Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[N:17]([CH2:28][C@H:29]([NH2:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48](O)=[O:49])=[CH:45][CH:46]=2)[NH:41][CH:40]=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[N:17]([CH2:28][C@H:29]([NH:36][C:48]([C:44]3[CH:43]=[C:42]4[C:47]([C:39]([Cl:38])=[CH:40][NH:41]4)=[CH:46][CH:45]=3)=[O:49])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1CCC(CN(C[C@H](N)c2ccccc2)C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(CN(C[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
Using coupling method A, crude N-[(R)-2-amino-2-phenyl-ethyl]-N-(1-isopropylpiperidin-4-ylmethyl)carbamic acid 9H-fluoren-9-ylmethyl ester (980 mg, 2.0 mmol) and 3-chloro-indole-6-carboxylic acid (462 mg, 2.4 mmol) afforded, after purification (SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 300 mg (23%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[C:12]([O-])([O-])=O.[K+].[K+].[OH-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(3-chloro-4-hydroxylphenyl)ethanone (1.7 g, 10 mmol) in DMF was added K2CO3 (1.52 g, 11 mmol), 2 N NaOH solution (5 ml), and Mel (0.68 ml). The reaction mixture was stirred at room temperature for 2 hours. Another 1.24 ml of Mel was added, and the reaction mixture was stirred for an additional 30 minutes. Water (50 ml) was added, and the product was extracted with 200 ml of EtOAc and 100 ml of benzene. The organic layer was washed with brine (50 ml), and dried with MgSO4, and the solvent was removed in vacuo to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1
Reactant: CN(C)CCOCCO
Reactant: N#Cc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOCCOc1cc(C#N)ccn1
Temperature: 50 °C
Yield: 105.8 %

Procedure:
To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:57][CH2:56][N:48]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=3[CH:55]=[C:47]2[C:46]1=[O:58])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 27 %

Procedure:
Following Example 136d, 5-bromo-1-methyl-3-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyridin-2(1H)-one 170a and 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a were reacted to give 171a in 27% yield. LCMS: (M+H)+ 651
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([OH:51])=O)[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1N=C(C(C)C)O[CH:38]=1.[CH3:52][OH:53]>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:51])[CH:46]([CH3:47])[CH3:48])=[O:43])[CH2:33][C:34]1[CH2:38][N:1]([CH:2]([CH3:24])[CH3:3])[O:53][CH:52]=1
Reactant: CO
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)N(C)CC1=CON(C(C)C)C1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1-4% methanol in dichloromethane, 225 mg (80%) of the desired compound. 1H NMR (DMSO-d6) δ0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.35-1.54 (m, 2H), 1.80-1.95 (m, 1H), 2.55-2.73 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.53-3.63 (m, 1H), 3.73-3.86 (m, 1H), 3.92 (t, J=8.4 Hz, 1H), 4.08-4.34 (m, 3H), 4.65 (d, J=6 Hz, 1H), 5.04 (s, 2H) 5.91 (d, J=9 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.06-7.27 (m, 10H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.52 (d, J=2.4 Hz, 1H). Mass spectrum: (M+H)+ =689; (M+NH4)+ =706. Anal. Calcd for C37H48N6O7 : C, 64.52; H, 7.02; N, 12.20. Found: C, 64.52; H, 7.14; N, 12.06.
Reaction SMILES: Cl[Si:2]([CH3:17])([CH3:16])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:5]=[C:4]1[CH3:15].CCN(CC)CC.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCCCCC>[CH:25]1([NH:31][Si:2]([CH3:17])([CH3:16])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[CH:5]=[C:4]2[CH3:15])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) silane (5.67 g, 0.0216 moles) was stirred in hexane (50 mL) as NEt3 (2.18 g, 0.0216 moles) and cyclohexylamine (2.13 g, 0.0216 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (6.62 g, 94.3 percent).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18](O)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+].[N:48]1C=CC=CC=1>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:21])[C:18]([NH2:48])=[O:19])(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1
Reactant: c1ccncc1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(N)=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100160.7 %

Procedure:
To a suspension of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoic acid (Step H, 200 mg, 0.51 mmol) and di-tert-butyl dicarbonate (145 mg, 0.66 mmol) in acetonitrile (3 mL) were added ammonium bicarbonate (48 mg, 0.61 mmol) and pyridine (48 mg, 0.61 mmol) at room temperature. The mixture was stirred at room temperature for 20 h and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and dichloromethane (30 mL). The aqueous layer was separated and extracted with dichloromethane (30 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:3 as eluent) to afford the title compound (200 g, quant.) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14]CC)=[O:13])=[N:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[OH-].[K+].O.Cl>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([OH:14])=[O:13])=[N:9]2)=[CH:4][C:3]=1[C:18]([F:20])([F:19])[F:21]
Reactant: CCOC(=O)c1nc2cc(Br)c(C(F)(F)F)cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc2cc(Br)c(C(F)(F)F)cc2[nH]c1=O
Yield: 82.1 %

Procedure:
To a solution of ethyl 7-bromo-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate (120 mg, 329 μmol) in ethanol (4 ml) were added 1N aqueous solution of potassium hydroxide (1.32 ml, 1.32 mmol) and water (2 ml), and the mixture was refluxed for 30 minutes. After cooling with ice, the pH value was brought to 4 with 1.2N hydrochloric acid. The precipitate was collected by filtration, washed with water and then air-dried to obtain 91.0 mg of the title compound as yellowish brown powder. Yield 82%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](O)=[O:5].CSC.B.CO>C1COCC1.COB(OC)OC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(F)cccc1I
Agent: B
Agent: COB(OC)OC
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1c(F)cccc1I
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-fluoro-6-iodobenzoic acid (10 mmol) in THF (6.5 mL) and trimethylborate (3.25 mL) was added borane dimethylsulfide (12 mmol) slowly, maintaining the internal temperature at 20-25° C. Stirring was continued for an additional 16 h at room temperature and then methanol (1.44 mL) was added cautiously. The resulted solution was evaporated in vacuo to offer 2.5 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][C:49]=1[F:50])[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[C:45]#[N:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([C:45]#[N:46])=[C:32]([O:31][C:30]3[CH:47]=[CH:48][C:49]([F:50])=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=4[Cl:1])[CH:29]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)c(C#N)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (156 mg, 0.697 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (75 μL, 0.875 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (200 mg, 0.584 mmol) was added to the solution, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was successively purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→400/0) and silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (164 mg, 51%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-phenylethanone and isolated as light-green solid (9.5 mg, 55%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)[N:11]=1>[Mo](=O)(=O)=O.C1CCCCC1>[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:5][CH:1]3[CH2:4][CH2:19][CH2:18][CH2:17][CH2:3]3)[C:23]([CH3:30])([CH3:29])[CH2:22]2)[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([O:5][CH:1]3[CH2:4][CH2:22][CH2:21][CH2:20][CH2:3]3)[C:38]([CH3:45])([CH3:44])[CH2:37]2)[N:11]=1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Yield: 74 %

Procedure:
A mixture of 57.7 g (0.448 mol) of 70% aqueous tert-butyl hydroperoxide, 250 ml of cyclohexane and 100 ml of saturated sodium chloride solution is agitated vigorously and the organic layer is then separated and dried over anhydrous magnesium sulfate. The drying agent is removed by filtration. The filtrate, 30.0 g (0.056 mol) of 2-chloro-4,6-bis[N-(2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-s-triazine and 1.0 g of molybdenum trioxide are placed in a pressure bottle and heated at 130°-140° C. The reaction mixture quickly turns red and heating is continued till the red color is discharged. The reaction mixture is allowed to cool and solids are removed by filtration. The filtrate is concentrated under reduced pressure to give an oil which is purified by flash chromatography on silica gel to afford 30.3 g. (74% yield) of the title compound as a white glass.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[C:8]=1[CH2:17][C:18]([OH:20])=[O:19].[CH3:21]O>>[CH3:21][O:19][C:18](=[O:20])[CH2:17][C:8]1[C:7]([Cl:6])=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]=1[Cl:16]
Reactant: CO
Reactant: O=C(O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Concentrated sulfuric acid (2 mL, 37.33 mmol, 0.73 equiv) is added dropwise to a solution of (2,6-dichloro-4-nitro-phenyl)-acetic acid (EP 87218) (14.2 g, 51.1 mmol) in MeOH (500 mL). The resulting brown solution is stirred for 6 h at reflux. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc (400 mL) and a bit of water, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (Hexane/EtOAc, 2:1→1:1) provides the title compound as a yellow solid: ES-MS: 262.1/264.1 [M+H]+; tR=3.78 min (System 2); Rf=0.40 (Hexane/EtOAc, 2:1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=O)[NH:18][CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].CC(O)=O.C1(C)C(C)=CC=CC=1>[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)C1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 165 °C

Procedure:
2-(2-Oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (22.83 g, 60 mmol), NH4OAc (ammonium acetate) (63.5 g, 824 mmol), AcOH (acetic acid) (30 mL), and xylene (350 mL) were mixed at room temperature, and with stirring the reaction mixture was warmed in an oil bath at 165° C. for about 6 hours. The reaction mixture was then cooled to room temperature and poured into brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 31.24 g of off white powder. This sample was triturated in ethyl ether (100 mL), filtered, and rinsed liberally with ethyl ether to yield 15.12 g (70% over two steps) of the desired product 2-(4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester as a white solid. HPLC analysis showed the compound to be 100% pure at 254 nm and 98.1% pure at 214 nm.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[C:27](O)(=[O:29])[CH3:28]>S(=O)(=O)(O)O.ClCCl>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:21][CH2:22][CH:23]([O:26][C:27](=[O:29])[CH3:28])[CH2:24][CH2:25]1
Reactant: CC1CCc2c(N3CCC(O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Reaction time: 5 h
Yield: 31.2 %

Procedure:
In a 25 ml flask were placed 0.43 g of 9-fluoro-8-(4-hydroxy-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 0.2 g of acetic acid and 5 ml of dichloromethane and the mixture was refluxed after adding 5 drops of concentrated sulfuric acid. During the reaction oily substance appeared on the bottom of the flask. After 5 hours the reaction was stopped, dichloromethane was removed and water was added to the product followed by filtration. Crystals thus obtained were washed with methanol to give 150 mg of 9-fluoro-8-(4-acetoxy-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 250°-253° C., pale yellow rhombic crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[C:8]([S:11](Cl)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[C:8]([S:11]([NH:22][C:20]3[N:19]([C:23]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:24]=4[CH:25]=[CH:26][CH:27]=[N:28]5)[N:18]=[C:17]([CH3:16])[CH:21]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc3c(c2)CC(C)(C)O3)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 39 %

Procedure:
A stirring mixture of 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonyl chloride (0.10 g, 0.41 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.11 g, 0.49 mmol) in pyridine (0.41 mL) was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.070 g, 0.16 mmol, 40%). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J=3.2 Hz, 1H), 7.19 (d, J=6.8 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.24 (s, 1H), 2.89 (s, 2H), 2.34 (s, 3H), 1.51 (s, 6H); MS: (ES) m/z calculated for C23H23N4O3S [M+H]+ 435.2. found 435.3.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Product: CC(=O)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-methyl-3-nitroaniline (3.60 g, 23.7 mmol) in acetic anhydride (28 mL) was allowed to stir at room temperature. After 16 h, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (25 mL), washed with saturated sodium bicarbonate (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 4.20 g (Y: 99%) of the title compound; 1H-NMR (CDCl3): δ 8.10 (d, J=1.7 Hz, 1H), 7.75 (dd, J=8.5, 1.7 Hz, 1H), 7.38 (bs, 1H), 7.29 (d, J=8.5 Hz, 1H), 2.56 (s, 3H), 2.21 (s, 3H); MS (DCI) m/e: 195 (MH+).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:11])[CH2:8][CH2:9][OH:10].[CH3:18]I.[Mg].S(=O)(=O)(O)O>O.CCOCC.C1COCC1>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:11])([CH3:18])[CH2:8][CH2:9][OH:10]
Reactant: CI
Reactant: O=C(CCO)c1ccccc1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.26 of 1-p-biphenylyl-3-hydroxypropan-1-one (obtainable by acylating biphenyl with 3-methoxypropionyl chloride to give 1-p-biphenylyl-3-methoxypropan-1-one and subsequent ether splitting) in 20 ml. of THF is added dropwise at 20°, with stirring, to a Grignard solution prepared from 3 g. of methyl iodide and 0.5 g. of magnesium in 100 ml. of ether. The mixture is stirred for a further 4 hours, the resulting alcoholate is decomposed by means of water and dilute sulfuric acid, and standard working up gives 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.