Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[C:13](I)[C:8]=3[O:7][N:6]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CC1(C)C(C)(C)OBO1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.Br[C:59]1[C:64](=[O:65])[N:63]([CH3:66])[C:62]2[N:67]([C:70]3[C:75]([F:76])=[CH:74][CH:73]=[CH:72][C:71]=3[F:77])[N:68]=[CH:69][C:61]=2[CH:60]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[CH:1]1([NH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([C:59]4[C:64](=[O:65])[N:63]([CH3:66])[C:62]5[N:67]([C:70]6[C:75]([F:76])=[CH:74][CH:73]=[CH:72][C:71]=6[F:77])[N:68]=[CH:69][C:61]=5[CH:60]=4)[C:8]=3[O:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc2c(NC3CC3)noc2c1I
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NC3CC3)noc2c1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 100 °C

Procedure:
A mixture of N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (0.100 g, 0.32 mmol), triethylamine (0.17 ml, 1.25 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.95 ml of 1.0 M in THF solution, 0.95 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.023 g, 0.065 mmol) and palladium acetate (0.0036 g, 0.016 mmol) in 2.0 mL of dioxane in a sealed glass tube was heated in a microwave at 100° C. for 20 min. After cooling to RT, the reaction mixture was transferred to a 50 mL round-bottom flask and treated with 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (0.089 g, 0.26 mmol) and sodium carbonate (1.0 mL of 2.0 M aqueous solution). Tetakis(triphenylphosphine)palladium (0) (9 mg) was added, and the reaction mixture was heated at 110° C. in an oil bath for 5 h. It was cooled to RT, treated with 5 mL of 1 N NaOH and 60 mL of EtOAc. The organic phase was separated, washed with brine, separated from the aqueous layer, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2 (EtOAc/hexane=80/20) to give the title compound as a yellow crystalline solid. MS (ESI, pos.ion) m/z: 448.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]([C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:22]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 L three necked 24/40 round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a dropping funnel was first added a solution of 36.0 g (0.185 mol) of methyl 4-hydroxy-3-n-propylbenzoate dissolved in 700 mL of anhydrous DMF followed by 66.4 g (0.204 mol) of cesium carbonate. The flask was purged with nitrogen and the reaction mixture was stirred at room temperature for 2 hours. A solution of 58.5 g (0.204 mol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate dissolved in 100 mL of DMF was then added via an addition funnel over a 15 minute period. The reaction mixture was stirred an additional 1 hour at room temperature then quenched by addition to 5 L of a 5% aqueous citric acid solution. The organic product was extracted into diethylether (2×4 L), the organic layers were separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated. The residue was applied to a silica gel (2 kg; 70-230 mesh) column equilibrated in 10% CH2Cl2 -hexane. The column was then eluted successively with 12 L of 10% CH2Cl2 -hexane, 12 L of 5% EtOAc-hexane, 4 L of 7.5% EtOAc-hexane, 12 L of 10% EtOAc-hexane, and finally 8 L of 20% EtOAc-hexane. Combination of the purified fractions and evaporation in vacuo afforded 76.3 g (74.2 theoretical) of the title compound as a pale yellow oil which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH2:19][CH3:20]>>[CH2:19]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH3:20]
Reactant: CCI
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Product: CCN1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and 1-iodoethane, the title compound was recovered by the procedure described in Example 2; MS m/z (rel. intensity, 70 eV) 276 (M+, 46), 261 (41), 190 (30), 84 (30), 57 (bp).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].[OH-].[Na+].C(=O)(O)[O-].[Na+].[CH3:54][O:55][C:56]1[CH:57]=[C:58]([CH:62]=[C:63]([O:67][CH3:68])[C:64]=1[O:65][CH3:66])[C:59](Cl)=[O:60]>CC(C)=O.O>[CH3:68][O:67][C:63]1[CH:62]=[C:58]([CH:57]=[C:56]([O:55][CH3:54])[C:64]=1[O:65][CH3:66])[C:59]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:60]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (6.0 g, 8.84 mmol) acetone (40 mL), water (40 mL), sodium hydroxide (0.335 g, 8.87 mmol), and sodium bicarbonate (3.73 g, 8.87 mmol). Cool to about 0° C. Add a solution of 3,4,5-trimethoxybenzoyl chloride (2,2 g, 9.7 mmol) in acetone (12 mL) over about 15 minutes. After 3 hours, partition the reaction mixture between ethyl acetate and brine. Extract the organic layer with 1 M sodium hydroxide solution, saturated sodium bicarbonate solution, 1 M hydrochloric acid solution, then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.11 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([CH2:45][C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:46](=[O:47])[CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)Cc1ccccc1)CC2(C)C
Temperature: 25 °C
Yield: 11.3 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (9.2 mg, 0.021 mmol) in CH2Cl2 (5 mL) was added Et3N (8.98 μl, 0.064 mmol) followed by 2-phenylacetyl chloride (4.26 μl, 0.032 mmol) and the mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product was dissolved in MeOH and repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm) to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-phenylacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.3 mg, 10% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 7.38-7.60 (1H, m), 7.00-7.40 (7H, m), 6.97 (1H, d, J=7.02 Hz), 4.75-4.85 (1H, m), 4.35-4.47 (0.5H, m), 4.17-4.34 (1H, m), 3.98 (0.5H, d, J=16.48 Hz), 3.77-3.93 (1.5H, m), 3.57-3.77 (3H, m), 3.53 (0.5H, d, J=13.12 Hz), 1.22-1.42 (9H, m), 1.11-1.22 (3H, m), 0.87-1.04 (9H, m). LCMS (M+H) calcd for C33H40FN2O4: 547.29. found: 547.4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:19][C:20]1[C:27]([F:28])=[C:26]([C:29]([F:32])([F:31])[F:30])[C:25]([F:33])=[C:24]([F:34])[C:21]=1[CH2:22]Br>CN(C=O)C>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][C:21]2[C:24]([F:34])=[C:25]([F:33])[C:26]([C:29]([F:30])([F:32])[F:31])=[C:27]([F:28])[C:20]=2[F:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of 5-aminosalicylic acid (1.02 g, 6.66 mmole, purchased from Aldrich Chemical Company, USA, A7, 980-9) and triethylamine (1 ml) in dried DMF (80 ml) was added 2,3,5,6-tetrafluoro-4-trifloromethylbenzyl bromide (1.23 g, 7.18 mmole) (Aldrich, 40, 640-6) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hr at room temperature and then solvent was removed in vacuo. The reaction mixture was diluted with ethyl acetate and then extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous MgSO4. After evaporation of the solvent, the residue was recrystallized from ether/hexane (1:10) to give 1.60 g (64% yield) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][O:24][CH3:25])#[N:2].C(Cl)Cl>C(O)(C(F)(F)F)=O>[C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][O:24][CH3:25])#[N:2]
Reactant: COCC1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 68.5 %

Procedure:
4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(methoxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (12 mg, 0.018 mmol; Peak 2 from Step 5) was dissolved in a 1:1 mixture of TFA:DCM (3 mL) and was stirred for 1 h. Solvent was removed in vacuo. The residue was then stirred in a solution of methanol (1.5 mL), containing ammonium hydroxide solution (0.15 mL). Purification via preparative HPLC-MS (C18 eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded product (6.5 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 12.12 (br s, 1H), 8.81 (s, 0.6H), 8.79 (s, 0.4H), 8.68 (s, 0.6H), 8.67 (s, 0.4H), 8.37 (s, 1H), 8.00-7.94 (m, 1H), 7.80-7.73 (m, 1H), 7.63-7.55 (m, 2H), 6.98 (d, 0.6H), 6.97 (d, 0.4H), 4.90-4.76 (tt, 1H), 3.71-2.12 (m, 16H); 19F NMR (400 MHz, DMSO-d6): δ −114.74 (s, 1F), LCMS (M+H)+: 528.0.
Reaction SMILES: ClC(OC)=O.[CH2:6]([O:8][C:9](=[O:31])[C:10]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=1)([CH2:14][CH3:15])[C:11](O)=[O:12])[CH3:7].CCN(CC)CC.[BH4-].[Na+].Cl>C1COCC1.C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:31])[C:10]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:21][CH:22]=1)([CH2:11][OH:12])[CH2:14][CH3:15])[CH3:7]
Reactant: CCOC(=O)C(CC)(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CO)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 0.83 h
Yield: 44.6 %

Procedure:
Methyl chloroformate (150 pL, 1.95 mmol) was added dropwise to a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethyl-malonic acid monoethyl ester (700 mg, 1.91 mmol) and Et3N (275 μL, 1.97 mmol) in THF (15 mL) at −20° C. under nitrogen. The reaction mixture was stirred for 50 min., filtered and added dropwise to a suspension of NaBH4 (80 mg, 2.1 mmol) in THF (15 mL) at −20° C. The reaction was stirred for 16 h at room temperature. 0.2 M HCl was added followed by methylene chloride. The organic phase was washed with brine and dried. Concentration under reduced pressure followed by chromathography (toluene/EtOAc, 3:1→1:3) gave 2-(6-tert-butoxycarbonylamino pyridin-3-ylmethyl)-2-hydroxymethyl-butyric acid ethyl ester (300 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.BrC1C=CC(OC)=C(N[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])C=1.C(OCC)(=O)C.CCCCCCC.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:6][CH:7]=1
Reactant: COc1ccc(Br)cc1NC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cn1

Procedure:
The compound was prepared from 5-bromo-2-pyridinamine in the manner described for compound (2): 1H NMR (DMSO-d6, 400 MHz) δ 9.96 (s, 1H), 8.49 (d, 1H), 7.93 (dd, 1H), 7.78 (d, 1H), 1.47 (s, 9H); TLC (ethyl acetate/heptane 5:95) Rf 0.28; RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.50 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[OH-].[K+].[CH2:15](Br)[CH:16]=[CH:17][CH3:18]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH2:15]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:16]=[CH:17][CH3:18]
Reactant: CC=CCBr
Reactant: CCOC(=O)NCC(OC)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC=CCN(CC(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alternatively 90 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl) -carbamate are dissolved in 500 ml of toluene, 100 g of powdered potassium hydroxide and 1.5 g of triethylbenzylammonium chloride are added and 80 g (0.6 mol) of crotyl bromide (isomer mixture) are added dropwise. The mixture is stirred overnight at room temperature, the salts are dissolved in water, and the aqueous phase is separated off and extracted once using 100 ml of toluene. The extract is dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=[N:6][NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[O:1]1[CH2:5][CH2:4][CH:3]([NH:6][NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1
Reactant: O=C(NN=C1CCOC1)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NNC1CCOC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Benzyl 2-[dihydrofuran-3(2H)-ylidene]hydrazinecarboxylate (14.8 g) was suspended in water (96 mL). Acetic acid (42.1 mL) was added to the suspension at room temperature. The mixture was stirred at room temperature for one hour. The suspension turned into a solution. Sodium cyanoborohydride (4.0 g) was added to the solution in small portions. The mixed solution was stirred at room temperature for two hours. The reaction mixture was cooled to 0° C. The reaction mixture was neutralized by adding a 5 N aqueous sodium hydroxide solution. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate, 5%). The title compound (13.9 g) was obtained.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Clc1ncccn1
Reactant: COC(=O)c1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ncccn2)ccc(F)c1F
Temperature: 90 °C

Procedure:
A stirred suspension of methyl 2,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 2-chloropyrimidine, PdCl2(dppf) and K2CO3 in 1,4-dioxane and water (3:1, v/v) was heated at 90° C. under nitrogen for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was directly purified by flash column chromatography on silica gel (0% to 50% EtOAc/hexanes) to give the title compound. ESI MS (M+H) 251.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([NH:17][C@H:18]1[CH2:24][S:23][CH2:22][C@@H:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[N:20]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]([C@@H:8]([NH:17][C@H:18]1[CH2:24][S:23][CH2:22][C@@H:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[N:20]([CH2:30][C:31]([OH:33])=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)O)C1=O

Procedure:
100 mg of isomer B of t-butyl α-[6(R)-(1-butoxycarbonyl-3-phenylpropylamino)-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 23) was treated with trifluoroacetic acid to remove its t-butyl group in the same manner as in Example 3. 60 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:46][OH:47]>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH:46][OH:47])=[O:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 36.5 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide was prepared by the procedure of example 8 from 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.6 g, 1.3 mmol), CDI (0.32 g, 2.0 mmol) and hydroxylamine hydrochloride (0.19 g, 2.6 mmol) in THF (30 ml) to give 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N-hydroxy-propionamide as white solid (0.22 g, 40% yield): mp 121-123° C.; 1H NMR (DMSO-d6): δ 1.34 (t, J=7.5 Hz, 3H, OCH2CH3), 2.16 (s, 3H, CH3), 2.89 (d, J=7.5 Hz, 2H, CH2), 4.10 (q, J=7.0 Hz, 2H, OCH2CH3), 4.24 (d, J=17.5 Hz, 1H, CH2N), 4.59 (d, J=17.5 Hz, 1H, CH2N), 5.69 (m, 1H, CHN), 6.93 (m, 1H, Ar), 7.03 (t, JH-F=75 Hz, 1H, CF2H), 7.15 (m, 3H, Ar), 7.52 (t, J=7.5 Hz, 1H, Ar), 8.26 (d, J=8 Hz, 1H, Ar), 8.85 (s, 1H, NHOH), 10.26 (s, 1H, NHOH), 10.35 (s, 1H, NHCO). 13C NMR (DMSO-d6): δ 14.4, 24.4, 34.5, 51.5, 64.2, 93.9, 113.0, 116.6, 117.3, 117.5, 120.7, 121.3, 122.5, 132.8, 134.0, 137.0, 137.8, 142.2, 149.8, 165.7, 168.0, 168.5; Anal. Calcd. for C22H23F2N3O6+0.13H2O: C, 56.73; H, 5.03; N, 9.02; Found: C, 56.35; H, 4.89; N, 8.75; H2O, 0.34.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=[O:34]>>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]([NH:22][C:23]3[N:24]=[CH:25][C:26]([C:29]([NH2:30])=[O:34])=[N:27][CH:28]=3)[CH:21]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncn2)CC1
Reactant: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Nc2cc(NCC3CCNCC3)ncn2)cn1
Temperature: 82 °C
Yield: 15 %

Procedure:
A mixture of tert-butyl-4-((6-(5-cyanopyrazin-2-ylamino)pyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (0.15 mmol) and trifluoroacetic acid was heated at 82° C. for 4 hours. The solution was evaporated to dryness and the residue was purified by preparative HPLC to give 5-(6-(piperidin-4-ylmethylamino)pyrimidin-4-ylamino)pyrazine-2-carboxamide (7.36 mg, 15%).
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C(Cl)(Cl)Cl.C(O)C>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: OCc1ccncc1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=c1ncc(Cl)cn1Cc1ccncc1
Temperature: 90 °C
Yield: 23.7 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.8 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (522 mg) and 4-pyridylcarbinol (611 mg) in dry N,N-dimethylformamide (10 ml) under nitrogen and the the mixture was then heated at 90° C. After 41/2 h the reaction mixture was evaporated to a brown solid which was subjected to column chromatography on silica developing and eluting with chloroform-ethanol, 14:1. This gave a yellow crystalline solid which was subjected to p.l.c. on silica developing with chloroform-ethanol, 9:1 (three runs). The major band was eluted with chloroform-ethanol, 1:1, to give a pale yellow foam which was crystallised from acetone to give off white crystals of the title pyrimidinone (210 mg), m.p. 205°-206° C., λmax (EtOH) 246 nm (ε 7.050), 332.5 nm (ε 950).