Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[NH2:25][C:22]1[O:23][CH2:24][C@:18]2([N:21]=1)[C:19]1[CH:20]=[C:7]([C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[C:17]2=[CH:16][C:15]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])=[CH:14][C:13]=1[F:32]
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(N3CCCC3=O)cc12
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(N3CCCC3=O)cc12
Temperature: 90 °C

Procedure:
Resealable tube was charged with (S)-2-amino-4′-fluoro-2′-(2-oxopyrolidin-1-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol), pyridin-3-ylboronic acid (51.0 mg, 0.42 mmol). DMF (1.3 mL) and sodium carbonate (2M, 0.4 mL, 0.8 mmol) were added and the mixture was sealed and heated at 90° C. for 2 h. The mixture was partitioned between water (1 mL) and ethyl acetate (5 mL), organic layer was washed with water, concentrated and purified by FC on 12 g RediSep Gold column using 10-80% DCM/MeOH/NH4OH 90:10:1 in DCM. The fractions containing pure product by TLC were combined and concentrated to afford (S)-1-(2-amino-5′-fluoro-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)pyrolidin-2-one.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13](O)[CH3:14]>>[C:1]1([CH:7]([CH3:11])[C:8]([O:10][CH2:13][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)c1ccccc1
Reaction time: 60 h

Procedure:
Dissolve 2-phenylpropionic acid (30 g) in 2B ethanol (100 mL and add anhydrous HCl (10 g). Allow to sit for 48-72 hours, evaporate the solvent in vacuo and purify by distillation to give ethyl 2-phenylpropionate (31 g); bp 100 C. at 6 mmm.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12]>C1C=CC=CC=1>[CH2:1]([NH:8][CH2:10][C:11]([NH:13][C:14]([CH3:20])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(C)(C)NC(=O)CCl
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: CCCCCC(C)(C)NC(=O)CNCc1ccccc1

Procedure:
A solution of benzylamine (21.4 g, 0.2 mol) and 2-chloro-N-(1,1-dimethylhexyl)acetamide (20.6 g, 0.1 mol) in benzene (100 ml) was held at room temperature for five days then refluxed for 24 hours.The mixture was filtered and the filtrate was evaporated then distilled under reduced pressure to give 2-benzylamino-N-(1,1-dimethylhexyl)acetamide as a pale yellow oil, b.p. 153°-156° C. at 0.05 mm Hg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:46])[C@H:9]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([Cl:45])[CH:37]=3)=[CH:31][CH:30]=2)[NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:12])=[CH:3][CH:2]=1>[Cl-].O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:46])[C@H:9]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([Cl:45])[CH:37]=3)=[CH:31][CH:30]=2)[NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)N[C@@H](Cc2ccc(Oc3cc(Cl)ccc3[N+](=O)[O-])cc2)C(=O)Nc2ccncc2)CC1
Agent: [Cl-]
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](C(=O)N[C@@H](Cc2ccc(Oc3cc(Cl)ccc3[N+](=O)[O-])cc2)C(=O)Nc2ccncc2)CC1

Procedure:
To a solution of N-(t-butyloxycarbonyl)-4-hydroxy-L-phenylalanine 4-pyridylamide (5.35 g) in dimethyl sulfoxide (100 ml) was added oily sodium hydride (0.62 g), followed by stirring at room temperature for 30 minutes. Thereafter, 2,4-dichloronitrobenzene (2.88 g) was added and stirred at room temperature for 10 hours. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-(3-chloro-6-nitrophenoxy)-L-phenylalanine 4-pyridylamide dihydrochloride (6.66 g) was obtained. The above compound (I) (6.50 g) was allowed to react with 4N-hydrogen chloride/dioxane solution (50 ml) to obtain 4-(3-chloro-6-nitrophenoxy-L-phenylalanine 4-pyridylamide dihydrochloride, which was further allowed to react with trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid mixed acid anhydride obtained in Example 5 to obtain N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-(3-chloro-6-nitrophenoxy)-L-phenylalanine 4-pyridylamide (II) (7.16 g). The above compound (II) (7.00 g) was allowed to react with 4N-hydrogenn chloride/dioxane solution (150 ml) to obtain N-(trans-4-aminomethylcyclohexylcarbonyl)-4-(3-chloro-6-nitrophenoxy)-L-phenylalanine 4-pyridylamide (6.06 g).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18](C(OC(C)(C)C)=O)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:33])(=[O:4])=[O:3].[ClH:34].CO>CO>[ClH:34].[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:33])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: Cl
Solvent: CO
Product: COc1cc(-c2cc3ccccc3[nH]2)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 72 %

Procedure:
In a similar manner to Step 2 of Example 8, 4-methanesulfonyloxy-5-methoxy-7-(1-(tert-butoxycarbonyl)indol-2-yl)isoindolinone (54.5 mg, 0.115 mmol) was dissolved in methanol (1.5 mL), and the solution was treated with 10% hydrogen chloride-methanol solution (1.5 mL). The precipitated solid was collected by filtration and washed with methanol, followed by drying under reduced pressure to obtain Compound 381 (31.0 mg, yield 72%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)[C:21]=1[Cl:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:47][C:21]1[C:22]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][OH:18]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a suspension of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzene (17.6 g) in tetrahydrofuran (138 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (38.4 ml) at ambient temperature. The reaction mixture was stirred for 1 hour. The mixture was concentrated and diluted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo to give 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]-benzene (8.14 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22](=O)[CH2:21][C:20]3([CH3:29])[CH3:28])[N:8]=2)[CH2:3][CH2:2]1.C(OCC)(=O)C.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pt]>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=[C:9]([N:19]3[C:20]([CH3:29])([CH3:28])[CH2:21][CH:22]([NH:40][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][C:24]3([CH3:26])[CH3:25])[N:10]=2)[CH2:18][CH2:17]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CCCCN
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
12 g of 2,4-bis-morpholino-6-(4-oxo-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 21) are hydrogenated in 120 ml of methanol and 60 ml of ethyl acetate at 40° and a pressure of 80 bar with 5% platinum on charcoal as the catalyst in the presence of 6 g of butylamine and 0.25 g of p-toluenesulfonic acid until the reaction has ended. The reaction mixture is filtered and evaporated. After dissolving the residue in methylene chloride and washing with water, the organic phase is dried over Na2SO4 and evaporated. The residue is dissolved in toluene/acetone and purified chromatographically on an SiO2 column. The oily product crystallizes after a few days and melts at 82°-87°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol), benzaldehyde (312 mg, 2.94 mmol) and NaBH(OAc)3 (778 mg, 3.67 mmol) in AcOEt (15 ml) was stirred at room temperature overnight. The resulting solution was partitioned between water and DCM and the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) to give 390 mg of 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:20].CCCCCC.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:3]12[O:20][CH:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH2:2]2
Reactant: O=C(c1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
Into a solution of 10 (2.27 g, 12.1 mmol) in CH2Cl2 (20 mL), a solution of 3-chloroperoxybenzoic acid (5.43 g, 77% pure, 24.3 mmol) in CH2Cl2 (40 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 5 hrs. After the reaction was complete as determined by TLC (hexane/ethyl acetate, 1/1, v/v), saturated Na2CO3 solution (50 mL) was added into the reaction vial slowly with stirring. The reaction mixture was stirred for 30 min. The organic layer was washed with saturated Na2CO3 solution (50 mL×3), brine solution (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatograph using hexane/ethyl acetate (3/1, v/v) as the mobile phase to afford the product as a sticky oil (1.54 g, 62%). 1H NMR (CDCl3): δ 2.04-2.18 (m, 2H), 3.09-4.40 (m, 6H), 7.28-7.47 (m, 5H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH:37][CH2:38][C:39]6[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=6)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(NCc6cccnc6)c5)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (75 mg, 0.15 mMol) in dimethylformamide (2 mL) under nitrogen was added 3-(Aminomethyl) pyridine (0.078 mL, 0.77 mMol) and the resulting solution stirred overnight at room temperature. Upon arrival the reaction mixture was diluted with ethyl acetate (50 mL) and washed three times with water (50 mL) followed by brine (50 mL). The organics were dried with magnesium sulfate, filtered, and evaporated to dryness. Purification by flash column chromatography on silica gel and 5% methanol in dichloromethane as eluant yielded 50 mg of (5-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol -4-yl]-piperazin-1-ylmethyl}-2-nitro-phenyl)-pyridin-3-ylmethyl-amine as a yellow-orange solid (56% yield). 1H NMR (CDCl3): δ=9.24 (s, 1H), 8.66 (s, 1H), 8.55 (m, 1H), 8.43 (m, 1H), 8.16 (d, 1H, J=7.5 Hz), 8.03 (m, 1H), 7.93 (d, 2H, J=7.5 Hz), 7.69 (d, 1H, J=6.0 Hz), 7.49 (d, 2H, J=7.5 Hz), 7.14 (m, 1H), 7.04 (d, 1H, J=6.0 Hz), 6.87 (s, 1H), 6.73 (m, 1H), 6.59 (d, 1H, J=6.0 Hz), 4.60 (m, 2H), 3.55 (m, 6H), 2.68 (m, 4H), 1.34 (s, 9H). LC/MS (Method A), rt=1.05 mins., purity=98.5%, calculated mass=575, [M+H]+=576, [M−H]−=574.
Reaction SMILES: FC1C(NC2C=CC(I)=CC=2F)=C(C(N2CC(C(O)CC3OCCO3)(O)C2)=O)C=CC=1F.C(N(CC)CC)C.[CH:40]([C:43]1[CH:48]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[C:44]=1[S:55](Cl)(=[O:57])=[O:56])([CH3:42])[CH3:41].C([O:62][CH2:63][CH3:64])(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:42][CH:40]([C:43]1[CH:48]=[C:47]([CH:49]([CH3:50])[CH3:51])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[C:44]=1[S:55]([O:62][CH2:63][CH3:64])(=[O:56])=[O:57])[CH3:41]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(O)CC2OCCO2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 35 °C
Reaction time: 3.5 h
Yield: 14 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (38 mg, 0.31 mmol), triethylamine (0.036 mL, 0.262 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) at 35° C. for 15 h. 2,4,6-Triisopropylbenzenesulfonyl chloride (100 mg, 0.33 mmol) was added and the mixture was stirred at 35° C. for 3.5 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 40-50% ethyl acetate in hexanes and then 100% ethyl acetate) to give 1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (30 mg, 0.0361 mmol, 14% yield): MS (EI) for C36H42F3IN2O7S: 831 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[Cl:23].[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[O:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.CO>CN(C)C=O.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1.C(OCC)(=O)C>[Cl:23][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:2]=1[NH:1][C:34]([NH:33][C:31](=[O:32])[CH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:35])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1Cl
Reactant: O=C=NC(=O)Cc1ccccc1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Pyrrolidine-1-carboxylic acid [4-(4-amino-3-chlorophenoxy)pyridin-2-yl]amide (20 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and then a solution of phenylacetyl isocyanate in hexane (0.019 ml, Production Example 1) was added thereto, followed by stirring at room temperature for 1 hr. To the reaction mixture was added ethyl acetate and water to partition. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then suspended in ethyl acetate:methanol=1:1. The solid was filtered off, washed with methanol, and dried under aeration to provide the titled compound (10 mg, 34%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23].[OH-].[Na+].Cl.C(Cl)Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC)cc3F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)c(F)c1
Temperature: 75 °C
Yield: 27.1 %

Procedure:
A mixture of methyl 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylate (50 mg, 0.15 mmol) in methanol (1.5 mL) and aqueous 1M sodium hydroxide (1M, 0.50 mmol, 0.50 mL) was heated at 75° C. for 24 hours. The reaction was then acidified with 1M HCl to pH=2 and diluted with ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a crude solid. A small amount of methylene chloride was added and the crude material slurried for 5 minutes. The solid was then filtered and washed with ethyl acetate to provide the title compound (13 mg, 27% yield).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 35 °C

Procedure:
9.6 ml (75 mmol) of benzenesulphonic acid chloride are placed in 100 ml pyridine and 7.9 ml (75 mmol) of tert.butylamine are added dropwise at 5° C., whereupon the temperature increases to 35° C. After the addition has ended the mixture is stirred for another hour at 35° C. Then it is poured onto ice water and the crystalline precipitate is suction filtered.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C>CC(C)=O.C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([O:40][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: CCCC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 65 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A mixture of chloromethyl butyrate (16.2 μL, 129 μmol) and NaI (19.4 mg, 129 μmol) in acetone (0.7 mL, 10 mmol) was heated at 65° C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 mL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (6.5 mg, purity 100%). MS m/z [M+H]+ calc'd for C26H27ClFN3O8, 564.15. found. 564.
Reaction SMILES: COC1C=CC(C2(C3C=CC(OC)=CC=3)O[C:13]3[C:15]4[C:20]([C:21](C5C=CC=CC=5)=[C:22]([C:23](OCCO)=[O:24])[C:12]=3C=C2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=CC=1.C(N([CH2:48][CH3:49])CC)C>C(OCC)C>[CH:12]1[C:13]2[C:15]3[C:20]([CH:21]=[CH:48][C:49]=2[O:24][CH2:23][CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: COc1ccc(C2(c3ccc(OC)cc3)C=Cc3c(C(=O)OCCO)c(-c4ccccc4)c4ccccc4c3O2)cc1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: C1=Cc2c(ccc3ccccc23)OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(2-hydroxyethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 6,113,814) (0.20 g, 0.34 mmol) was dissolved in anhydrous diethyl ether (20 ml) under nitrogen. To this solution was added triethylamine (0.2 ml) followed by the Acid Chloride Terminated Polydimethylsiloxane (Example 1, Step 2) (0.264 g), dropwise. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the crude product then purified by column chromatography (silica gel, diethyl ether/hexane, 5:1) giving the bulk product, Naphthopyran Terminated Polydimethylsiloxane, as a pink tar. Analysis by 1H NMR gave a spectrum consistent with the structure, having an average molecular weight (Mn) of 2,592 (nPDMS=14.1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42](Cl)[O:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>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:34][C:27]1[CH:26]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42]([C:6]3[CH:7]=[C:8]([CH:10]4[CH2:11][CH2:12]4)[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[O:43][CH:44]=2)=[O:39])[CH3:36])[CH:24]=[C:23]([F:22])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C3CC3)c2)OC1(C)C
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cc(C3CC3)cc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 3.8 %

Procedure:
2-(3,5-Dicyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (74 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (5 mg, 4%) after purification by flash chromatography on silica gel (% EtOAc in hexane=30%˜70%).