Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[C:24]([B:25]([C:37]2[C:42]([F:43])=[C:41]([F:44])[C:40]([F:45])=[C:39]([F:46])[C:38]=2[F:47])[C:26]2[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=2[F:36])=[C:23]([F:48])[C:22]([F:49])=[C:21]([F:50])[C:20]=1[F:51].[CH2:52]([N:70]([CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH3:71])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]>C1(C)C=CC=CC=1>[F:43][C:42]1[C:37]([B:25]([C:24]2[C:19]([F:18])=[C:20]([F:51])[C:21]([F:50])=[C:22]([F:49])[C:23]=2[F:48])[C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[C:38]([F:47])[C:39]([F:46])=[C:40]([F:45])[C:41]=1[F:44].[F:43][C:42]1[C:37]([B:25]([C:24]2[C:19]([F:18])=[C:20]([F:51])[C:21]([F:50])=[C:22]([F:49])[C:23]=2[F:48])[C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[C:38]([F:47])[C:39]([F:46])=[C:40]([F:45])[C:41]=1[F:44].[CH2:72]([NH+:70]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH3:71])[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89].[C:1]1([C:7]2[N:8]=[CH:9][N-:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCCCCCCCCCCCCCCCCC
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[NH+](C)CCCCCCCCCCCCCCCCCC
Product: c1ccc(-c2nc[n-]c2-c2ccccc2)cc1

Procedure:
4,5-diphenylimidazole (0.4302 g, 1.953 mmol), tris(pentafluorophenyl)borane (2.0000 g, 3.9063 mmol) and dioctadecylmethylamine (1.0469 g, 1.9531 mmol) were placed in a 50 mL flask, taken up in 21 mL of toluene and refluxed under argon for 15 hours. The volatiles were then stripped under vacuum. Yield, 3.217 g, 92.52 percent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:24])=[CH:21][N:20]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(-c2ccccc2F)nc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccccc2F)nc1

Procedure:
Using the procedure outlined in Example 104, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.19 mmol) and 6-(2-fluorophenyl)-nicotinic acid (D74) (50 mg, 0.23 mmol) as a yellow solid. MS(ES): MH+ 344, M-H+ 342
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Cl[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:8])[C:3]2([CH:7]=[CH:6][CH:5]=[CH:4]2)[CH:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCl
Reactant: CC(C)=C1C=CC=C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1C(C)(C)C12C=CC=C2

Procedure:
A well stirred, 10°-15° C. nitrogen blanketed mixture of 10.6 g. of 6,6-dimethylfulvene, prepared above, and 12.2 g. of ethyl chloroacetate was treated dropwise over 1.5 hr. with a solution of 11.7 g. of potassium t-butoxide in 75 ml. of dry t-butyl alcohol. The reaction was stirred an additional 1.5 hr. at 10° C. and most of the alcohol was then removed at reduced pressure. Ether extraction of an aqueous solution of the residual semisolid afforded 15.2 g. of yellow oil. Subsequent distillation afforded 2.5 g. (13%) of yellow ester, b.p. 75°-80° C. (0.25 mm.). Gas chromatographically purified ester exhibited the following spectral properties: ir (film) 5.77, 8.33, 8.69, 9.24, 12.0, 12.7 μ; nmr (CCl4) τ 3.38, 3.69, 3.99 (3m, 4, --CH=CH--CH=CH--), 5.99 (q, 2, J = 7 Hz, OCH2CH3), 7.41 (s, 1, CHCO2Et), 8.47, 8.60 (6, CH3 's), 8.80 (t, 3, J = 7 Hz, OCH2CH3).
Reaction SMILES: [CH2:1](O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=C[C:10]([C:16]#[N:17])=[CH:9]2.[CH3:18][NH:19][NH2:20]>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:18]1[N:19]([CH3:1])[N:20]=[C:16]([NH2:17])[C:10]1=[CH:9]2
Reactant: CNN
Reactant: CCO
Reactant: COc1ccc2ncc(C#N)cc2c1
Solvent: CO
Product: COc1ccc2nc3c(cc2c1)c(N)nn3C
Yield: 75 %

Procedure:
6-Methoxy-1-methyl-1H-pyrazolo[3,4-b]quinolin-3-amine, orange crystals, m.p. 185°-186° C. (from ethanol) was prepared in 75% yield from 6-methoxy-3-quinolinecarbonitrile (Example 1c) and methylhydrazine in methanol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])[N:7]=1.[NH3:36].CO>>[NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:18][CH2:17][OH:16])[C:15]([NH2:36])=[O:19])[N:7]=1
Reactant: N
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC3CCOC3=O)N2)n1
Solvent: CO
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC(CCO)C(N)=O)N2)n1
Reaction time: 8 h
Yield: 89 %

Procedure:
3-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)one (14.3 mg, 0.03 mmol) was dissolved in 7N NH3-MeOH solution and stirred overnight in a sealed tube. The solvent was removed and residue dried to afford the title compound 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxybutanamide (13.2 mg, 89%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 1.83-2.16 (m, 2H) 2.58 (d, J=6.06 Hz, 3H) 2.85-3.03 (m, 1H) 3.07-3.25 (m, 1H) 3.70 (q, J=7.24 Hz, 2H) 3.90 (d, J=11.37 Hz, 3H) 4.54 (td, J=7.83, 5.05 Hz, 1H) 4.97-5.17 (m, 1H) 6.69-6.85 (m, 1H) 7.11 (dd, J=7.71, 2.40 Hz, 1H) 7.14-7.26 (m, 2H) 7.57-7.72 (m, 1H) 7.76 (dd, J=15.03, 6.69 Hz, 1H). MS (ES) [M+H] calculated for C24H27FN7O4, 496.50. found 496.40.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1.Br[CH2:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([O:20][CH2:21][CH3:22])=[CH:15][C:14]=1[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C.O>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([F:23])[C:13]([CH2:12][N:1]2[C:5]3[CH2:6][CH2:7][CH2:8][C:4]=3[C:3]([C:9]#[N:10])=[N:2]2)=[C:18]([F:19])[CH:17]=1)[CH3:22]
Reactant: N#Cc1n[nH]c2c1CCC2
Reactant: CCOc1cc(F)c(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(F)c(Cn2nc(C#N)c3c2CCC3)c(F)c1
Temperature: 25 °C

Procedure:
3.40 g of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile (CAS-RN 851776-29-9) (25.5 mmol, 1.00 eq) were dissolved in 35 mL dry DMF under nitrogen atmosphere. 7.05 g 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (28.1 mmol, 1.10 eq.) and 9.98 g cesiumcarbonate (30.1 mmol, 1.20 eq.) were added and stirred over night at rt. DCM and water were added, the aqueous phase was washed twice with DCM, the organic phase was washed with brine and was dried with magnesiumsulfate, was concentrated in vacuo and purified by flash chromatography (hexane/tert-butyl methyl ether-gradient with hexane 100-70%) to provide 1.07 g (3.45 mmol, 14%) of the analytically pure target compound.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][CH:7]([CH3:14])[CH2:6]1)=[O:3].[N:15]1C=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N)CCC.Cl>C1(C)C=CC=CC=1.O>[CH:11]([C@@H:10]1[CH2:9][CH2:8][C@@H:7]([CH3:14])[CH2:6][C@H:5]1[O:4][C:2](=[O:3])[NH:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:13])[CH3:12]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCN
Solvent: O
Product: CCCCNC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
66.6 g of menthyl chloroformate (70% in toluene) were added to a mixture of 16.6 g of pyridine and 21.9 g n-butylamine in 100 mL toluene at 0° C. over a period of 50 minutes. After stirring for 12 hours at room temperature, 100 mL of 2M HCl and subsequently 50 mL water were added, the phases separated and the water phase discarded. After washing with saturated NaHCO3-solution and water the organic phase was dried and evaporated to yield 55.1 g of crude product which was recrystallized from 30 g n-heptane to give 34.5 g of the analytically pure product as white crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16](B5OC(C)(C)C(C)(C)O5)=[CH:17][CH:18]=4)[CH2:13][CH2:12][C:11]=3[CH:10]=2)O1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:46][CH:47]=[C:48](Br)[N:49]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].[C:51]([O-:54])(O)=[O:52].[Na+]>COCCOC.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>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:49][C:48]([C:9]2[CH:10]=[CH:11][C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:48]5[NH:49][C:45]([CH:41]6[CH2:42][CH2:43][CH2:44][N:40]6[C:51]([O:54][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:52])=[N:46][CH:47]=5)=[CH:17][CH:18]=4)[CH2:13][CH2:12][C:21]=3[CH:22]=2)=[CH:47][N:46]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1(C)OB(c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)c[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1
Temperature: 80 °C
Yield: 23.9 %

Procedure:
Pd(PPh3)4 (31 mg, 0.03 mmol) was added to a mixture 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane (115 mg, 0.27 mmol), 2-(4-bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (173 mg, 0.55 mmol), NaHCO3 (159 mg, 1.9 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 6 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (42 mg, 24%). m/z 651.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[C:9]([CH2:18][CH:19]=O)=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[C:13]#[N:14].[C:21]([BH3-])#[N:22].[Na+]>CO>[N:1]1([CH2:19][CH2:18][C:9]2[C:8]([F:7])=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:6][CH2:5][N:4]([CH2:19][CH2:18][C:9]2[C:8]([F:7])=[CH:15][C:12]([C:21]#[N:22])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1cc(CC=O)c(F)cc1C#N
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3cc(OC)c(C#N)cc3F)CC2)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of piperazine (13 mg, 0.15 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.30 mmol) in methanol (3.0 mL) at 0° C. was added sodium cyanoborohydride (24 mg, 0.38 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 4,4′-(piperazine-1,4-diyldiethane-2,1-diyl)bis(5-fluoro-2-methoxybenzonitrile). LC-MS (IE, m/z): 441.4 [M+1]+. (0.34 μM)
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:3]([CH2:2][N:22]3[CH2:23][C@@H:18]4[CH2:24][C@H:21]3[CH2:20][N:19]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:4][N:5]=[N:6]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (10 mL) was added 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (377 mg, 1.90 mmol, commercially available, for example from Sigma Aldrich Corporation) and triethylamine (0.796 mL, 5.71 mmol). The mixture was then heated to 120° C. for 20 min in a microwave reactor.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(OCC)(=O)C>[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
To a solution of 4-fluoroaniline (0.2 g) in dichlbromethane (10 ml) were added in turn pyridine (0.19 ml) and diphenylcarbamoyl chloride (0.417 g) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 10 hours, and to the mixture was added N,N-dimethylaminopyridine (0.22 g), and the mixture was allowed to stir for another 1 hour. The reaction mixture was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give N,N-diphenyl-N′-4-fluorophenylurea (0.384 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1C=CC(F)=[C:6]([N+:11]([O-])=O)[CH:5]=1)C.C([N:18](CC)CC)C>>[N:3]1([CH2:4][CH2:5][CH2:6][NH2:11])[CH:14]=[CH:15][N:18]=[CH:1]1
Reactant: CCN(CC)CC
Reactant: CCN(CC)c1ccc(F)c([N+](=O)[O-])c1
Product: NCCCn1ccnc1

Procedure:
A mixture of 8.8 g (0.041 mol) of diethyl(4-fluoro-3-nitrophenyl)amine obtained in the preceding stage, 17.0 g (0.136 mol) of 3-(imidazol-1-yl)propylamine (RN 5036-48-6) and 6.7 ml of triethylamine was heated at reflux with stirring for 2 hours.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])=[CH:22][C:21]=2[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[C:4]([C:12]([NH2:14])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=1.[N:47]([O-])=O.[Na+]>O1CCCC1.CO.O>[OH:1][C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])=[CH:22][C:21]=2[C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[C:4]([C:12]([NH2:14])=[O:13])[C:5]2[C:10]([C:11]=1[N:47]=[N:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCC(C)(C)c1ccc(OCCCCc2c(O)cc3ccccc3c2C(N)=O)c(C(C)(C)CC)c1
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)c1ccc(OCCCCc2c(O)c(N=Nc3ccc(OC)cc3)c3ccccc3c2C(N)=O)c(C(C)(C)CC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 20 g (0.042 mole) of 3-hydroxy-2-[4-(2,4-di-t-pentylphenoxy)-n-butyl]naphthamide in 200 ml tetrahydrofuran was added a solution of 8 g sodium hydroxide in 200 ml methanol. The mixture was cooled to 0° C. and treated with a diazonium solution prepared from a solution of 5.2 g (0.042 mole) p-anisidine in 40 ml water containing 10 ml conc. hydrochloric acid and a solution of 2.9 g (0.042 mole) sodium nitrite in 30 ml water. Then 400 ml water was added, and the mixture was stirred at 0° C. for 2 hrs. and at room temperature for one hour. The oil which separated after acidification with 30 ml acetic acid was extracted with ether. The solution was dried and concentrated to 21 g of a red oil which was used without further purification in the next step.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].O.[OH:10][C:11]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:12]=1[CH:13]=O>CO>[OH:10][C:11]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:12]=1[CH:13]=[N:7][OH:8]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(O)c(C=NO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 68.0 g (0.83 mol) of sodium acetate and 68.0 g (0.98 mol) of hydroxylamine hydrochloride in. 300 ml of water is added dropwise to a solution of 80.5 g (0.45 mol) of 2-hydroxy-5-methoxycarbonylbenzaldehyde in 300 ml of methanol and the mixture is stirred at 25° C. for 2 hours. The product which has precipitated is filtered off with suction, washed with water and dried in vacuo over phosphorus pentoxide to give 70.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>ClCCl>[C:45]([NH:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 70 mg (0.69 mmol) acetic anhydride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 100 mg (92%) of the title compound as white solid. MS m/e (%): 537 (M+, 68), 282 (100).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.C(Cl)[Cl:34]>>[ClH:34].[NH2:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:27]([N:28]([CH3:30])[CH3:29])=[O:31]
Reactant: ClCCl
Reactant: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Product: CN(C)C(=O)C(N)Cc1ccc(-c2ccc(CCC(N)=O)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The amide compound 51 (1.0 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 52 as a white amorphous solid that was extremely hygroscopic (0.68 g, 79.5%). 1H NMR (DMSO-d6): 7.62 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 6.78 (br, 1H), 4.58 (m, 1H), 2.95 (m, 2H), 2.81-2.85 (m, 5H), 2.72 (s, 3H), 2.38 (t, J=8.0 Hz, 2H). LCMS (m/e): Obsd. [MH]+ 340, Calcd. 339.4.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])O)=[CH:4][CH:3]=1.[OH-:13].[Na+].Cl.[Cl-].[Na+]>C(OCC)(=O)C.CCCCCC.O>[CH2:9]([CH:7]1[C:2]([OH:6])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(O)c1ccc(C)o1
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC1C(=O)C=CC1(C)O
Temperature: 40 °C

Procedure:
In a reaction vessel, water (40 ml) and 5-methyl-2-furyl-n-butylcarbinol (0.5 g) were charged, and the pH value was regulated to 5 with an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. The temperature was elevated up to 100° C. to reflux, and the mixture was stirred under reflux for 30 hours while maintaining a pH value of 5 to 5.5 by the addition of an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. After cooling to 40° C., the reaction mixture was neutralized with an aqueous 1 N NaOH solution, and sodium chloride (12 g) was added thereto. The mixture was extracted with toluene (40 ml) five times. From the extract, toluene was removed by distillation at 60° C. under reduced pressure to give an oily substance (0.48 g), which was subjected to a thin layer chromatography on silica gel with a mixture of ethyl acetate-n-hexane (1:2 by volume) as the developing solvent. The objective part of the silica gel layer was collected by scraping and eluted with ethyl acetate. The silica gel was eliminated by filtration, and the filtrate was concentrated to obtain 2-n-butyl-3-hydroxy-3-methyl-4-cyclopentenone (3.5 g). Yield, 70%. NMR spectrum (CCl4, internal standard TMS, δ ppm, 60 MHz): 7.25 (d, 1H, 4-H); 5.85 (d, 1H, 5-H); 3.63 (broad s, 1H, 3--OH); 2.20 (m, 1H, 2-H); 1.25 (s, 3H, 3-CH3).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[C:5]([Br:9])=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.O.N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:6]=[C:7]([Cl:8])[CH:2]=[CH:3][C:4]=1[C@@H:10]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11]1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)c(Br)cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C[C@H](c2ccc(Cl)cc2Br)CN1
Temperature: 55 °C
Yield: 55 %

Procedure:
(4R)-4-(3-Amino-6-bromo-4-chlorophenyl)pyrrolidin-2-one was dissolved in 32 mL of sulfuric acid aqueous solution (1M) and the heated at 55° C. for 20 min. The reaction mixture was cooled to 0° C. and 160 mL ethyl acetate/water added. To this mixture, 1.5 equivalent of NaNO2 was added portion wise. The reaction was monitored by LCMS. After the starting material was consumed, the mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with water and brine, and dried over sodium sulfate. The solvent was removed to provide the title compound as an off-white solid (4.7 g, 55% yield). 1H-NMR (400 MHz, CD3OD): δ 2.38-2.44 (dd, J=17.2, 4.0 Hz, 1H), 2.73-2.80 (dd, J=17.2, 9.2 Hz, 1H), 3.33-3.37 (dd, J=10.0, 6 Hz, 5.6 Hz, 1H), 3.78-3.83 (dd, J=10.0, 8.0 Hz, 1H), 4.06-4.13 (m, 1H), 7.64-7.65 (m, 1H), 7.38 (m, 2H); MS (ESI) m/z 275.89 (M+H)+.