Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:23])=[CH:6][C:7]([F:22])=[C:8]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12][C:11]2=[O:21])[CH:9]=1)([OH:3])=O.S(Cl)([Cl:26])=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:26][C:1]([C:4]1[C:5]([Cl:23])=[CH:6][C:7]([F:22])=[C:8]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:18])([F:20])[F:19])[CH2:12][C:11]2=[O:21])[CH:9]=1)=[O:3]
Reactant: O=C(O)c1cc(N2C(=O)CC(C(F)(F)F)CC2=O)c(F)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(N2C(=O)CC(C(F)(F)F)CC2=O)c(F)cc1Cl
Temperature: 90 °C

Procedure:
To a mixture of N-(5'-carboxy-4'-chloro-2'-fluorophenyl)-3-(trifluoromethyl)glutarimide (Compound 62) (3.0 g, 8.5 mmol) and 35 ml toluene was added thionyl chloride (0.80 ml, 1.3 g, 1.1 mmol) followed by 2 drops of N,N-dimethylformamide and the suspension was heated to 90° C. for two hours. The resulting clear, orange solution was cooled to room temperature and the solvents were removed in vacuo (1 mm Hg). The resulting N-(5'-chlorocarbonyl-4'-chloro-2'-fluorophenyl)-3-(trifluoromethyl)glutarimide, a dark semisolid, could be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.C(OO)(=O)C>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)OO
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 35 °C
Reaction time: 8 h

Procedure:
144.5 G. of 2,4-diamino-6-chloropyrimidine are suspended in 2000 ml. of ethanol. While stirring, the suspension is warmed to 35° C. (about 15 minutes), the greater part of the substance passing into solution. The mixture is then cooled to 6°-8° C. and, at this temperature, there are added dropwise within the course of 40 minutes 175 ml. of 40% peracetic acid in glacial acetic. After completion of the addition, the mixture is stirred at 6°-8° C. for a further 30 minutes. The mixture is then left to warm up to room temperature and stirred at this temperature for 3 hours. 2000 Ml. of petroleum ether are then added, the mixture is left to stir for 1 hour and then left to stand overnight. The separated precipitate is filtered off, back-washed with 200 ml. of petroleum ether and dried under reduced pressure, there being obtained 2,4-diamino-6-chloropyrimidine-3-oxide. Recrystallization yields analytically pure product, having a melting point of 193° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=N[CH:6]=[C:7]([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.[CH:27]1C2NC3C(=CC=CC=3)C=2C=CC=1.[H-].[Na+].Br.NC1N=C(N)C2N=C(CBr)C=CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[N:8]=[C:7]([CH2:13][N:14]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:16]4[C:15]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:6]=[CH:27][C:4]=2[N:3]=1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: Br
Agent: Nc1nc(N)c2nc(CBr)ccc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(Cn3c4ccccc4c4ccccc43)ccc2n1

Procedure:
N-[(2,4-Diaminopyrido[3,2-d]pyrimidin-6-yl)methyl]carbazole (Formula I: Ar=2,4-diaminopyrido[2,3-d]pyrimidin-6-yl; W=CH2; X=N; Z=chemical bond; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using carbazole (129 mg, 0.77 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[3,2-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [Sm].ICCI.CN(C)P(N(C)C)(N(C)C)=O.[CH3:17][C:18]([Si:21]([CH3:46])([CH3:45])[O:22][C@@H:23]1[CH2:39][C:38]2[C@@:26]([CH3:44])([C@@H:27]3[C@@H:35]([CH2:36][CH:37]=2)[C@H:34]2[C@@:30]([CH3:43])([C@@H:31]([C:40](=[O:42])[CH3:41])[CH2:32][CH2:33]2)[CH2:29][CH2:28]3)[CH2:25][CH2:24]1)([CH3:20])[CH3:19].Br[CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53]>O1CCCC1>[CH3:20][C:18]([Si:21]([CH3:46])([CH3:45])[O:22][C@@H:23]1[CH2:39][C:38]2[C@@:26]([CH3:44])([C@@H:27]3[C@@H:35]([CH2:36][CH:37]=2)[C@H:34]2[C@@:30]([CH3:43])([C@@H:31]([C@@:40]([OH:42])([CH2:48][CH2:49][CH2:50][CH2:51][CH:52]([CH3:54])[CH3:53])[CH3:41])[CH2:32][CH2:33]2)[CH2:29][CH2:28]3)[CH2:25][CH2:24]1)([CH3:17])[CH3:19]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)CCCCBr
Agent: ICCI
Agent: [Sm]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)CCCC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a stirred suspension of samarium metal (758 mg, 5.0 mmol) and 3 Å molecular sieves (0.5 g) in anhydrous tetrahydrofuran (THF, 9.5 mL) was slowly added a solution of 1,2-diiodoethane (1.3 g, 4.6 mmol) in THF (9.5 mL) at ambient temperature. After the reaction stirred for 30 min, hexamethylphosphoramide (HPMA, 3.0 mL, 17.2 mmol) was added to the reaction mixture and continued stirring for an additional 20 min. Then, a solution of ketone 1 (500.0 mg, 1.16 mmol) in THF (6.0 mL) was added followed by a solution of 1-bromo-5-methylhexane (208.0 mg, 1.16 mmol) in THF (2.0 mL). The reaction was allowed to stir for an additional hour until the starting material was completely consumed. After this, the reaction mixture was slowly treated with saturated NaHCO3, filtered through Celite and rinsed three times with an excess amount of diethyl ether. The filtrate was treated with water and extracted with diethyl ether. The ether extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo to give a residue which was purified via silica gel chromatography. Elution with hexane-diethyl ether (4:1, v/v) afforded compound 2 (350.0 mg, 0.6 mmol, 57%) as a white powder (Honda et al. (1996) J. Chem. Soc., Perkin Trans. 1, 2291-2296).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OC1CCNCC1Cc1ccccc1

Procedure:
A mixture of 1,3-dibenzyl-4-hydroxypiperidine (1.7 g, 6.0 mmole) and 20% palladium hydroxide (0.3 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 12 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-benzylpiperidine as oil. Yield 1.0 g (91%), C12H17NO, m/z 192 (M+1) PMR (CDCl3): 1.66 (1H, m, H3), 1.94 (1H, m, H5), 2.26 (2H, m, H5, & OH, D2O exchangeable), 2.62 (1H, m, H2), 2.74 (1H, m, H6), 3.02 (1H, m, H2), 3.34 (1H, m, H6), 3.52 (1H, bs, NH, D2O exchangeable), 3.9 (1H, m, H4), 4.74 (2H, m, CH2-Ar), 7.28 (5H, m, ArH).
Reaction SMILES: OS(O)(=O)=O.C(OC([N:13]1[C@H:17]([C:18](=[O:30])[NH:19][C@:20]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][C@H:21]2[CH:23]=[CH2:24])[CH2:16][C@@H:15]([O:31][C:32]([N:34]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[F:43])[CH2:35]2)=[O:33])[CH2:14]1)=O)(C)(C)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([C@@:20]1([NH:19][C:18]([C@H:17]2[NH:13][CH2:14][C@H:15]([O:31][C:32]([N:34]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][C:40]=4[F:43])[CH2:35]3)=[O:33])[CH2:16]2)=[O:30])[CH2:22][C@H:21]1[CH:23]=[CH2:24])=[O:26])[CH3:29]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1)C(=O)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
A solution of 64.4 g (630 mmol) of H2SO4 in 120 mL of EtOAc was added to a suspension of 1.7 L of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester (theoretical amount: 600 mmol; as obtained from example 8) in EtOAc at 50-60° C. The dropping funnel was rinsed with 80 mL of EtOAc and the reaction mixture was stirred for 3 h at 60° C. To the reaction mixture 800 mL of an aqueous solution of Na2CO3 (10 wt %) was added. The phases were separated and the organic layer was washed with 400 mL of water. The organic layer was concentrated at a jacket temperature of 105° C. to a residual volume of 450 mL. To the residue 1000 mL of toluene was added. To initiate crystallization the temperature was decreased to 60° C. and maintained for 30 min at this value. The suspension is cooled to −2° C. and stirred for 1 h at this temperature. The crystals were collected on a suction filter and washed three times with a total of 400 mL of toluene. After drying at 53° C. under reduced pressure there was obtained 198.2 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as colorless crystals in a purity of 98.0 wt % and a yield of 75% over 4 steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[N-:13]=[N+]=[N-].[Na+].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH2:6][NH:13][C:5](=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1NCCOc2ccc(F)cc21
Reaction time: 30 h

Procedure:
6-Fluoro-chroman-4-one (539 mg, 3.24 mmol) was dissolved in Sulfuric acid (6.0 mL) and Sodium azide (258 mg, 3.97 mmol) was added at room temperature. The reaction was stirred for 30 h, then poured into water. The solids were collected by filtration, washing with 50 mL water. After drying, 7-Fluoro-3,4-dihydro-2H-b enzo[f][1,4]oxazepin-5-one was isolated as a white solid (395 mg, 67%). 1H-NMR (CDCl3): 7.65 (m, 1H), 7.15 (m, 1H), 7.01 (m, 1H), 6.74 (s, 1H),
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)=[CH:35][CH:34]=1>>[N:39]1([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][N:18]3[C:14]4=[N:15][C:16]([CH3:17])=[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([OH:9])=[O:8])[C:12]([C:21]5[CH:22]=[C:23]6[C:28](=[CH:29][CH:30]=5)[O:27][CH2:26][CH2:25][CH2:24]6)=[C:13]4[CH:20]=[CH:19]3)=[CH:34][CH:35]=2)[CH:43]=[N:42][CH:41]=[N:40]1
Reactant: BrCc1ccc(-n2cncn2)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccc(-n3cncn3)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.61 (br. s., 1 H), 8.13 (br. s., 1 H), 7.67 (d, J=8.4 Hz, 2 H), 7.52-7.39 (m, 3 H), 7.24-7.17 (m, 1 H), 7.12 (t, J=3.1 Hz, 1 H), 6.95 (dd, J=4.7, 8.4 Hz, 1 H), 6.37 (dd, J=3.5, 11.3 Hz, 1 H), 5.80-5.70 (m, 1 H), 5.64-5.52 (m, 2 H), 4.30 (t, J=4.2 Hz, 2 H), 2.96-2.77 (m, 5 H), 2.16-2.05 (m, 2 H), 1.05-0.91 (s, 9 H); LC/MS (m/z) ES+=552.39 (M+1).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17](C)[C:16]2=[O:25])[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[NH:9]1[CH2:10][CH2:11][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:25])[CH2:13][CH2:14]1
Reactant: Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccccc2n1C1CCNCC1
Reaction time: 1 h

Procedure:
A stream of hydrogen chloride gas was dispersed through a stirred, ice cold solution of 0.383 g of 1,3-dihydro-1-(1-tert-butyloxycarbonylpiperidin-4-yl)-3-methyl-2H-benzimidazol-2-one in 500 mL of ethyl acetate for 30 min. Stirring was continued at 0° C. for 1 h, then at ambient temperature for 1 h. The suspension was partitioned between 250 mL of chloroform and 50 mL of saturated Na2CO3. Drying under reduced pressure gave 0.296 of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][CH:52]=[C:53]([CH:56]=2)[C:54]#[N:55])O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:49]4[CH:50]=[N:51][CH:52]=[C:53]([CH:56]=4)[C:54]#[N:55])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cncc(C#N)c4)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 105 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
In a dry tube under an atmosphere of argon to a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) (250 mg, 412 μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (142 mg, 617 μmol) in 1,2-dimethoxyethane (3 ml) were added consecutively an aqueous solution of sodium carbonate (2M, 0.6 ml), triphenylphosphine (22.3 mg, 82.3 μmol), and, after flushing the mixture with argon, palladium(II)acetate (9.24 mg, 41.2 μmol). The tube was sealed and heated under stirring at 105° C. for 15 hours. After evaporation at reduced pressure, the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The 5-[3-((4R,5R)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile (260 mg, 100% yield) as a white foam. MS (ISP): m/z=631.4 [M+H]+.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15]([OH:17])=O.[CH3:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][NH:26][C:27](=[O:42])[C@H:28]([CH3:41])[CH2:29][C@H:30]([OH:40])[C@@H:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.ClCCl>[CH2:32]([C@H:31]([NH:39][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([F:21])=[C:12]([Br:11])[CH:13]=1)[C@@H:30]([OH:40])[CH2:29][C@H:28]([C:27](=[O:42])[NH:26][CH2:25][CH2:24][C:23]([CH3:22])([CH3:43])[CH3:44])[CH3:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (265 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with a solution of 1-hydroxybenzotriazole (0.45 mmol) in DMF (1.0 ml) followed by 3-bromo-4-fluorobenzoic acid (99 mg, 0.45 mmol), dichloromethane (1 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (90 mg, 0.30 mmol) in dichloromethane (0.5 ml)/DMF (0.5 ml). After stirring gently overnight at room temperature, methylisocyanate polystyrene (150 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (250 mg @ 3.20 mmol/g; ex. Novabiochem) were added and the mixture was stirred for a further 1.5 h. It was then filtered and the spent resins were washed with DMF and dichloromethane. The combined filtrates were evaporated to dryness and the residue was filtered through a short column of silica gel to give the title compound, 126 mg.
Reaction SMILES: NC(C)/[CH:3]=[CH:4]/[C:5]([NH:7][C@@H:8]1[CH2:13][C@H:12](C)[C@H:11](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)C2)[O:10][C@@H:9]1C)=O.NC(C)/C=C\C(N[C@@H]1C[C@H](C)[C@H](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)C2)O[C@@H]1C)=[O:40].[P:69]([O-:73])([O-:72])([O-:71])=[O:70].[Na+].[Na+].[Na+].C(N)(C)C>CS(C)=O.P([O-])([O-])([O-])=O>[CH3:9][C:8]1[N:7]=[CH:5][C:4]([CH2:3][O:70][P:69]([OH:73])([OH:72])=[O:71])=[C:12]([CH:11]=[O:10])[C:13]=1[OH:40].[P:69]([O-:73])([O-:72])([O-:71])=[O:70]
Reactant: CC(/C=C/[C@@H]1C[C@]2(CO2)C[C@@H](CC(N)=O)O1)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\C(C)N)C[C@@H]1C
Reactant: CC(/C=C/[C@@H]1C[C@]2(CO2)C[C@@H](CC(N)=O)O1)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C/C(C)N)C[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)N
Product: Cc1ncc(COP(=O)(O)O)c(C=O)c1O

Procedure:
Synthesis of (2E)-4-amino-N-[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3S,5S,7S)-7-(2-amino-2-oxoethyl)-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]pent-2-enamide (#B271) and (2Z)-4-amino-N-[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3S,5S,7S)-7-(2-amino-2-oxoethyl)-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]pent-2-enamide (#B272): To 100 mM sodium phosphate buffer pH 7.4 (3.57 ml) were added #B129 (7 mg, in 0.23 ml DMSO, 1 eq.), isopropylamine (1.475 ml of a 1 M solution made in phosphate buffer pH 3, giving a solution of pH ˜7, 100 eq.), pyridoxal phosphate (0.295 ml of a 50 mM solution in phosphate buffer pH 7.4, 1 eq.), and ATA-P2-B01 enzyme preparation (33 mg, in 0.33 ml phosphate buffer pH 7.4, Codexis, lot #D11134, R-selective for acetophenone). After incubation at 30° C., 200 rpm for 19 hours, pH was adjusted to ˜12 with sodium hydroxide and the reaction was extracted seven times with equal volume of ethylacetate. The solvent was evaporated under reduced pressure, the residue resuspended in 0.25 ml acetonitrile/water 1:1, filtered and purified by reverse phase chromatography in a total of 10 runs (Method I). The fractions with retention time of 10 and 13 min were collected and neutralized with ammonium hydroxide before freeze-drying to afford #B271 and #B272, respectively, as white solids.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][C:22]=3[O:31][CH2:32][O:33][CH3:34])=[CH:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([Si:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][C:22]=3[O:31][CH2:32][O:33][CH3:34])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1ccc(C2=CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Reaction time: 17 h
Yield: 101 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added tert-butyl(4-{4-[2,4-bis(methoxymethoxy)phenyl]-3-cyclohexen-1-yl}phenoxy)dimethylsilane (118 mg, 0.24 mmol) and ethanol (15 ml). To the stirred solution, palladium (catalytic amount, 10% on activated carbon) was added in one portion. The reaction vessel was then evacuated and placed under an atmosphere of hydrogen. This process was repeated for 10 cycles before leaving under a hydrogen atmosphere. The reaction mixture was stirred vigorously for 17 hr then filtered through celite, washing with ethyl acetate. The filtrate was concentrated in vacuo affording the title compound as a colourless oil (118 mg, 100%) and a mixture of diastereoisomers. δH(CDCl3) 0.15 (6H, s), 0.92 (9H, s), 1.51 (2H, m), 1.63 (2H, m), 1.81 (2H, m), 1.94 (2H, m), 2.43 and 2.90 (1H, m), 2.84 and 3.02 (1H, m), 3.38 and 3.39 (3H, s), 3.40 (2×1.5H, s), 5.04 and 5.06 (2H, s), 5.08 and 5.10 (2H, s), 6.56 and 6.61 (1H, m), 6.70 (3H, m), 7.03 (2H, m), 7.11 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:30]([CH:27]3[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]3)=[O:31])[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(N)c(Cl)c3)ccn2)CC1
Reaction time: 19 h
Yield: 58 %

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (600 mg), 1-t-butyloxycarbonylpiperidine-4-carboxylic acid (700 mg), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop Reagent) (1.4 g), triethylamine (0.71 ml) and dimethylformamide (10 ml) were stirred at 60° C. for 3.5 hours and then at room temperature for 19 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate and the organic layer was washed with water, after which silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 660 mg of a reddish-brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:19])[C:11](=[O:18])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([CH2:45][O:46][NH2:47])[CH2:44][CH2:43]1.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[CH:42]1([CH2:45][O:46][NH:47][C:15]([C:14]2[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH3:19])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:20])=[O:17])[CH2:44][CH2:43]1
Reactant: NOCC1CC1
Reactant: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)NOCC2CC2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A mixture of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.022 g, 0.064 mmol), EDCI (0.019 g, 0.097 mmol), and HOBt (0.019 g, 0.097 mmol) in DMA (1 mL) was stirred for 30 minutes at room temperature under N2. O-Cyclopropylmethyl-hydroxylamine (0.017 g, 0.19 mmol) was added followed by Et3N (0.022 mL, 0.016 g, 0.16 mmol). After the reaction mixture was stirred for 16 hours at room temperature, it was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.015 g (57%) pure desired product as a yellow solid. MS APCI (−) m/z 410, 411 (M−, Br pattern) detected, 1H NMR (400 MHz, DMSO-d6) δ 11.4 (s, 1H), 9.81 (s, 1H), 7.58 (m, 2H), 7.28 (d, 1H), 6.82 (t, 1H), 6.17 (d, 1H), 3.46 (d, 2H), 3.22 (s, 3H), 0.99 (m, 1H), 0.48 (m, 2H), 0.18 (m, 2H).