Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(OCc2ccccc2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(O)ccn1
Yield: 99.9 %

Procedure:
A solution of 4-(benzyloxy)-2-methoxypyridine produced in Example (16a) (4.65 g, 21.6 mmol) and 10% palladium carbon (2.30 g, 2.16 mmol) in ethanol (100 mL) was stirred in a hydrogen atmosphere at room temperature for 30 minutes. The insoluble matter was separated by filtration and then the filtrate was concentrated to obtain the title compound (2.70 g, 99%) as a colorless oil.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:48]=[C:47]([CH3:49])[C:42]4[NH:43][C:44](=[O:46])[O:45][C:41]=4[CH:40]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([O:36]C)=[O:35])[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:50]=[CH:51][CH:52]=[CH:53][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:38][C:39]3[CH:48]=[C:47]([CH3:49])[C:42]4[NH:43][C:44](=[O:46])[O:45][C:41]=4[CH:40]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[C:34]([OH:36])=[O:35])[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:50]=[CH:51][CH:52]=[CH:53][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(C)c3[nH]c(=O)oc3c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of 17 mg (0.71 mmol) LiOH in 3 mL water was added to a solution of 200 mg (0.29 mmol) (R)-2-[4-((S)-2-methoxycarbonyl-pyrrolidin-1-yl)-piperidin-1-yl]-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 9 mL THF and the reaction mixture was stirred for 66 h at RT. The solvents were eliminated in a nitrogen current and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)n1
Reactant: C1CCNC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(COc2cccc(N3CCCC3)n2)cc1
Yield: 95.3 %

Procedure:
In a dried microwave reactor, 526 mg (2.0 mmol) of 2-(benzyloxy)-6-bromopyridine and 1.70 ml (20 mmol) of pyrrolidine were placed, and the mixture was reacted using microwave at 150° C. for 10 min. The reaction mixture was mixed with 20 ml of water, extracted twice with 100 ml portions of ethyl acetate, and the organic layer was separated dried over anhydrous and kept under a reduced pressure to remove the solvent. The residue thus obtained was subjected to column chromatography using 10% ethyl acetate/hexane as an eluent to obtain 485 mg (yield 95%) of 2-(benzyloxy)-6-(pyrrolidin-1-yl)pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[C:7]1[CH:12]=[C:11]([C:13]2[C:17](C)=[CH:16]S[CH:14]=2)[CH:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]=2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C1C=C(OCCCCCCC2C=CC=C(OCCCC(OCC)=O)C=2CCC(OCC)=O)C=C(Br)C=1)(C)(C)C.[O:92]1[C:97]2C=CC(B(O)O)=C[C:96]=2[O:95][CH2:94][CH2:93]1>>[C:1]([O:5][C:6](=[O:48])[C:7]1[CH:8]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]=2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:94][C:93]3[O:92][CH2:97][CH2:96][O:95][C:16]=3[CH:17]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC

Procedure:
The title compound was prepared by the same method as 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid tert-butyl ester starting from 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester and 1,4-benzodioxane-6-boronic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]=[N+]=[N-])[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(OCC)(=O)C.[Pd]>[C:36]([NH:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:17])[N:8]([C:6]2[CH:5]=[CH:4][C:3]([N:18]3[CH2:22][CH:21]4[CH2:23][C:24]5([CH2:29][CH:20]4[CH2:19]3)[O:28][CH2:27][CH2:26][O:25]5)=[C:2]([F:1])[CH:7]=2)[CH2:12]1)(=[O:38])[CH3:37]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 5 h
Yield: 51 %

Procedure:
10 g (24.8 mmol) of 2-[2-fluoro-4-[(5R)-5-(azidomethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 9 was dissolved in 100 ml of ethyl acetate, and 1 g of 10% palladium/active carbon, 4.01 ml (45.6 mmol) of pyridine and 3.5 ml (37.2 mmol) of acetic anhydride were added, and then, the mixture was stirred for 5 hours under hydrogen gas balloon. After the reaction was completed, the reaction mixture was filtered to remove solid and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 5.30 g (51%) of the title compound, of which NMR data is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[F:21][C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24](I)([F:29])[C:25]([F:28])([F:27])[F:26]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.COC(C)(C)C>[F:26][C:25]([F:27])([F:28])[C:24]([F:29])([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:23]([F:31])([F:32])[C:22]([F:34])([F:33])[F:21]
Reactant: Nc1ccccc1
Reactant: FC(F)(F)C(F)(F)C(F)(I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: COC(C)(C)C
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.8 %

Procedure:
4.90 g (52.6 mmol) of aniline, 10.1 g (58.0 mmol) of 85% sodium hydrosulfite, and 1.90 g (5.77 mmol) of tetrabutylammonium hydrogen sulfate were charged to a mixed solution of 150 ml of t-butyl methyl ether and 150 ml of water using a light-shielded reaction vessel, and 4.84 g (57.6 mmol) of sodium hydrogen carbonate was added thereto. 20.0 g (57.8 mmol) of nonafluoro-s-butyliodide was added dropwise thereto at room temperature, followed by stirring at room temperature for 5 hours. The organic phase was collected by separation, washed with 2 mol/L of an aqueous hydrochloric acid solution twice, and then washed with saturated brine, an aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to prepare 8.32 g (yield 51%) of a target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([OH:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH:40]1[CH2:42][CH2:41]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:30][CH2:39][CH:40]3[CH2:42][CH2:41]3)=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:10][CH:11]=1
Reactant: BrCC1CC1
Reactant: COC(=O)CCc1ccc(Cn2c(-c3cccnc3O)nc3cc(F)c(F)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Yield: 67 %

Procedure:
To a stirred solution of 3-{4-[5,6-difluoro-2-(2-hydroxy-pyridin-3-yl)-benzoimidazol-1-ylmethyl]-phenyl}-propionic acid methyl ester (72 mg, 0.17 mmol) in acetone (10 ml) was added cesium carbonate (85 mg, 0.26 mmol) followed by bromomethyl-cyclopropane (26 mg, 0.19 mmol; CAS Reg. No. 7051-34-5) and the reaction was refluxed for 2 h. The reaction mixture was filtered and the filtrate removed under reduced pressure. The residue was purified by column chromatography using silica gel (50-60% ethyl acetate/n-hexane) to afford the desired product as a brown solid (67%). MS (Turbo Spray): m/z=478.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:3]=1.[Cl-].[CH:29](/B(O)O)=[CH:30]\[CH3:31].C([O-])([O-])=O.[K+].[K+]>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].C1COCC1>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][CH2:19][NH:18][C:4]1[N:3]=[C:2](/[CH:29]=[CH:30]/[CH3:31])[CH:17]=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: C/C=C/B(O)O
Reactant: O=C(NCc1cccnc1)c1ccc(Cl)nc1NCCc1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C/C=C/c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A mixture of chloride 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (100 mg, 0.260 mmol), trans-1-propen-1-yl boronic acid (27 mg, 0.312 mmol), PdCl2(dppf)2 (14 mg, 0.026 mmol), 2N K2CO3(0.39 mL, 0.78 mmol) and THF (1.5 mL) was stirred at 125° C. for 30 min. The mixture was filtered through the silica gel pad and washed with EtOAc. The filtrate was concentrated to dryness and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (E)-2-(3-fluorophenethylamino)-6-(prop-1-enyl)-N-(pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (59 mg, 86%). LRMS (M+H+) m/z 391.2.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][OH:22])[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:24]1[CH:56]=[CH:55][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]2=[O:54])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][O:22][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][CH:29]4[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]4=[O:54])=[CH:26][CH:25]=3)[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=NOCCO)c1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 88.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 1.006 g of 2-[1-(4-phenylsulfonylphenyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 35), 1.40 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 866 mg of triphenylphosphine and 549 mg of diethyl azodicarboxylate, 2.05 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([C:4]2[CH:3]=[CH:2][C:1]([N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)=[N:35][CH:36]=1
Reactant: Brc1ccc(I)nc1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)nc1
Temperature: 95 °C
Yield: 87 %

Procedure:
A mixture of N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)naphthalen-1-amine (Compound 29) (2.32 g, 5.51 mmol), 2-iodo-5-bromo-pyridine (3.13 g, 11 mmol), Pd(PPh3)4 (0.346 g, 0.3 mmol) and K2CO3 (1.38 g, 10 mmol) in dioxane/water (60 mL/10 mL) was degassed and heated at about 95° C. overnight. The resulting mixture was mixed with ethyl acetate/brine, dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 3:1). The desired fraction was collected and a light yellow solid (Compound 30) was obtained after removal of solvents (2.17 g, in 87% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[OH:13][C:14]([C:17]1[CH:18]=[C:19]([CH:23]=O)[CH:20]=[N:21][CH:22]=1)([CH3:16])[CH3:15].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:23]2[C:19]2[CH:18]=[C:17]([C:14]([OH:13])([CH3:15])[CH3:16])[CH:22]=[N:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)cc1NC1CC1
Reactant: CC(C)(O)c1cncc(C=O)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1cncc(-c2nc3ccc(F)cc3n2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.479 g, 2.88 mmol) in DMF (6.97 mL) and water (0.23 mL) were added the title compound from Step C (0.302 g, 1.83 mmol) and OXONE® (0.729 g, 1.19 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (100% ethyl acetate) provided a product that was further purified by reverse phase HPLC(C18 OBD column, 20 to 90% acetonitrile/water, both 0.1% v/v trifluoroacetitic acid). Fractions containing the desired product were combined, washed sequentially with aqueous 1 N sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound: LCMS m/z 312.01 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.7 Hz, 1 H), 9.85 (d, J=1.9 Hz, 1 H), 8.40 (s, 1 H), 7.73 (dd, J=8.8, 4.8 Hz, 1 H), 7.29 (dd, J=8.7, 2.2 Hz, 1 H), 7.08-7.04 (m, 1 H), 3.57-3.55 (m, 1 H), 2.21 (br s, 1 H), 1.69 (s, 6 H), 1.20-1.16 (m, 2 H), 0.79-0.75 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.CN1CCOCC1.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.00 g, 22.8 mmol) in methylene chloride (100 mL) and 4-methylmorpholine (16 mL) at 0° C. was added methanesulfonyl chloride (2.1 mL, 28 mmol). The mixture was stirred at room temperature for 2 hr, and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to provide N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide as a white solid (6.32 g, 93% yield). MS m/z 298 (M+1).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:15]2[O:17][CH2:18][CH2:19][F:20])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([C:14]2[C@@H:15]([O:17][CH2:18][CH2:19][F:20])[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(2-fluoroethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (30 mg, 0.0664 mmol) in THF (4 mL) at 0° C. was added TBAF (0.13 mL, 0.132 mmol, 1M Solution in THF) and stirred for 1 h at room temperature. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Crude product was purified by preparative TLC method using 2% methanol in DCM as eluent.
Reaction SMILES: C([N:5]1[C:9]([NH:10]C(=O)C(F)(F)F)=[C:8]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34](CC3C=CC(OC)=CC=3OC)[C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:33])=[O:32])=[CH:27][C:26]=2[C:51]#[N:52])[CH:7]=[N:6]1)(C)(C)C.Cl>CO>[NH2:10][C:9]1[NH:5][N:6]=[CH:7][C:8]=1[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[S:39][N:38]=[CH:37][N:36]=2)(=[O:32])=[O:33])=[CH:27][C:26]=1[C:51]#[N:52]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3cnn(C(C)(C)C)c3NC(=O)C(F)(F)F)c(C#N)c2)c(OC)c1
Agent: Cl
Solvent: CO
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1N
Temperature: 60 °C
Yield: 59 %

Procedure:
To a solution of the N-{1-tert-butyl-4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)phenyl]-1H-pyrazol-5-yl}-2,2,2-trifluoroacetamide (Preparation 419, 157 mg, 0.20 mmol) in methanol (15 ml) was added hydrogen chloride (4 M in 1,4-dioxane, 3 ml). The resulting yellow solution was stirred and heated at 60° C. for 48 hours. The solvent removed in vacuo to afford a pale yellow residue. The material was purified by column chromatography (80 g silica gel column) eluting with methanol:dichloromethane (5:95, by volume) to afford the title compound as a yellow oily solid, 56 mg, 59% yield.
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=2)[O:3][CH2:2]1.[Mg].II.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[CH2:21]C1C=C(C)C=CC=1S([O-])(=O)=O.[Cl-].[NH4+]>O1CCCC1.C1C=CC=CC=1.[Cu+]>[CH2:1]1[O:12][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:21][C:20]3[CH:33]=[CH:34][CH:35]=[C:18]([O:17][CH3:16])[CH:19]=3)=[CH:7][CH:6]=2)[O:3][CH2:2]1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: COc1cccc(Cc2cc(C)ccc2S(=O)(=O)[O-])c1
Agent: [Cu+]
Agent: II
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(Cc2ccc(C3OCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.8 %

Procedure:
To a solution of 4-bromobenzaldehyde ethylene acetal (1.5 g, 6.5 millimol) in tetrahydrofuran (7 ml) were added magnesium (170 mg, 7 millimol) and a small amount of iodine, and the mixture was vigorously stirred under nitrogen atmosphere. After most of magnesium was dissolved, the solution was added to a solution of 3-met hoxybenzyltosylate (1.46 g, 5 millimol) and copper(I) bromidedimethylsulfide complex (50 mg, 0.25 millimol) in benzene (14 ml). The mixture was stirred at room temperature for 22 hours. Next, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure, The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (850 mg, 3.14 millimol, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:7]1[C:2]([Cl:1])=[N:3][C:4]([NH2:14])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(Br)c(-c2ccccc2)n1

Procedure:
To 1.5 g (7.3 mM) of 4-chloro-6-phenyl-2-pyrimidinamine is added 75 ml of glacial acetic acid. This mixture is stirred to dissolve and 0.44 ml of bromine is added. The reaction is stirred at ambient temperature for 24 hours. The solution is evaporated to dryness under vacuum to yield 1.75 g of 5-bromo-4-chloro-6-phenyl-2-pyrimidinamine.
Reaction SMILES: [C:1]([S@@:5]([N:7]=[C:8]([C:14]([CH3:18])([CH3:17])[CH2:15][F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C1COCC1>C1COCC1>[CH3:4][C:1]([CH3:2])([S@@:5]([NH:7][C@@H:8]([C:14]([CH3:18])([CH3:17])[CH2:15][F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3]
Reactant: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)C(C)(C)CF
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](N[S@@](=O)C(C)(C)C)C(C)(C)CF
Temperature: -78 °C
Reaction time: 4 h
Yield: 34.3 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butylsulfinylimino)-4-fluoro-3,3-dimethylbutanoate (1.1 g, 3.94 mmol) in THF (8 mL) was added L-Selectride/THF (5.12 mL, 5.12 mmol) via a syringe pump at 6 mL/h rate at −78° C. The reaction mixture was stirred at −78° C. for 4 h after the completion of addition. The reaction was quenched by addition of aq. NH4Cl at −78° C., diluted with EtOAc and washed with water, brine, dried (MgSO4), concentrated and purified on silica gel chromatography (EtOAc/hexane) to afford (S)-ethyl 2-((S)-1,1-dimethylethylsulfinamido)-4-fluoro-3,3-dimethylbutanoate (0.38 g). 1H NMR (400 MHz, MeOD-d4) δ ppm 4.20-4.44 (4H, m), 3.99 (1H, s), 1.35 (3H, t, J=7.15 Hz), 1.13 (6H, dd, J=15.81, 2.01 Hz).