Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:10]1[CH:9]=[N:8][C:3]2[NH:4][C:5](=[O:7])[CH2:6][O:1][C:2]=2[CH:11]=1
Reactant: O=C1COc2cccnc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.6 g 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one dissolved in 85 ml of DMF under nitrogen is added 7.96 g NBS in 50 ml of DMF. This is allowed to stir at room temperature overnight. To this is added 35 ml of water and chilled. The solid material which separates is filtered and washed with 3×100 ml H2O. This is then dried in a vac oven at 70° C. and then used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[C:4]([F:12])[C:3]=1[F:13].CCN(C(C)C)C(C)C.[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=2)[CH2:25][CH2:24]1>C1COCC1>[CH:23]1([C:26]2[NH:30][N:29]=[C:28]([NH:31][C:5]3[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[C:3]([F:13])[C:4]=3[F:12])[CH:27]=2)[CH2:25][CH2:24]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
To 1,2,3,4-tetrafluoro-5-nitrobenzene (3.0 g, 15.4 mmol) and DIEA (3.7 ml, 21.0 mmol) in dry THF (20 ml) was added 5-cyclopropyl-1H-pyrazol-3-amine (1.7 g, 14.0 mmol) in THF (5 ml) drop wise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 16 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=4:1). This was recrystallized from Et2O (20 ml) and hexanes (˜150 ml) to give the title compound as red crystals (0.650 g, 16%). 1H NMR (400 MHz) 11.84 (s, 1H), 8.67 (s, 1H), 8.06 (m, 1H), 5.57 (s, 1H), 1.82 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 298; Found: [M+H]+ 299.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(tetrahydro-furan-3-ylmethoxy)-nicotinic acid (example CK) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (+) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 483.1038 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:6][CH:5]=1.CO>[Pd].C1COCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:6][CH:5]=1
Reactant: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1N
Reaction time: 8 h

Procedure:
A mixture of N-(4-trifluoromethoxyphenyl)-2-(morpholinyl)-4-(2-hydroxy-2-methyl-propylamino)-5-nitro-benzoic acid amide (100 mg, 0.20 mmol), Pd/C (50 mg), MeOH (3.5 mL) and THF (10 mL) is stirred under 4 bar H2-atmosphere overnight. The mixture is filtered, and the filtrate is concentrated. Yield: 94 mg. HPLC Rt=1.36 min (method H). MS m/z: 468 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][OH:32])=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1>C1COCC1.CC(N(C)C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:39]4[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Br)cn3)nn2C)nc1
Reaction time: 0.08 h
Yield: 24.9 %

Procedure:
To a solution of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 43) (18 mg) in anhydrous THF (0.5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 3.3 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (11.3 mg) in dimethylacetamide (0.1 ml). After stirring for 90 min, the reaction mixture was partitioned between ethyl acetate (3 ml) and saturated ammonium chloride solution (5 ml). The ethyl acetate layer was dried (MgSO4) and blown down under nitrogen to afford a gummy residue. Purification of the residue by column chromatography on silica gel (5 g), eluting in an isocratic fashion with ethyl acetate:hexane (7:4) afforded the title compound as a white solid (6 mg) after freeze drying from t-butanol.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.O[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:14]([C:9]2[C:10](=[O:11])[C:4]3[C:5]([C:7](=[O:12])[CH:8]=2)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(O)CCCCC(=O)O)cc1
Reactant: Oc1ccc(O)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=CC(=O)c3ccccc3C2=O)cc1
Reaction time: 8 h
Yield: 21.2 %

Procedure:
1,4-Naphthohydroquinone (8 g) was reacted with 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (11.9 g) in the presence of p-toluenesulfonic acid (3.8 g) in toluene (200 ml) at 80° C. for 15 hours. Then, the reaction mixture was extracted with ethyl acetate and concentrated. The residue was submitted to an overnight reaction with an aqueous solution (120 ml) of iron (III) chloride hexahydrate (31 g) (0.1 ml) in acetic acid (70 ml) at room temperature. This reaction mixture was extracted with ethyl acetate and concentrated and the residue was purified by silica gel column chromatography. Recrystallization from hexane-ethyl acetate gave 4 g of the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH:16]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:21])[C:17](=O)[CH3:18])[C:5](=[O:15])[CH2:6]P(=O)(OCC)OCC)[CH2:3][CH2:2]1.[Cl-].[Li+].C(N(CC)CC)C>O1CCCC1>[CH:1]1([N:4]2[C:5](=[O:15])[CH:6]=[C:17]([CH3:18])[CH:16]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:21])[CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC(=O)N(C1CC1)C(C(C)=O)C(=O)NCc1ccc(Cl)cc1Cl)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=CC(=O)N(C2CC2)C1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a solution of diethyl (2-{cyclopropyl[1-({[(2,4-dichlorophenyl)methyl]amino}-carbonyl)-2-oxopropyl]amino}-2-oxoethyl)phosphonate (0.043 g, 0.087 mmol, prepared as described below) in anhydrous tetrahydrofuran (2.5 ml) at 0° C. was added lithium chloride (0.016 g, 0.39 mmol). The mixture was stirred until all of the lithium chloride dissolved and then triethylamine (0.066 ml, 0.87 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 18 hrs. Evaporation of the solvent in vacuo and purification of the resulting residue by mass-directed automated HPLC gave 1-cyclopropyl-N-[(2,4-dichlorophenyl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxamide (0.012 g) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].O>C1COCC1>[C:12]([CH:11]([C:10]#[N:14])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)#[N:13]
Reactant: N#CCC#N
Reactant: COc1ccc(I)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)C#N)cc1
Yield: 63.9 %

Procedure:
To a mixture of 4-iodoanisole (2.3 g, 10 mmol), malononitrile (750 mg, 11 mmol) and KOBu-t (2.5 g, 22 mmol) in THF (40 ml) was added PdCl2 (PPh3)2 (300 mg, 0.4 mmol) at room temperature. After the mixture was refluxed for 25 hours, the mixture was poured into H2O (10 ml), and extracted with ether. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil, which was purified by a column chromatography on silica gel to give Compound 35 as a colorless solid (1.1 g, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1)#[N:28]>>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:6]2[CH:7]=[C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([CH:30]=3)[C:27]#[N:28])[CH:3]=[CH:4][C:5]=2[F:26])([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)[N:9]=1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Reactant: N#Cc1cncc(B(O)O)c1
Product: Cc1cc(C2(c3cc(-c4cncc(C#N)c4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 38 %

Procedure:
The title compound was synthesized as described for Example 1 in 38% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol) and 5-cyanopyridin-3-ylboronic acid (37.1 mg, 0.25 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[CH:11]=O>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:11][CH:10]=[N:9]2
Reactant: Nc1ccc(Br)cc1N
Reactant: O=CC=O
Solvent: CCO
Solvent: O
Product: Brc1ccc2nccnc2c1

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (4.0 g, 21 mmol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) solution in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in 100 mL of EtOAc. The organic solution was washed with 40 mL of satd. NaHCO3 and 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos. ion) m/z: 208.9 (M+1).
Reaction SMILES: [C:1]([Si:5]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:6][CH2:7][C:8]([C:11]1[CH:12]=[C:13]([NH2:32])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:48]([O:50][CH2:51][C:52]([Cl:55])([Cl:54])[Cl:53])=[O:49]>CCOC(C)=O.O>[Cl:53][C:52]([Cl:55])([Cl:54])[CH2:51][O:50][C:48](=[O:49])[NH:32][C:13]1[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Yield: 126.7 %

Procedure:
A solution of Intermediate 153e (0.41 g, 0.67 mmol) in EtOAc (3 6 mL) was treated with aqueous 1N NaOH (1.2 mL, 1.2 mmol) then 2,2,2-trichloroethyl chloroformate (0.10 mL, 0.74 mmol) and the mixture was stirred at RT for 4 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red oil (0.67 g). The oil was purified by FCC, using 0-25% EtOAc in cyclohexane to give the title compound as a pale golden gum (0.38 g, 72%). LCMS (Method 3): Rt 5.86 min, m/z 788.3, 790.3 [MH+].
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[CH3:11])[CH2:3]1.[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>>[CH3:11][C:10]1[N:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[C:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=2[CH:9]=1
Reactant: CC(=O)CC1CC(C)CCC1=O
Reactant: Nc1ccc(C(=O)O)cc1
Product: Cc1cc2c(n1-c1ccc(C(=O)O)cc1)CCC(C)C2
Yield: 66 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxopropyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated, in 66% yield (98% purity by HPLC). MS(ESI+): 270.5; MS(ESI−): 268.4.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].[NH2:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:35]4[CH2:36][CH2:37][C@H:33]([NH2:32])[CH2:34]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: N[C@H]1CCNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 60 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 60 mg of (3S)-3-aminopyrrolidine, and the mixture was heated under reflux with stirring at 90° C. for 1 hour. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 41 mg of the title compound as a pale brown powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:31]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)c(NCCO)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 46.4 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of 4-methoxyisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 131 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[CH2:10]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=2)=[C:4]([F:9])[CH:3]=1
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCCCc1ccc(C#Cc2ccc(Br)cc2F)cc1
Temperature: 5 °C
Yield: 41.3 %

Procedure:
4-Bromo-2-fluoro-1-iodobenzene (57 g) was dissolved in diethylamine (66 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.5 g) and copper(I) iodide (0.5 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-pentylphenylacetylene (36 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (40 ml) and ice (30 g). After extraction with chloroform, the resultant was washed twice with water, followed by distilling off chloroform therefrom. The residue was distilled under reduced pressure (b.p. 205° to 210° C./3 mmHg), and then recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-2-fluoro-4'-pentyltolane (27 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]=[C:4]2[N:16]([CH3:19])[N:17]=[CH:18][C:3]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[N:16]([CH3:19])[N:17]=[CH:18][C:3]3=[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=3)[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: COc1cc(-c2cc(Cl)c3cnn(C)c3n2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cnn(C)c3n2)ccn1
Temperature: 150 °C
Yield: 50.2 %

Procedure:
To 4-chloro-6-(2-methoxypyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.4 g) and 4-(methylsulfonyl)phenol (0.5 g) was added DMF (3.4 mL) and potassium carbonate (1.0 g). Nitrogen was bubbled through the solution for 5 min. The reaction mixture was heated in a microwave reactor for 1 h at 150° C., then purified by reverse phase HPLC to provide 118 (0.3 g). MS (ESI) m/z 411.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:28]=[C:14]2[C:15]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:16][CH:17]=[C:18]([F:19])[C:13]2=[N:12]1.I([O-])(=O)(=O)=[O:30].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:28]=[C:14]2[C:15]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:16][CH:17]=[C:18]([F:19])[C:13]2=[N:12]1)[CH:8]=[O:30]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4Cl)cc23)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of [2-(2,6-dichloro-4-vinylphenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)amine (193 mg, 0.47 mmol) in acetone (10 mL) and water (2.5 mL) was added osmium (VIII) oxide (2.5% wt in tert-butanol, 0.465 mL), followed by sodium periodate (257 mg, 1.2 mmol) and the reaction mixture was stirred at room temperature overnight. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (80% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (129 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 10.10 (s, 1H), 9.35 (d, J=2.6 Hz, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.31 (s, 2H), 8.01 (d, J=3.5 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To tert-butyl 3-hydroxyoctadecanoate (120 g) in pyridine (500 ml) was added palmitoyl chloride (120 g) at 0° C. The mixture was stirred at 0° C. for 5 hours and then allowed to stand over-night at room temperature. Pyridine was removed under reduced pressure and the residue was poured into water. The resulting mixture was stirred at ambient temperature for 2 hours, acidified with 1N HCl, extracted with ethyl acetate, and washed with water. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography (30% CH2Cl2 --CCl4) to afford tert-butyl 3-hexadecanoyloxyoctadecanoate (160 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][C@H:10]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([N:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([N:52]3CCN(C)CC3)=[O:51])[CH2:45]1)=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:38]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:30][NH:29][C:25]2[N:24]=[C:23]([N:44]3[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([NH:52][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)=[O:51])[CH2:45]3)[N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[C@@H:10]2[CH2:11][C@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[C@@H:13]([OH:14])[C@H:9]2[OH:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N5CCN(C)CC5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5ccccn5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to 4-methyl-piperazine-1-carboxylic acid {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-amide trifluoro acetate (Example 77) by replacing 1-methyl piperazine with 2-amino pyridine.