and at 40° C. for a further 10 minutes, and left to stand at room temperature overnight. After the solvent had been distilled off, the residue was admixed with water and extracted with ethyl acetate, and the insoluble fraction was filtered off. The organic phase was washed with water and dried over sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[N:7][CH:8]=1)#[N:2].O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cccs1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1cnc(Nc2cccc(N)c2)nc1-c1cccs1

Procedure:
N-3-Aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amine was prepared by heating a solution of 5-cyano-N-3-nitrophenyl-4-thien-2-ylpyrimidine-2-amine (2.77 g, 8.57 mmol) and tin(II)chloride dihydrate (7.73 g, 34.05 mmol) in ethanol (160 mL) at reflux for 18 h. On cooling the reaction was concentrated under reduced pressure and partitioned between CH2Cl2 and 2M NaOH. The organic phase was dried (MgSO4) and evaporated to give the desired material (320 mg) as a yellow solid, m.p. 221-222°. δH (d6 DMSO) 10.16 (1H, s), 8.83 (1H, s), 8.24 (1H, d, J 3.9 Hz), 7.97 (1H, d, J 5.1 Hz), 7.32 (1H, dd, J 5.0, 4.0 Hz), 6.97 (3H, bm), 6.31 (1H, m) and 5.04 (2H, bs).