Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(O)CCC>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16]
Reactant: COc1ccnc(Cl)n1
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1ccnc(N2CCN(C(=O)c3ccco3)CC2)n1
Yield: 70.2 %

Procedure:
A solution of 1.0 g (6.92 mmol) of 2-chloro-4-methoxypyrimidine, 1.49 g (8,30 mmol) of 1-(2-furylcarbonyl)piperazine and 1.39 g (13.84 mmol) of triethylamine in 20 mL of n-butanol is maintained under gentle reflux conditions overnight. The solvent is evaporated off under reduced pressure and the crude residue is diluted in chloroform and washed in water. The organic phase is dried over NaSO4 and evaporated to dryness to give a crude product which is purified using silica-gel chromatography eluting with ethyl acetate/petroleum ether 70:30 to yield an oil which solidifies when left to stand. The solid is suspended in petroleum ether to yield 1.4 g (4.86 mmol) of 2-[4-(2-furylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine. m.p.=85-86° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([O:22][CH3:23])=[CH:6][CH:5]=2.[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: COc1ccc2[nH]c(C)c(C(=O)c3ccccc3C(=O)O)c2c1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]c(C)c(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)c2c1
Yield: 91.5 %

Procedure:
A mixture of 2.0 g (0.006 mole) of 2-[(2-methyl-5-methoxy-3-indolyl)carbonyl]benzoic acid, obtained as described in part A above, 1.1 g (0.0067 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and six ml of acetic anhydride were interacted at 50°-55° C. in a manner similar to that described in Example 2, part B to obtain 2.5 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(2-methyl-5-methoxy-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =OCH3), as a light pink-colored solid melting at 196°-198° C. with decomposition. The infrared spectrum, showing a significant maximum at 1740 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum were in accord with the structure. A toluene solution of this product spotted on a phenolic resin coated paper developed an intense violet-colored image.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:17]O>C1(C)C=CC=CC=1>[CH3:17][CH:14]1[CH2:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CO
Reactant: O=C1C=CCCCCCCCCCCCC1
Agent: O=C1/C=C/CCCCCCCCCCCC1
Solvent: Cc1ccccc1
Product: CC1CCCCCCCCCCCCC(=O)C1
Reaction time: 15 h

Procedure:
In 10 ml of dried toluene was dissolved 5 mmol of (E)-2-cyclopentadecenone, and the solution was added dropwise to the above solution, followed by allowing the reaction to proceed at -78° C. to -60° C. for 15 hours. Thereafter, the same procedures as in Example 14 were followed to obtain muscone having an optical rotation of +11.8° (at 21° C., c 5.13, MeOH) and an optical purity of 100 %ee in a chemical yield of 90 mol %.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[Na+].OO>O.S([O-])([O-])(=O)=O.[Mn+2]>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=O
Reactant: C=Cc1ccccc1
Agent: [Mn+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: O
Product: c1ccc(C2CO2)cc1

Procedure:
To a mechanically stirred solution of styrene (0.1 mol), dodecane (0.01 mol), urea (2.08 mol), sodium bicarbonate (0.03 mol) and manganese sulphate (0.0001 mol) in 50.0 ml of water at 20° C. is added 30% aqueous hydrogen peroxide (0.22 mol) drop-wise over a period of 4 h. After 4.5 h the organic layer of the reaction mixture was separated by a separating funnel. The aqueous layer was extracted with 4×20 mL diethyl ether. The combined organic layer was distilled to yield styrene oxide. The conversion to epoxide is 99% with 94% selectivity.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([CH2:46][O:47][CH3:48])=[CH:41][C:40]=4[F:49])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[F:45][C:44]1[CH:43]=[C:42]([CH2:46][O:47][CH3:48])[CH:41]=[C:40]([F:49])[C:39]=1[C:34]1[N:33]=[C:32]([C:30]([NH:29][C:12]2[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:31])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the amide intermediate, THF (6 mL), MeOH (6 mL) and 1.0 M aq. NaOH (6.32 mL, 6.32 mmol) were added. The mixture was stirred at room temperature for 20 min. The volatile solvents were removed under reduced pressure. The resulting residue was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and then concentrated to dry to give tert-butyl ((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate as a second intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:29])[CH:25]=2)[CH:20]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)[C@@H:33]1C[C@H](C#N)C[N:34]1C(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:33]#[N:34])[CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:29])[CH:25]=2)[CH:20]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Reactant: COC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1

Procedure:
Title compound was prepared according to the method employed to prepare pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester in Example CL, substituting pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester with N-Boc-cis-4-cyano-L-proline methyl ester (643 mg, 67%)
Reaction SMILES: [H-].[K+].C([O:7][C:8](=[O:18])[CH2:9][CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=O)(C)(C)C>C1COCC1>[CH2:14]([CH:10]1[CH2:11][O:18][C:8](=[O:7])[CH2:9]1)[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) suspension of potassium hydride (1.08 g, 27 mmol) (previously washed 3 times with pentane) in THF (15 mL) was added, under an argon atmosphere, a solution of methyl methylthiomethyl sulfoxide (0.93 mL, 8.92 mmol, previously dried over molecular sieves for 3 hours) in THF (2 mL) over a period of 1 hour. After stirring for a further 30 minutes, a solution of 3 (2.16 g, 8.93 mmol) in THF (1 mL) was added, at 0° C., over a period of 1 hour. The reaction mixture was then allowed to warm up to room temperature and was stirred overnight. The mixture was quenched by addition of aqueous ammonium chloride (6 mL, 25%). After 10 minutes, the solid was filtered off and the filtrate concentrated. The residue was taken up in ether (20 mL), and 9N sulfuric acid (0.03 mL) was added. After stirring for 30 hours, saturated sodium hydrogen carbonate was added. The ether phase was separated and concentrated to 5 mL. Saturated sodium hydrogen sulphite (1.5 g) solution was added and the mixture stirred for 30 minutes. The phases were separated. The ethereal phase was stirred for further 30 minutes with a saturated sodium hydrogen sulphite (0.5 g) solution. The phases were separated, and the collected aqueous phases were treated with aqueous sodium hydroxide (5 mL, 20%) and extracted with ether. The ether phase was dried (MgSO4), and the solvent was evaporated under reduced pressure to give 4 as a yellow liquid (0.141 δH, 15%); SH (400 MHz; CDCl3): 2.25 (4H, m), 2.0 (4H, m), 1.7 (2H, m).
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].O[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([N:3]([S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][O:27][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)=[CH:24][N:25]=1)=[CH:17]2)[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCN(c1cccc2cc(-c3ncc(COc4ccc(C(=O)OC)cc4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
N-ethyl-N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (420 mg) and methyl 4-hydroxybenzoate (153 mg) were dissolved in tetrahydrofuran (10 mL), and tri-tert-butylphosphine (263 mg) and 1,1′-(azodicarbonyl)dipiperidine (328 mg) were added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtrated and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane (1:1) to give the title compound (200 mg, yield 36%) as pale-yellow crystals. melting point 191° C.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Br:12][C:13]1[C:22]([Cl:23])=[C:21]2[C:16]([CH2:17][CH2:18][NH:19][C:20]2=[O:24])=[C:15]([Cl:25])[CH:14]=1.[CH2:26]([O:33][C:34]1[C:39]([CH2:40]Cl)=[C:38]([CH3:42])[CH:37]=[C:36]([CH3:43])[N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.C(OC)(C)(C)C.C(O)(=O)C>[CH2:26]([O:33][C:34]1[C:39]([CH2:40][N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[C:22]([Cl:23])[C:13]([Br:12])=[CH:14][C:15]=3[Cl:25])[C:20]2=[O:24])=[C:38]([CH3:42])[CH:37]=[C:36]([CH3:43])[N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1NCCc2c(Cl)cc(Br)c(Cl)c21
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(Br)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reaction time: 0.08 h
Yield: 64.1 %

Procedure:
Potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 190 mL, 0.19 mol) was added dropwise to a cooled (0° C.) solution of 7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253f, 47 g, 0.16 mol) in anhydrous N,N-dimethylformamide (500 mL) under a nitrogen atmosphere. Stirring was continued at 0° C. for 5 minutes, then 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 40.2 g, 0.15 mol) was added in one portion. After stirring for 10 minutes at 0° C., the mixture was treated with concentrated acetic acid (2 mL) and poured into methyl tert-butyl ether (600 mL). The organic solution was washed with water (800 mL) and saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 to 20:1 petroleum ether/ethyl acetate), affording 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253g, 50 g, 64% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.45-7.43 (m, 2H), 7.32-7.29 (m, 3H), 6.76 (s, 1H), 5.38 (s, 2H), 4.71 (s, 2H), 3.24 (t, J=6 Hz, 2H), 2.72 (t, J=6 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H). MS: 521 [M+1].
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1>C(Cl)Cl>[O:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCN2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCN1CCOCC1)C1CCNCC1
Yield: 93.8 %

Procedure:
Trifluoroacetic acid (4.4 ml) is added to a solution of tert-butyl 4-(3-morpholinopropylcarbamoyl)piperidine-1-carboxylate (2.3 g) in CH2Cl2 (30 ml), and the mixture is stirred over night. The solvent is removed under reduced pressure to give crude N-(3-morpholinopropyl)piperidine-4-carboxamide (1.55 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([N:65]1[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[O:49])[CH2:67][CH2:66]1)=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])ccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 39.4 %

Procedure:
DIPEA (230 mg, 0.33 mL, 1.8 mmol) was added to a stirred solution of 2-bromo-5-nitro-benzoic acid (114 mg, 0.46 mmol) in DMF (2 mL). HOBT (93 mg, 0.69 mmol) and EDCI (220 mg, 1.15 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (150 mg, 0.46 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 100 mg (39.5% yield) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-nitro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.4%. 1H NMR (CDCl3): δ 8.4 (bs, 1H), 8.2 (m, 2H), 7.9 (d, 2H), 7.6 (m, 5H), 7.5 (m, 3H), 7.4 (m, 1H), 6.0 (d, 1H), 4.4 (m, 2H), 4.0 (m, 2H), 3.8 (m, 3H), 3.6 (m, 3H), 3.5-(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]=[N+:12]=[N-:13])[CH:5]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)#[N:16].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>ClCCl.C(OCC)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[N:13]=[N:12]2)[CH:5]=1
Reactant: COC(=O)c1cccc(CN=[N+]=[N-])c1
Reactant: C#Cc1ccc(C#N)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cccc(Cn2cc(-c3ccc(C#N)cc3)nn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Treat a solution of 3-azidomethyl-benzoic acid methyl ester (0.4 g, 2.1 mmol) and 4-cyanophenylacetylene (0.25 g, 2.00 mmol) in 1 mL of dichloromethane with 1 mL of 0.1 M aqueous copper (II) sulfate solution and sodium ascorbate (0.06 g, 0.30 mmol). Stir at room temperature overnight, dilute the reaction with CH2Cl2 and wash 3 times with H2O. Dry the organic layer over sodium sulfate, filter and concentrate to afford a solid. Suspend the residue in diethyl ether and filter to give 0.53 g, 84% yield of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid methyl ester.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([OH:28])=O.[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH2:40])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:29]([C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][C:26](=[O:28])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F
Reactant: Cc1cc(C(C)(C)C)cc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)cc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)n1
Yield: 21.9 %

Procedure:
Combine [2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid dihydrochloride (0.66 g, 1.57 mmol), 4-tert-butyl-6-methyl-pyridin-2-yl-amine (0.26 g, 1.57 mmol), HATU (0.72 g, 1.57 mmol), diisopropylethylamine (8.12 g, 11.2 mL, 6.28 mmol) in DMF (10 mL) and stir at ambient temperature for 3 hours. Pour the reaction contents onto a pre-washed (with methanol) Varian SCX column (25 g) and wash the column with portions (30 mL) of dichloromethane (2×) and methanol (3×). Elute the product with 2N methanolic ammonia (75 mL) and concentrate the solution to dryness. Chromatograph the crude product on silica using (0-5%) methanol in dichloromethane. Recrystallization from dichloromethane/ether/hexanes provides N-(4-tert-Butyl-6-methyl-pyridin-2-yl)-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide (0.17 g). MS(ES), m/z 494 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14]([CH2:16][O:17][C:18](=[O:30])[NH:19][C:20]4[C:28]5[C:27](=[O:29])[O:26][NH:25][C:24]=5[CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[CH:31]=2)=[CH:4][CH:3]=1>OS(O)(=O)=O.[Zn]>[NH2:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:19][C:18]([O:17][CH2:16][C:14]2[O:15][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:31][C:12]=3[CH:13]=2)=[O:30])[C:28]=1[C:27]([OH:29])=[O:26]
Reactant: O=C(Nc1cccc2[nH]oc(=O)c12)OCc1cc2cc(-c3ccc(F)cc3)ccc2o1
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: Nc1cccc(NC(=O)OCc2cc3cc(-c4ccc(F)cc4)ccc3o2)c1C(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
(3-Oxo-1,3-dihydrobenzo[c]isoxazol-4-yl)carbamic acid 5-(4-fluorophenyl)benzofuran-2-ylmethyl ester (70 mg, 0.17 mmol) was dissolved in 2M H2SO4 at room temperature. Zinc dust was added and the mixture was stirred at 80° C. for 4 hours. Upon cooling, the mixture was filtered. The filtrate was neutralized with diluted NaOH and extracted with CH2Cl2. The organic extracts were dried over anhydrous Na2SO4 and concentrated en vacuo to give 23 mg (32.86%) of 2-amino-6-[5-(4-fluorophenyl)benzofuran-2-ylmethoxycarbonylamino]benzoic acid 701, as a tan powder: mp: 176.4-178.5° C. Anal Calcd for C23H17FN2O5: C, 65.71; H, 4.08; N, 6.66. Found: C, 66.71; H, 4.56; N, 5.95.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[CH:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH:31]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]([N:3]2[CH2:4][CH2:5][C:6]3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]=3[CH2:2]2)=[O:29])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)C(c1ccccc1)C1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Step a): To a stirred solution of Intermediate 1 (25 mg, 0.085 mmol), cyclohexyl-phenylacetic acid (27.7 mg, 0.127 mmol) and DIEA (73 μl, 0.424 mmol) in dichloromethane (1 ml) is added POCl3 (9 μl, 0.093 mmol). The resulting yellow reaction mixture is stirred at rt overnight, then saturated aqueous NaHCO3 solution (2 ml) is added. The organic layer is separated and washed with water (2 ml). Evaporation of the solvent gave a crude that is purified by silica gel column chromatography (hexane/EtOAc 3:1) affording ethyl [2-(2-cyclohexyl-2-phenyl-acetyl)-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-acetate as a white solid (29 mg) in 74% yield: tR (LC-2) 2.74 min; ESI-MS (positive ion): m/z 459.25 [M+H]+ (calcd 458.59 for C29H34N2O3).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:15][C:16](=[O:26])[CH:17]([C:23](=O)[CH3:24])[C:18](=O)[CH2:19][O:20][CH3:21])[CH3:14]>>[CH2:13]([O:15][C:16]([C:17]1[C:18]([CH2:19][O:20][CH3:21])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[C:23]=1[CH3:24])=[O:26])[CH3:14]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C(C)=O)C(=O)COC
Product: CCOC(=O)c1c(COC)nn(-c2cccc(C(F)(F)F)c2)c1C
Yield: 25 %

Procedure:
In analogy to the procedure described in Example 38A], 3-(trifluoromethyl)phenylhydrazine and rac-2-acetyl-4-methoxy-3-oxo-butyric acid ethyl ester gave after purification by flash column chromatography (CH2Cl2 to 5% Et2O/CH2Cl2) 5-methoxymethyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester and in 25% yield as light brown solid. MS: 343.0 (MH+) and 3-methoxymethyl-5-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester and in 36% yield as orange oil. MS: 343.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])/[CH:4]=[CH:5]\[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]
Reactant: COC(=O)/C=C\C(C)(C)c1cccc(OC)c1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCC(C)(C)c1cccc(OC)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
23.30 g (84.33 mmol) of E/Z-4-(2-fluoro-3-methoxyphenyl)-4-methylpent-2-enoic acid methyl ester is mixed in 310 ml of ethanol with 1.2 g of palladium on carbon, and it is stirred under a hydrogen atmosphere overnight at room temperature. The catalyst is removed by filtration via a glass fiber filter, and the residue that remains after concentration by evaporation is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 19.58 g (83.4%) of the desired compound is isolated.