Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl([O-])=[O:15].[Na+].Cl([O-])=O.P([O-])([O-])([O-])=O>O.CC(O)C>[Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]([OH:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cn1c(Br)c(C=O)c2ccccc21
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cn1c(Br)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a vigorously stirred solution of 2.38 g (10 mmol) of 2-bromo-1-methylindole-3-carboxaldehyde [XXVI: R1 =H, R3-dioxane at 25° C. was added dropwise over ca. 15 minutes a solution of 5 (55 mmol) of sodium chlorite and 5 g (36 mmol) of NaH2PO4.H2O in 25 mL of water. The solution was maintained at 25° C. After 3.5 hours, the mixture was treated with an additional 2.5 g each of the chlorite and phosphate. After a total reaction time of 24 hours, the mixture was extracted 3 times with dichloromethane, then the aqueous phase was acidified to pH 2 with aqueous HCl, and extracted once more. The combined organic extracts were washed with water, dried, and evaporated to leave a solid residue that was boiled in 2-propanol. After cooling, the solids were collected by filtration, washed with a little 2-propanol, and dried to leave 2.21 g (87%) of 2-bromo-1-methyl indole-3-carboxylic acid [XXVII: R1 =H, R3 =CH3, X=Br] as a beige solid; mp ca. 198° C. (dec), in 2 crops.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][NH:10][C:4]=3[CH:3]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)cc(-c2cc3[nH]ncc3cn2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (500 mg, 3.2 mmol) (Frontier Cat. No. Z13659), (3,5-dimethoxyphenyl)boronic acid (890 mg, 4.9 mmol) (TCI Cat. No. D3513), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (200 mg, 0.3 mmol), and sodium carbonate (1.0 g, 9.8 mmol) in 1,2-dimethoxyethane (4 mL) and water (0.6 mL) was degassed, and sealed. The mixture was stirred at 110° C. overnight. After cooling it was partitioned between ethyl acetate and water. After separation the aqueous solution was extracted with ethyl acetate twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.80 g). LCMS (M+H)+=256.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1.B(F)(F)F.CCOCC>[C:5]1([C:1]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCNCC1
Reactant: CCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC=C(c1ccccc1)N1CCCCC1
Yield: 62.2 %

Procedure:
In 30 ml of toluene, 2.68 g of propiophenone, 5.30 g of piperidine and 0.14 g of boron trifluoride etherate were dissolved. The mixture was treated in a manner similar to Example 1 to obtain 2.50 g of the desired enamine (yield: 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 4 h
Yield: 23 %

Procedure:
To a solution of 0.14 g (0.94 mmol) of 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 6.0 ml of methanol and 6.0 ml THF 90.0 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 4 h, then filtered and evaporated to dryness in vacuo. The residue was crystallized from diethyl ether to yield 0.105 g (75%) 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. F.p.: 222-223° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:15])([CH3:14])[CH:12]=[O:13].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>C(O)(C)C>[CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13]
Reactant: C=C(C)C1CCC(C)=C1CC(C)(C)C=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: C=C(C)C1CCC(C)=C1CC(C)(C)CO

Procedure:
103 g (0.5 mole) of the product from Example 1 were reduced with 60 g of isopropanol and 20 g of aluminum triisopropylate by the Meerwein-Ponndorf method. The conversion was 78% and the yield of the above compound (for characteristics thereof, see Example 3), based on the above conversion, was 73%.
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]>CN(C)C=O>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 86 %

Procedure:
A stream of methylamine was bubbled through a solution of 1,3 g (6,2 mmol) 4-fluoro-3-nitrobenzotrifluoride in 25 ml dimethylformamide at 25° C. for 5 min. Stirring was continued at 25° C. for 2 h, and then the reaction mixture was evaporated in vacuo. The residue was stirred with water, and the precipitate was filtered off to give 1,17 g (86%) 4-methylamino3-nitrobenzotrifluoride. NMR (CDCl3): 8.4 (1H, s), 8.2 (1H, broad s), 7.6 (1H, dd), 6,9 (1H, d), 3.1 (3H, d).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][C:10]1[N:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][C:10]1[N:15]=[CH:14][C:13]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=Cc1cnc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ncc(C=O)s2)cn1
Temperature: 110 °C
Yield: 41.4 %

Procedure:
A mixture of 2-bromothiazole-5-carbaldehyde (400 mg, 2.08 mmol), (6-methylpyridin-3-yl)boronic acid (428 mg, 3.12 mmol, 1.5 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (170 mg, 0.21 mmol, 0.1 equiv) and 2.0 M aqueous sodium carbonate (5.2 mL, 10.4 mmol, 5 equiv) in 1,2-dimethoxyethane (6.9 mL) was heated in a microwave reactor at 110° C. for 20 minutes. The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc) provided 2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde (0.176 g, brown solid) in 41% yield. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 9.15 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.19 (dd, J=8.1, 2.4 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 2.66 (s, 3H). MS m/z 205.0 (M+H)+; Rt-0.36 min.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:43]([C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 75.7 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-fluorobenzenesulfonyl chloride (1.72 g) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (1.59 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:29])C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-:29])=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.15 g (0.423 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline) was dissolved in a mixed solvent of 5 ml of ethyl acetate and 5 ml of chloroform and 0.11 ml (0.508 mmol) of 32% peracetic acid was added thereto. The mixture was heated at 50° C. and stirred for 3 hours. After the reaction mixture was poured into a sodium hydrogencarbonate aqueous solution, the resulting solution was extracted with chloroform, dried (Na2SO4), then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1 (v/v)) to obtain 0.13 g (0.351 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5-oxide shown below as a white solid. ##STR59## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3230, 2980, 1710, 1540, 1440, 1370, 1280, 1170, 880, 770.
Reaction SMILES: O[C@H:2]([CH3:22])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1OC(=O)[C@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2S,3R)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-butanoic acid (0.3 g, 0.89 mmol) in dry CH2Cl2 (30 mL), Et3N (0.37 mL, 2.67 mmol) and subsequently TBTU (0.34 g, 1.06 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.18 g, 70%), as white solid. [α]25D +21.3 (c 0.1, CHCl3). MS (ESI) m/z: 292 [M−H]+; (ESI) m/z: 290 [M−H]−. 1H NMR (DMSO-d6) δ 1.37-1.28 (m, 2H), 1.33 (d, J=6.4 Hz, 3H), 1.64-1.53 (m, 4H), 2.57 (t, J=7.7 Hz, 2H), 4.06-3.93 (m, 2H), 4.84 (dq, J=6.1, 6.4 Hz, 1H), 5.40 (dd, J=6.1, 9.4 Hz, 1H), 7.30-7.13 (m, 5H), 8.19 (d, J=9.4 Hz, 1H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:45][C:42]3[S:43][CH:44]=[C:40]([CH3:39])[N:41]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: CN1CC[C@H](Oc2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(C(=O)O)c2)C1=O
Reactant: Cc1csc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.10 mL, 0.75 mmol) was added to a solution of the 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 6) (265 mg, 0.62 mmol) in DCM (5 mL) and stirred at ambient temperature for 30 minutes, a further aliquot of 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.10 mL) was added and stirring continued for a further 30 minutes. 4-Methyl-1,3-thiazol-2-amine (142 mg, 1.2 mmol) and pyridine (0.10 mL, 1.2 mmol) were added and the reaction stirred for 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and DCM (15 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give the crude product which was purified by flash chromatography on silica, eluting with a gradient of 0-5% methanol in DCM, to afford the product (181 mg, 58%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 4H), 2.38 (quintet, 2H), 2.50-2.63 (m, 1H), 2.93 (s, 3H), 3.33-3.56 (m, 2H), 4.26 (t, 2H), 4.69 (t, 2H), 4.84 (t, 1H), 6.54 (s, 1H), 7.15 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H), 8.32 (s, 1H), 8.82 (s, 1H), 10.43 (s, 1H); m/z 509 (M+H)+
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]([CH:31]=O)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:22][C:23]1[CH:24]=[C:25]([CH2:31][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30]
Reactant: O=Cc1cnc(CO)c(Br)c1
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cnc(CO)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 21: 50.9 mg, 0.175 mmol) and 5-bromo-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 40: 37.9 mg, 0.175 mmol) in DCE (3 ml) was stirred under N2 at room temperature overnight. Then, sodium triacetoxyborohydride (112 mg, 0.526 mmol) was added and the mixture was stirred for 8 h at RT overnight. Saturated NaHCO3 was added and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Flash-Master chromatography on a 2 g silica gel cartridge using DCM/MeOH 9/1 as eluent to give 1-{2-[4-({[5-bromo-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (21.5 mg, 25%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(Nc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.100 g, 0.267 mmol), cesium carbonate (0.305 g, 0.936 mmol), 1,4-Dioxane (2.5 mL) and aniline (0.049 mL, 0.535 mmol). The stirring suspension was degassed with nitrogen for 10 min. Added next were BINAP (0.033 g, 0.053 mmol) and palladium(II) acetate (6.01 mg, 0.027 mmol). The sealed mixture was stirred at 105° C. overnight. After cooling to room temperature, the contents were poured onto EtOAc and filtered through Celite. The filter pad was washed with additional 50% THF/EtOAc. The combined filtrates were treated with silica gel and concentrated in vacuo. The crude product was purified by silica gel chromatography (dry loaded, eluent: Gradient 5-80% of DCM and chloroform containing 10% 2M Ammonia (in methanol))). The isolated solid was dried in a vacuum oven overnight and the final product collected as 0.061 g (52%). LCMS E-S (M+H)=431.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.35 (d, J=5.05 Hz, 2H), 4.98-5.11 (m, 1H), 5.90 (s, 1H), 6.93-7.00 (m, 2H), 7.34 (t, J=7.96 Hz, 2H), 7.86 (d, J=7.58 Hz, 2H), 7.97 (s, 1H), 8.59 (t, J=5.05 Hz, 1H), 9.62 (s, 1H), 11.58 (br. s., 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O:38][C:39](=[O:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47](O)[CH3:48])=[CH:43][CH:42]=1)C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C@H:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C:39]([OH:50])=[O:38])=[CH:42][CH:43]=1)[CH3:48])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1
Solvent: Oc1ccccc1
Product: C[C@H](Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccc(CC(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of example 69 using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol as the phenol and [4-(1-Hydroxy-ethyl)-phenyl]-acetic acid ethyl ester as the alcohol .MS (ESI) m/z 540;
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CCCNC(=N)N.CC(CC(O)=O)=O>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(=O)CC(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.02 His: 0.95 Phe: 0.95 Ala: 2.00 Tyr: 0.91 Leu: 1.00 Arg: 0.90 Pro: 0.96 Recovery: 103% (calculated as the diacetate).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:34]([O:41][CH2:42][C@H:43]([C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]([CH3:59])([CH3:58])[C:55]([OH:57])=O)[CH:52]=2)[NH:47][C:46]=1[C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=1)[CH3:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:68]1[CH:73]2[CH2:74][NH:75][CH:70]([CH2:71][CH2:72]2)[CH2:69]1.Cl.C(N(CC)CC)C.O.[Cl-].[Na+].O>C(Cl)Cl>[CH:70]12[CH2:69][CH2:68][CH:73]([CH2:72][CH2:71]1)[CH2:74][N:75]2[C:55](=[O:57])[C:54]([C:51]1[CH:52]=[C:53]2[C:45]([C@H:43]([CH3:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:46]([C:60]3[CH:61]=[C:62]([CH3:67])[CH:63]=[C:64]([CH3:66])[CH:65]=3)[NH:47][C:48]2=[N:49][CH:50]=1)([CH3:58])[CH3:59]
Reactant: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Reactant: C1CC2CCC1CN2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)N4CC5CCC4CC5)cc3c2[C@H](C)COCc2ccccc2)c1
Reaction time: 12 h
Yield: 95 %

Procedure:
PyBOP (1.51 g, 2.89 mmol) was added to a stirred mixture of (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo-[2,3-b]pyridin-5-yl]-2-methylpropanoic acid (1.20 g, 2.63 mmol), isoquinuclidine.HCl (0.78 g, 5.26 mmol) and triethylamine (1.47 mL, 10.5 mmol) in CH2Cl2 (26 mL) at ambient temperature. After approximately 12 h, the reaction mixture was poured into water/brine (1:1) and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient eluton; 60-75% ethyl acetate/hexanes as eluent) to give the title compound as a colourless foam (1.37 g, 95% overall).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10](=O)[CH2:11]Br)=[CH:8][CH:9]=1)=[O:4].CC([O-])=O.[Na+].[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[N:19]=[C:20]([NH2:22])[S:21][CH:11]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)CBr)o1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2csc(N)n2)o1

Procedure:
5-(2-Bromo-acetyl)-furan-2-carboxylic acid methyl ester (0.39 g, 1.61 mmol) was treated with NaOAc (0.185 g, 2.25 mmol) and thiourea (0.12 g, 1.6 mmol) in EtOH to give 5-(2-Amino-thiazol-4-yl)-furan-2-carboxylic acid methyl ester; MS: 225.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][OH:22])[O:18][C:17]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[O:18][C:17]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (900 mg) was dissolved in pyridine (20 ml), and cooled to 0° C. Triethylamine (0.5 ml) and methanesulfonyl chloride (0.24 ml) were added, and stirring continued at 5° C. for 2 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 3% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(3-fluoro-4-{4-methyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (990 mg).