Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Cl.[F:24][C:25]1([F:29])[CH2:28][NH:27][CH2:26]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:24][C:25]1([F:29])[CH2:28][N:27]([C:16]([C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][N:5]=4)[CH:8]=3)=[CH:13][CH:14]=2)=[O:17])[CH2:26]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1)N1CC(F)(F)C1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (52 mg) was dissolved in DMF (2 mL). 3,3-difluoroazetidine hydrochloride (26 mg), diisopropylethylamine (35 μL) and HATU (93 mg) were added sequentially. After 24 h, added additional amounts of Diisopropylethylamine (105 μL) and HATU (279 mg). When the reaction was mostly complete, quenched with ethyl acetate/water, washed with 0.1N HCl, and concentrated NaHCO3. Purified on prep-TLC plate using 5% MeOH/dichloromethane. Isolated 37 mg of (3,3-difluoroazetidin-1-yl)(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)methanone (57%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]1[CH2:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Li])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[CH2:1]([N:8]([CH2:10][CH:11]1[CH2:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)CC1CC(=O)c2ccccc2O1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: CN(Cc1ccccc1)CC1CC(O)(c2ccccc2)c2ccccc2O1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(N-benzyl-N-methylaminomethyl)chroman-4-one (4.9 g) in dry diethyl ether (200 ml) under an atmosphere of dry nitrogen at room temperature, was added a two molar excess of phenyllithium solution and the resulting mixture was boiled for 2 hours before being poured onto ice/dilute HCl. The solution was basified and extracted with ether to give the crude 2-(N-benzyl-N-methylaminomethyl)-4-phenyl-4-hydroxychroman as an orange oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:20]=[C:19]([O:21][C@H:22]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:23]32[CH2:25][CH2:24]3)[CH:18]=[N:17][CH:16]=1)([CH3:5])C.[C:37](O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH2:25]1[C:23]2([CH2:26][CH2:27][NH:28][CH2:29][C@@H:22]2[O:21][C:19]2[N:20]=[C:15]([C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([CH:3]([CH3:5])[CH2:2][OH:1])[CH:7]=4)[N:11]([CH3:37])[N:10]=3)[CH:16]=[N:17][CH:18]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3n[nH]c4ccc(C(C)(C)CO)cc34)n2)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(CO)c1ccc2c(c1)c(-c1cncc(O[C@H]3CNCCC34CC4)n1)nn2C
Yield: 52.8 %

Procedure:
A solution of (R)-tert-butyl 4-((6-(5-(1-hydroxy-2-methylpropan-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (18 mg, 0.036 mmol) in TFA (41.6 mg, 0.365 mmol) was stirred at RT for 30 min. The mixture was concentrated and was dissolved in MeOH (˜20 mg/ml) and injected (1×1.000 ml) onto the Shimadzu preparatory LC (Protocol B) before the pure fraction was concentrated via rotary evaporation to give impure product. A preparatory TLC plate was loaded with the crude mixture and run 2 times in 20% MeOH/DCM; scraping the plate, extraction with MeOH, filtration, and concentration via rotary evaporation afforded 2-(3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-1-methyl-1H-indazol-5-yl)-1-propanol (7.6 mg, 0.019 mmol, 53.0% yield) as a beige solid. MS (ESI, pos. ion) m/z: 394.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:4]([F:19])[CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][N:12]=2)(=[O:10])=[O:9])=[C:4]([F:19])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(Br)cc2F)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2ccc(Br)cc2F)n[nH]1
Yield: 90.2 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-benzenesulfonyl)-6-methoxy-pyridazine (260 mg), dioxane (5 mL), and concentrated hydrochloric acid (1 mL) was prepared and refluxed for two hours. The reaction mixture was then evaporated to dryness. The resulting residue was triturated with water and the precipitated solid was collected and air-dried to obtain the title compound (90%, 225 mg); mp, >220° C.; NMR 7.05 (d, 1H), 7.7 (d, 1H), 7.9 (m, 3H), 13.8 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:29]([CH:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH2:35][CH2:34][N:33]1[C:41](OCC1SC=CN=1)=[O:42])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:29]([CH:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH2:35][CH2:34][N:33]1[C:41]([O:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:42])([CH3:31])[CH3:30]
Reactant: Cc1cc(CO)no1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(COC(=O)N2CCc3[nH]cnc3C2C(C)C)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.8 %

Procedure:
5-Methylisoxazole-3-methanol (1.64 g, 14.5 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (1.47 g, 1.40 mL, 14.5 mmol) and 4-nitrophenyl chloroformate (2.93 g, 14.5 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. A solution of Intermediate 1 (1.87 g, 3.60 mmol) in DCM (20 mL) and DIPEA (1.87 g, 2.52 mL, 14.5 mmol) was added and the resulting solution was stirred for 3 d and concentrated in vacuo. The residue was dissolved in MeOH (8 mL) and 1 M aq NaOH solution (6 mL) and the reaction mixture was stirred for 18 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL per min, gradient 0% to 20% (over 5 min) to 90% (over 40 min) MeOH in water) and reverse phase HPLC (YMC ODS-A 150×20 mm, 5 μm, 25 mL per min, gradient 40% to 80% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (5-methylisoxazol-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (107 mg, 9.7%) as a colourless gum.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1[C:18]([C:19](OCC)=[O:20])=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[CH:16]=[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:14]=1.C(OCC)(=O)C>O1CCCC1>[OH:20][CH2:19][C:18]1[C:13]([CH3:12])=[N:14][C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:16][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CO
Temperature: 0 °C
Yield: 30.5 %

Procedure:
To a suspension of lithium aluminum hydride (0.32 g) in a mixture of dry tetrahydrofuran (4 ml) and diethyl ether (8 ml) was dropwise added a solution of ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (1 g) in dry tetrahydrofuran (4 ml) at -20° C. to -10° C. The excess lithium aluminum hydride was decomposed by a careful addition to ice water. Ethyl acetate (25 ml) was added thereto and the separated organic layer was washed with 10% sulfuric acid (15 ml), saturated aqueous sodium bicarbonate and aqueous sodium chloride successively and concentrated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with chloroform. The fractions containing the desired compound were combined and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.27 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]([O:25][CH2:26][N:27]1[C:31]2[N:32]=[CH:33][N:34]=[C:35](Cl)[C:30]=2[CH:29]=[CH:28]1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:19]([O:25][CH2:26][N:27]1[C:31]2[N:32]=[CH:33][N:34]=[C:35]([N:16]3[C:17]4[C:13](=[CH:12][CH:11]=[C:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)[CH:18]=4)[CH:14]=[CH:15]3)[C:30]=2[CH:29]=[CH:28]1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C(=O)OCn1ccc2c(-n3ccc4ccc(-c5cccc([N+](=O)[O-])c5)cc43)ncnc21
Temperature: 25 °C
Yield: 89.8 %

Procedure:
6-(3-Nitrophenyl)-1H-indole (100 mg, 0.42 mmol) and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (112 mg, 0.42 mmol) were dissolved in 1,4-dioxane (5 mL) in a sealed reactor and then Cs2CO3 (270 mg, 0.83 mmol) was added. After removing the gas included in the solution using ultrasonic wave and sequentially adding Xantphos (CAS No. 161265-03-8; 49 mg, 0.084 mmol) and Pd(OAc)2 (9.4 mg, 0.042 mmol), the reaction mixture was stirred at 120° C. for 2 hours. After cooling to room temperature and adding ethyl acetate and water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, methylene chloride 100%) yielded (4-(6-(3-nitrophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (177 mg, 0.377 mmol) as white solid.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:3]=1[CH:4]=[N:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].CC(C)([O-])C.[K+].Cl>CN1C(=O)CCC1.O>[I:20][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][CH:18]=1)[N:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[N:5]=[CH:4]2
Reactant: O=C(O)c1cccc(NN=Cc2cc(I)ccc2F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cccc(-n2ncc3cc(I)ccc32)c1
Yield: 107.4 %

Procedure:
3-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (3.47 g, 9 mmol) and potassium tert. butoxide (2.3 g, 20.5 mmol) was stirred under argon atmosphere in NMP (45 mL) at 150° C. for 30 min. After cooling, the mixture was diluted with water (100 mL), acidified with aqueous HCl (1.7 M) and extracted trice with EtOAc. The combined organic phases were washed twice with water and then with brine. Evaporation of the organic phase afforded crude title compound (3.52 g, quant.) as a light brown, amorphous, gummy solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>>[C:27]([C:26]1[CH:30]=[CH:31][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:23]=2)=[CH:33][C:25]=1[Cl:24])(=[O:28])[NH2:29]
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(Cl)c4)ccc3o2)CC1
Yield: 13.7 %

Procedure:
Following the General Procedure-2, the titled compound (25 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110 mg, 0.4 mmol) as a brown solid. M.P.: 169-171° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.03 (s, 1H), 7.87 (bs, 1H), 7.82-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.59 (bs, 1H), 7.52 (d, J 7.9, 1H), 3.94 (d, J 12.9, 2H), 3.30-3.22 (m, 1H), 3.08-2.92 (m, 2H), 2.09 (d, J 10.6, 2H), 1.75-1.63 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4].C[Si](C)(C)Cl.[I-].[Na+]>C(#N)C>[F:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4]
Reactant: COc1ccc(OC(F)=C(F)F)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(OC(F)=C(F)F)cc1

Procedure:
A sample of 4-trifluoroethenyloxyanisole prepared as in Example 2 is treated with two equivalents of trimethylchlorosilane and sodium iodide in refluxing acetonitrile to give 4-trifluoroethenyloxyphenol. The product is extracted with ether, washed with sodium thiosulfate solution to remove iodine, and then concentrated by rotary evaporation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[C@H:10]([C:20](O)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:20](=[O:21])[NH:23][C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)[C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2cccc(Br)c2)C1
Reactant: N#Cc1cccc(N)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)Nc2cccc(C#N)c2)[C@H](c2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Cool a solution of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.50 g, 1.35 mmol) in pyridine (5 mL), to 0° C., and add 3-aminobenzonitrile (0.18 g, 1.48 mmol) followed by phosphorous oxychloride (0.14 mL, 1.50 mmol). Stir the mixture at 0° C. for 1 h then dilute with water. Extract the mixture with EtOAc and wash the combined organic portion with a 2 N solution of hydrochloric acid until the pH of the aqueous washings is strongly acidic. Wash the organic phase with brine then dry over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography to provide 0.53 g of trans-3-(3-bromo-phenyl)-4-(3-cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][CH:71]([CH3:75])[C@H:72]([NH2:74])[CH3:73]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][C@H:72]([CH3:73])[CH:71]([CH3:75])[CH3:70])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)[C@@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@H](C)C(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2R)-3-methyl-2-butanamine (10.5 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 40%). LC-MS m/z 591 (M+H)+.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@@H:17]([C:21]([N:23]([CH:39]2[CH2:41][CH2:40]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=2)=[O:22])[CH2:16]1)=O)(C)(C)C.O>C(Cl)(Cl)Cl>[CH:39]1([N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=2)[C:21]([C@@H:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)=[O:22])[CH2:41][CH2:40]1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNCCO2)C2CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N HCl/dioxane (1 ml) was added under ice cooling to (2R)-2-({cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylic acid tert-butyl ester (a compound of Reference Example 8, 368 mg) dissolved in chloroform (4 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture under ice cooling and the organic layer was separated. The aqueous layer was extracted with chloroform after being adjusted to pH 9 by addition of a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by NH-silica gel column chromatography (eluting solvent; n-hexane:ethyl acetate=1:1 to ethyl acetate only) to give (2R)—N-cyclopropyl-N-[4-methoxy-3-(3-methoxypropoxy)benzyl]morpholine-2-carboxamide (230 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.CNC1CCCCC1NC>CCOC(C)=O.O.[Cu]I.C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:3]=1
Reactant: COC(=O)c1ccc2c(F)c[nH]c2c1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(F)cn(-c3ccc(F)cc3)c2c1
Temperature: 95 °C

Procedure:
Compound 69a (0.264 mmol, 51 mg), CuI (0.0264 mmol, 5 mg) and K3PO4 (0.66 mmol, 40 mg) were combined in a sealed reaction tube and the vial was back-flushed with N2. 4-fluoro-iodobenzene 69b (0.264 mmol, 0.0394 mL) and N,N′-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) were added via sringe, followed by toluene. The reaction mixture was heated at 95° C. for 6 h. The reaction was diluted with EtOAc and water. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/hexanes) to give compound 69c.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:38]=[CH:37][C:36]([N:50]5[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:57])[CH2:54][CH2:55]5)=[C:35]([CH3:34])[CH:40]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(C)c4)cnc32)cc1
Yield: 77.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (200 g, 0.380 mmol) was coupled with tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69A) (280 mg, 0.694 mmol) using sodium carbonate (121 mg, 1.142 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.019 mmol) in DME/water (15/4 mL). This afforded 212 mg (77.3% yield) of the titled compound after purification by column (Silica gel 60/120) using 15% ethyl acetate in hexane as eluent. MS: m/z=721.3 (M+1).
Reaction SMILES: N[C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12>N1C=CC=CC=1>[C:11]([O:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH2:2][C:17](=[O:18])[N:4]2[C:5]=1[C:14]([OH:16])=[O:15])(=[O:13])[CH3:12]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1

Procedure:
3-Hydroxy-3,3-diphosphonopropanoic acid, tetramethyl ester is converted to 3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propionic acid and then to 3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propanoyl chloride. The acid chloride is then added to α-(Z-methoxyimino)-α-(2-aminothiazol-4-yl)-acetic acid and pyridine to form α-(Z-methoxyimino)-α-{2-[3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)-propanoyl-amino]-thiazol-4-yl}-acetic acid. The latter is reacted with oxaloyl chloride to form the acid chloride, α-(Z-methoxyimino)-α-{2-[3-(tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)-propanoyl-amino)-thiazol-4-yl]-acetyl chloride. This acid chloride is reacted with 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and pyridine and gives 7β-{α-(Z-methoxyimino)-α-[2-(3-tert-butoxycarbonyloxy)-3,3-bis(diethoxyphosphono)propanoyl-amino)-thiazol-4-yl]-acetamido}-3-acetoxymethyl-3-cephem-4-carboxylic acid. Deprotection with trifluoroacetic acid and anisole yields the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[C:30]2[C:29]([NH2:31])=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][C:25]=2[N:24]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[N:23]=1>CN(C=O)C>[F:21][C:22]1[C:30]2[C:29]([NH2:31])=[CH:28][C:27]([C:2]3[CH:3]=[C:4]4[CH:10]=[N:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:5]4=[N:6][CH:7]=3)=[CH:26][C:25]=2[N:24]([S:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)(=[O:37])=[O:38])[N:23]=1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(-c4cc(N)c5c(F)nn(S(=O)(=O)c6ccccc6)c5c4)cnc32)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
5-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrazolo[3,4-b]pyridine (605 mg) in DMF (4 ml) was added to a solution of 3-fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (650 mg) in DMF (6 ml), treated with Pd( )Ph3)4 (165 mg) and then heated at 120° C. for 21 h. The solution was allowed to cool, filtered, and then evaporated. The residue was dissolved in chloroform, loaded onto a 100 g silica cartridge which was eluted with 0-100% ethyl acetate:cyclohexane over 60 min using the Flashmaster II. Appropriate peaks were combined and evaporated to give the title compound as a white solid, 0.577 g.