Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.Cl[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1.C(P(C(C)(C)C)C[Si](C)(C)C)(C)(C)C.[F-].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)P(C[Si](C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccnc(-c2cc(C(F)(F)F)ccc2F)c1

Procedure:
10.0 g (0.0481 mol) of 2-fluoro-5-(trifluoromethyl)phenylboronic acid, 5.52 g (0.0433 mol) of 2-chloro-4-methyl-pyridine, 1.10 g (0.0012 mol) of tris(dibenzylideneacetone) dipalladium (0), 0.67 g (0.00289 mol) of di-tert-butyl-trimethylsilylmethyl-phosphane, 8.0 g (0.0527 mol) of cesium fluoride and 100 ml of dioxane were stirred at room temperature for 24 hours. The resultant mixture was poured into 200 ml of water and extracted twice with 200 ml of methylene chloride. The organic phase was dried on magnesium sulfate overnight and filtered. The solvent was removed on a rotovapor and the residue was purified by chromatography on silica gel with petroleum ether/ethyl ether (10/0.5) as eluent. Yield of 2-(2-fluoro-5-trifluoromethyl-phenyl)-4-methyl-pyridine: 4.70 g (42.57%) as a colorless liquid. 1H NMR (CD2Cl2) 2.30 (s, 3H, Me), 6.90-8.50 (m, 6H, arom-H). 19F NMR (CD2Cl2) −63.75 (s, 3F, CF3), −112.44 (s, 1F, F-arom). LC/MS calculated for C13H9F4N 255.07; found 255.07.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[CH:10][N:9]([Si](C)(C)C)[CH:8]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:9]1[CH:10]=[CH:11][CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:8]1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)N1C=CC([Si](C)(C)C)C(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i (0.2 mL, 1.36 mmol) in CH2Cl2 (6 mL) under Ar was added dropwise dimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture was stirred at RT for 1 day. It was then poured into a saturated solution of NaHCO3 (3 mL). The aqueous phase was extracted with CH2Cl2 (5 times). The combined organic layers were washed with water and brine and dried over MgSO4. Evaporation of the solvent under reduced pressure afforded 0.49 g of crude material that was purified by RPLC (silica gel, 5% EtOAc/hex) to give 59% (0.2506 g) of 3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylic acid dimethylamide iii as a clear oil. IR (thin film, neat, NaCl): 3363, 2924, 2348, 1657, 1449, 1377 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.65 (d, 1 H, J=6.9 Hz), 6.35 (s 1 H), 4.83–4.78 (m, 1 H), 3.14–3.09 (m, 1 H), 2.88 (s, 6 H), 2.80–1.25 (m, 13 H), 0.085 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47, 38.53, 33.04, 30.34, 29.91, 22.37, 0.63, −2.00. HRMS Calcd for C16H29N3OSi: 308.2157 [M+H]+. Found: 308.2157 [M+H]+. [α]25D−15.17 (CH2Cl2, c=0.145).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13]([OH:15])=[O:14]>C(Cl)Cl>[CH3:10][C:11]1[C:19]([N+:6]([O-:9])=[O:7])=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 46 ml of concentrated sulfuric acid and 23.5 ml of concentrated nitric acid was added slowly to a stirred solution of 2,6-dimethylbenzoic acid (50.0 g, 0.333 mole) in 200 ml of methylene chloride at a rate such that a gentle reflux was maintained throughout the addition. After complete addition, reflux was maintained for 30 minutes. The reaction mixture was cooled, poured onto 300 g of ice and the organic phase separated. The aqueous phase was extracted with three 200 ml portions of diethyl ether, and the organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give 2,6-dimethyl-3-nitrobenzoic acid (60.2 g) as a solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:43])[C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34])=[O:31]>>[CH3:28][N:29]([CH3:43])[C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:42]=1)[CH3:34])=[O:31]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(CC(=O)N(C)C)Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CC(=O)N(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(dimethylcarbamoyl-methyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=10:1) C29H30N4O4
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Brc1ncccn1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(c5ncccn5)C4)c3C2)cc1C(F)(F)F
Temperature: 160 °C
Yield: 22.4 %

Procedure:
To a glass vial was added 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (prepared using step 1 of example 91 from intermediate 13) (75 mg, 0.16 mmol), 2-bromopyrimidine (55 mg, 0.342 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.85 mmol). The vial was capped and the mixture heated in the microwave at 160° C. for 20 min. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyrimidin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a brown solid (17 mg, 21% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.23-2.43 (m, 2 H) 2.85-2.99 (t, 2 H) 3.22-3.94 (m, 9 H) 4.08-4.27 (m, 2 H) 5.70-5.80 (m, 1 H) 6.56-6.66 (t, 1 H) 7.76-7.87 (m, 1 H) 8.12-8.27 (m, 1 H) 8.28-8.42 (m, 2 H) 8.59-8.68 (m, 1 H) LCMS: [M+H]+=474.2, Rt(1)=1.91 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[C:17]([CH3:18])[C:12]2=[C:11]([CH2:19][N:20]2[C:25](C)([CH3:26])[CH2:24][N:23]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[C:22]([CH3:34])([CH3:33])[CH2:21]2)[CH:10]=1.[CH3:35][C:36]1C2C(=NC(C3C=CC(O)=CC=3)=CC=2CN2CC3(CCCC3)NCC2C)NN=1.COCC(Cl)=O>>[OH:8][C:6]1[CH:7]=[CH:2][C:3]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([CH3:18])[C:12]3=[C:11]([CH2:19][N:20]3[CH2:21][C:22]4([CH2:33][CH2:36][CH2:35][CH2:34]4)[N:23]([C:28](=[O:32])[CH2:29][O:30][CH3:31])[CH2:24][CH:25]3[CH3:26])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC4(CCCC4)NCC3C)c12
Reactant: COCC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1(C)C
Agent: COCC(=O)Cl
Product: COCC(=O)N1CC(C)N(Cc2cc(-c3ccc(O)cc3)nc3[nH]nc(C)c23)CC12CCCC2

Procedure:
The title compound was prepared in analogy to Example 75 (1-{4-[6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-2-methoxy-ethanone) using 4-[3-Methyl-4-(8-methyl-6,9-diaza-spiro[4.5]dec-9-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol and methoxyacetyl chloride.
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cccc(C)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 2-iodo-3-methylbenzoic acid (500 mg, 0.48 mmol) in benzene/MeOH (2 mL, 10:1) was added TMSCHN2 (1 mL, 2N), the reaction mixture was stirred at rt for 30 min and then concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/Hexanes, gradient) to afford 500 mg (91%) of Intermediate 299.1.
Reaction SMILES: C[C@@H]1N(S(O)(=O)=O)C(=[O:5])[C@H]1NC(/C(/C1N=C(N)SC=1)=N\OC(C(O)=O)(C)C)=O.C(N(CCCC)CCCC)CCC.OC1C2N=NNC=2C=CC=1.CN(C1C=CC=CN=1)C.[CH:61]1([N:67]=[C:68]=[N:69][CH:70]2[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]2)[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C=O>[C:68]([NH:67][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1)([NH:69][CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1)=[O:5]
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of aztreonam (2.29 g, 5.27 mmol) in 35 ml dimethylformamide were added tributylamine (0.97 g, 5.27 mmol), hydroxybenzotriazole (0.78 g, 5.79 mmol), dimethylaminopyridine (0.064 g, 0.53 mmol) and dicyclohexylcarbodiimide (1.19 g, 5.79 mmol). After stirring for 30 minutes, the resulting dicyclohexylurea (0.47 g, 40.1%) was filtered off and solution (a) was added to the filtrate. After stirring overnight at room temperature, the mixture was filtered (yielding 0.53 g, 45% of dicyclohexylurea) and evaporated. The residue was taken up in acetone, filtered, and 9.0 ml of 10% potassium perfluorobutane sulfonic acid in acetone were added. The resulting precipitate was filtered off (1.70 g), dissolved in water and chromatographed on XAD under MPLC conditions with a water - acetonitrile gradient. The sample-containing fractions were collected and freeze-dried to give 250 mg (6.9%) of Example 3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[NH:8][CH2:7][CH2:6][CH2:5]3)[CH:13]=1
Reactant: Brc1cnc2c(c1)CCCN2
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine (243 mg, 1.1 mmol), 3-pyridinyl-boronic acid (168 mg, 1.4 mmol) and K2CO3 (315 mg, 2.3 mmol) are mixed in 3.0 mL of 1,4-dioxane and 0.30 mL of water. Argon gas is bubbled through the mixture for 10 min and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (81 mg, 0.11 mmol) is added. The mixture is heated at 100° C. for 16 hrs. Then solvents are removed and EtOAc (50 mL) is added along with 30 mL of water. The mixture is filtered to remove any solid and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×25 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 143 mg of 6-Pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(N(C(C)C)CC)(C)C>C(#N)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)I>[F:8][C:6]1[CH:7]=[C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=[C:4]([F:11])[C:5]=1[O:9][CH3:10]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(F)cc(C#C[Si](C)(C)C)cc1F
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 2 g 5-bromo-1,3-difluoro-2-methoxy-benzene, 1.76 g ethynyl-trimethyl-silane, 629 mg bis(triphenylphosphine)palladium(II) dichloride, 3.1 ml diisopropylethylamine, and 85 mg copper iodide in 20 ml acetonitrile was degassed then heated at 80° C. for 2 hours. The mixture was diluted with dichloromethane and filtered through a plug of silica, washed with dilute ammonia and brine then dried over sodium sulphate, filtered and concentrated in vacuo. Purification over silica afforded 1.71 g (3,5-difluoro-4-methoxy-phenylethynyl)-trimethyl-silane.
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:20]=[C:21]1[NH:25][C:24](=[O:26])[NH:23][C:22]1=O)([O-])=O>CO.CN(C)C=O>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]3[N:6]=[C:22]4[NH:23][C:24](=[O:26])[NH:25][C:21]4=[CH:20][C:10]=3[CH:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)C(=Cc2cc(N3CCCC3)ccc2[N+](=O)[O-])N1
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc3cc(N4CCCC4)ccc3nc2[nH]1

Procedure:
This compound, m.p. >300° C. (obtained as a dimethylformamide solvate by crystallization from methanol-dimethylformamide), was prepared analogous to Example 4 from 5-[[2-nitro-5-(1-pyrrolidinyl)phenyl]methylene]-2,4-imidazolidinedione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH:9]([NH:24]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:24][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:32]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]carbamate (2.188 g, 4.762 mmol) and trifluoroacetic acid (10 ml) were stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure, diluted with water, alkalified with potassium carbonate, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and passed through APS-silica gel. The solvent was evaporated under reduced pressure to give the objective substance.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[C:20]1([Mg]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)(=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (8.0 g, 29.4 mmol) in THF (25 mL) was added PhMgCl (8.0 g, 58.8 mmol) dropwise at 0° C. After stirring at rt for 2 h, the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to afford tert-butyl 4-benzoylpiperidine-1-carboxylate (5 g, 59% yield) as a pale yellow solid which was used directly in the next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:27]=[C:15]2[N:16]=[C:17]([CH3:26])[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:19]([Cl:20])[N:14]2[N:13]=1.C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Br:11][C:12]1[CH:27]=[C:15]2[N:16]=[C:17]([CH3:26])[C:18]([CH:21]([OH:36])[C:22]([O:24][CH3:25])=[O:23])=[C:19]([Cl:20])[N:14]2[N:13]=1
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(Br)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 2.83 mL, 1.413 mmol) in THF (6 mL) at −78° C. was added a solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (300 mg, 0.942 mmol) in THF (6 mL) dropwise over 20 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (369 mg, 1.413 mmol) in THF (6 mL) was added over 15 min and the reaction mixture was stirred for additional 60 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (4 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (85 mg, 27%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.63 (3H, s), 3.84 (3H, s), 5.74 (1H, s), 6.71 (1H, s).
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11](=[O:27])[CH:12]([NH:14][C:15](=[O:26])[CH:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[OH:17])[CH3:13])=[CH:8][C:7]([C:28]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O>[F:25][C:20]1[CH:19]=[C:18]([CH:16]([OH:17])[C:15]([NH:14][CH:12]([CH3:13])[C:11]([NH:10][C:9]2[NH:5][N:6]=[C:7]([C:28]3([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:8]=2)=[O:27])=[O:26])[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: CC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)n[nH]1
Temperature: 25 °C

Procedure:
A solution of 0.04 g (0.1 mmol) of N-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-yl]-2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]propionamide in 2.0 mL of neat trifluoroacetic acid was refluxed for 15 min. The reaction mixture was then cooled to rt, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. Purification on silica gel afforded 2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-N-[5-(1-methyl-4 phenylpiperidin-4-yl)-2H-pyrazol-3-yl]propionamide.
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][O:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23](=[S:26])[NH:24][NH2:25]>C(O)C>[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]1[S:26][C:2]([CH2:3][CH2:4][O:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)NOCCC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Product: CC(C)(C)OC(=O)NOCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A mixture of tert-butyl 3-oxo-3-phenylpropoxycarbamate (1.09 g, 4.10 mmol) and 2,5-difluorobenzothiohydrazide (0.515 g, 2.74 mmol) in ethanol (3 mL) were stirred together at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product as a white solid (0.94 g, 79% yield).
Reaction SMILES: CI.[CH3:3][NH:4][C:5]([C:7]1[NH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6].[C:23]([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[CH3:3][NH:4][C:5]([C:7]1[N:15]([CH3:23])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: c1ccncc1
Product: CNC(=O)c1c(Sc2ccccc2)c2ncccc2n1C
Yield: 20.3 %

Procedure:
Add methyl iodide (20 mg, 0.164 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid methylamide (Ia-33, 47 mg, 0.166 mmol), Cs2CO3 (65 mg, 0.2 mmol) and pyridine (1.5 ml). Heat the reaction at 60° C. in a sealed vessel for 3 hrs. Add additional methyl iodide (20 mg) and monitor the progress on the reaction by chromatography. When complete, cool the mixture, concentrate to dryness and extract into ethyl acetate from brine. Separate the organic phase and concentrate. Purify the residue by flash chromatography twice (SiO2, 3 gm, elute with MeOH 0-4% in DCM; and SiO2, 1 gm, elute with heptane:DCM, 1:1) to provide title compound (10 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=297) were consistent for the title compound structure.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][CH2:14][O:15][C:16]([CH2:18][SH:19])=[O:17].CCN(CC)CC>CS(C)=O>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=2[S:19][C:18]=1[C:16]([O:15][CH2:14][CH3:13])=[O:17]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1sc2ccc([N+](=O)[O-])cc2c1N
Yield: 100.5 %

Procedure:
2-Fluoro-5-nitrobenzonitrile (1.664 g, 10 mmol), ethyl thioglycollate (1.21 g, 10 mmol) and NEt3 (3.06 g, 30 mmol) are stirred in DMSO (5 mL) at 100° C. under N2 for h h. The deep orange-red reaction mixture is poured onto ice-water (50 mL), and the solid is collected by suction filtration, rinsed with water, and dried in a vacuum oven at 60° C. to give ethyl 3-amino-5-nitrobenzothiophene-2-carboxylate (2.675 g, 100%) as a bright orange solid. 1H NMR (DMSO) δ9.23 (1H, d, J=2.1 Hz), 8.28 (1H, dd, J=2.3, 8.9 Hz), 8.10 (1H, d, J=9.0 Hz), 7.45 (2H, brs), 4.29 (2H, q, J=7.1 Hz), 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][C@@H:32]([CH3:35])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@@H](C)CO)nc2c1ccc(=O)n2-c1ccccc1F
Temperature: 23 °C
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and (S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 23° C. for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-20% EtOAc/CH2Cl2 gave the title compound as an off-white amorphous solid. mp 114-120°, LC MS m/z=423 (MH+) Retention time=2.0 min.