Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>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.C1(C)C=CC=CC=1>[S:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])=[CH:14]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1csc2ccccc12
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2csc3ccccc23)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
(3-Formylphenyl)boronic acid (1.7 g, 11.3 mmol), 3-bromo-1-benzothiophene (2.0 g, 9.39 mmol) and cesium carbonate (4.6 g, 14.1 mmol) were added to a mixed solution of ethanol (10 mL) and toluene (50 mL) and, after argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hr. After cooling the reaction mixture, the insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (2.1 g, yield 94%) as a pale-yellow oil. MS: m/z 239 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.064 mmol) was dissolved in anhydrous EtOH (0.6 mL) followed by addition of 2 M of sodium hydroxide in water (60 μL). Reaction was stirred at 50° C. for 4 hrs. Consumption of starting material was monitored by TLC. The sample was quenched with acetic acid, diluted with MeOH and purified by preparative LCMS. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash silica column chromatography to yield the desired product (16 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 9.02 (s, 1H), 7.18 (dd, J=9.1, 9.1 Hz, 1H), 6.97 (dd, J=6.6, 2.7 Hz, 1H), 6.69 (m, 1H), 5.68 (t, J=6.2 Hz, 1H) 4.72 (d, J=5.8 Hz, 2H); MF═C10H8ClFN4O3; LCMS calculated for C10H9ClFN4O3 (M+H)+: m/z=287.035.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:32](O)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:32](=[O:33])[C@H:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1

Procedure:
L-Serine methyl ester hydrochloride, 5 g., is dissolved in 75 ml. of dimethylformamide and the solution cooled in an ice bath. Triethylamine, 4.9 ml., is added then 11.9 g. of Nα -benzyloxycarbonyl-L-tryptophan, 5.25 g. of 1-hydroxybenztriazole and finally 8.0 g. of dicyclohexylcarbodiimide. The reaction is stirred with ice bath cooling overnight, allowing the temperature to rise to room temperature, then an additional twenty-four hours at room temperature. The mixture is filtered and the solid washed with dimethylformamide. The filtrate is evaporated under reduced pressure and the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid, saturated salt solution, three times with 5% sodium bicarbonate solution, saturated salt solution, and finally with water. The ethyl acetate solution is then dried over magnesium sulfate and evaporated. The residue is crystallized from 250 ml. of benzene and then from ethyl acetate and petroleum ether; 12.5 g.; m.p. 133°-135° C.; [α]D23 -12.4° (c 2, methanol); ultraviolet in methanol λmax 290 E11 115; λmax 281 E11 131; λmax 274 E11 122.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Br:38])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>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.C1(C)C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Br:38])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35].[CH3:37][O:36][C:32]1[CH:31]=[C:30]([P:1](=[O:18])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:29]=[C:28]([O:27][CH3:26])[C:33]=1[O:34][CH3:35]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cc(Br)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybromobenzene is prepared following the procedure of Tetrahedron Lett. 26 (1985):5939-5942. Dibenzyl phosphite is heated in the presence of tetrakis(triphenylphosphine)palladium (0), triethylamine and toluene with 3,4,5-trimethoxybromobenzene to give Dibenzyl 3,4,5-trimethoxyphenylphosphonate 2 following the procedure of J. Med. Chem. 32 (1989):1580-1590.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1>O.C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
108.5 g of malonic acid diethyl ester are added dropwise, at 50°, to a sodium ethylate solution freshly prepared from 15.6 g of sodium and 750 ml of ethanol. The mixture is kept at the above temperature for 2.5 hours and 220 g of p-toluenesulphonic acid 3-(4-chlorophenyl)-propyl ester are then added dropwise. After the addition, the mixture is stirred at 50° for 6 hours, 800 ml of water are then added and the mixture is extracted 3 times with a total of 1 liter of diethyl ether. The combined organic phases are dried over sodium sulphate, the solvent is evaporated off and the residue is distilled. 105.6 g of 3-(4-chlorophenyl)-propylmalonic acid diethyl ester of b.p. 145°-155° under 0.01 mm Hg (1.33 Pa) are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[C:40]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[N:21]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and acetic anhydride (4 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 8 mg (60%) of N-acetyl-N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (the compound of formula (Igg)): 1H NMR (CDCl3) δ 8.48 (s, 1), 8.08 (d, 1), 7.76 (s, 1), 7.09 (s, 1), 6.66 (m, 3), 6.33 (m, 1), 5.94 (s, 1), 5.91 (s, 1), 4.43 (m,3), 3.40 (m, 2), 2.11 (d, 3), 1.14 (m); MS: 450.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](/[N+:11]([O-:13])=[O:12])\[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[CH:35][NH:36]2)=[CH:32][CH:31]=1>C1COCC1>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34]([CH:8]([C:7]3[C:2]([CH3:1])=[C:3]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[CH:5][CH:6]=3)[CH:9]([N+:11]([O-:13])=[O:12])[CH3:10])=[CH:35][NH:36]2)=[CH:32][CH:31]=1
Reactant: COCCOc1ccc2cc[nH]c2c1
Reactant: C/C(=C\c1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)[N+](=O)[O-])c[nH]c2c1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
(E)-Benzyl 2-methyl-3-(2-nitroprop-1-enyl)phenylcarbamate (0.6849 g, 1.574 mmol) and 6-(2-methoxyethoxy)-1H-indole (0.602 g, 3.15 mmol) were dissolved in THF (50 mL), concentrated in vacuo, and melted at 140° C. for 12 h. After cooling to room temperature, the crude product was purified by flash chromatography using an ISCO 40 g column (solid loading) eluting with 20-75% EtOAc/hexane. Appropriate fractions were collected and concentrated in vacuo to give benzyl 3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate (0.4102 g, 0.793 mmol, 50.4% yield, mixture of 2 isomers) as a yellow oil, LC/MS (M+H)=518.12, 518.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[C:18]=[O:19].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)[CH2:5][NH:6][C:18]([NH:17][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[C:23]([CH3:30])[N:24]=[CH:25]2)=[O:19]
Reactant: CC1CCN(c2ccc(CN)cc2F)CC1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCC(C)CC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 3-fluoro-4-(4-methyl-1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.52 (s, 1H), 8.66 (s, 1H), 8.59 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.62 (t, 1H, J=6 Hz), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 3.31 (m, 2H), 2.79 (s, 3H), 2.69 (m, 2H), 1.71 (m, 2H), 1.49 (m, 1H), 1.32 (m, 2H), 0.95 (d, 3H, J=6 Hz). MS (ESI) 407 (M+H)+; Anal. Calcd for C24H27FN4O.2.3HCl: C, 58.79; H, 6.02; N, 11.43. Found: C, 58.73; H, 6.18; N, 11.19.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[CH2:2]1.C1C=CC=CC=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO.O>[CH2:18]([NH:25][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([OH:11])[CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CC(=O)c2ccccc21
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: OC1CC(NCc2ccccc2)c2ccccc21

Procedure:
Stir indan-1,3-dione (7.31 g.), benzene (200 ml.) and benzylamine (5.90 g.) and reflux into a water separator for 6 hours. Cool, filter, and wash the dark solid with ether. Boil the solid with methylene chloride, filter and remove the solvent by boiling and replace with ether. Filter to get 4.51 g. of dark solid. Stir 4.30 g. of this solid with methanol (150 ml.) and add sodium borohydride (12.0 g.) portionwise with stirring over 4 hours. Let the reaction stand at room temperature then evaporate the solvent in vacuo and digest the residue with water and ether. Extract the mixture with ether and wash, dry and evaporate the solvent in vacuo. Recrystallize the residue from cyclohexane-ether to obtain 1.996 g. of the pure free base of the title compound, m.p. 121°-125°.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+:22]>>[NH2:22][C:13]1[CH2:14][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:17])[CH3:1])=[CH:4][CH:5]=2)[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CN(C)c1ccc(C2CC(=O)C=C(N)C2)cc1

Procedure:
In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-(4-dimethylamino-phenyl)-cyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][NH:6][C:7](=[O:41])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:25][C:24]=2[C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[C:29]([C:28]1[CH:27]=[C:26]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:23]=1[O:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:41])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C(C)(C)C)c1

Procedure:
Racemic 3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester (0.333 g, 0.500 mmol) is dissolved in tetrahydrofuran (3.0 mL) and sodium hydroxide (3.0 mL, 5N) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with hydrochloric acid (3.0 mL, 5N) and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound is used without further purification. MS (ES): 652.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.CC(C)(O)C#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH:16]([OH:17])[C:18]#[N:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: CC(C)(O)C#N
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 143 %

Procedure:
To a solution containing N-benzyloxycarbonyl-L-valinal 22.2 g, 0.094 mol) in methylene chloride (500 mL) and triethylamine (5.81 g, 8.0 mL, 0.057 mol) was added acetone cyanohydrin (24.23 g, 26.0 mL, 0.2847 mol). The reaction was allowed to stir at room temperature overnight and then concentrated under reduced pressure. The residue was taken up into ether and washed with brine (3X). The solvent was removed under reduced pressure and purified by column chromatography (silica gel; 1:2 acetone:hexane) to give 21.38 g (86.6%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile as a pale yellow oil; TLC Rf =0.33 (silica gel; 1:2 acetone:hexane).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Sc1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Sc1ccccc1

Procedure:
The title compound was prepared as described in General Method 6 from 0.96 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.0 mmol of benzenethiol, and 1.0 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid (m.p. 78°-80° C.). 1H NMR (DMSO-d6) δ3.37 (bs, 2H), 6.35 (m, 2H), 6.93 (m, 3H), 7.29-7.49 (m, 10H).
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[N:21][OH:22])=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:35])([F:33])[F:34])[O:22][N:21]=[C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]([F:9])=[CH:11][CH:12]=3)[CH2:31]2)[CH:27]=[C:26]([Cl:36])[CH:25]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(F)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-chlorosuccinimid (4.7 g) is added to a solution of 4-fluoro-naphthalene-1-carbaldehyde oxime (6.6 g, example 5 step A) in DMF (50 ml). After 45 minutes at 40° C., the reaction is cooled down to 0° C. and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene, (8.4 g, example 1 step A) and triethylamine (5.4 ml) are added. The reaction is then further reacted at room temperature for 3 hours. Water is added (50 ml) and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is dissolved in dichloromethane and filtered over a pad of silica gel to yield 5-(3,5-dichloro-phenyl)-3-(4-fluoro-naphthalen-1-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole as a beige solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:47])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]=[C:21]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:20]4=[C:19]([N:31]4[CH2:38][CH:37]5[O:39][CH:33]([CH2:34][N:35](C(OC(C)(C)C)=O)[CH2:36]5)[CH2:32]4)[N:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl>ClCCl.CO.O1CCOCC1>[CH:33]12[O:39][CH:37]([CH2:36][NH:35][CH2:34]1)[CH2:38][N:31]([C:19]1[N:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]4[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=4)=[O:47])=[CH:16][CH:15]=3)[N:22]=[C:21]3[N:23]([CH2:26][C:27]([F:29])([F:30])[F:28])[N:24]=[CH:25][C:20]=13)[CH2:32]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc(NC(=O)Nc5ccncc5)cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CC4CNCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
Tert-butyl 7-(6-(4-(3-pyridin-4-ylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.hydrochloride (256 mg, 0.38 mmol) was dissolved in dichloromethane (20 mL) with the aid of a minimum volume of methanol. The solution was treated with 4 N hydrogen chloride in dioxane (2 mL), which caused the precipitation of a white solid within 10 minutes. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum. A portion of the crude solid (assumed dihydrochloride) was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 65% acetonitrile to provide 1-{4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-pyridin-4-ylurea.2TFA (22 mg). MS (ES+): 540.2 (M+H)+
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:9][CH:10]=1
Reactant: O=C(NCCCl)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCN1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of methyl 4-trifluoromethylaniline (3.47 g, 21.6 mmol) in dry toluene (50 mL) was added 2-chloroethylisocyante (2.50 g, 2.02 mL, 23.7 mmol). The mixture was stirred at 40° C. for 12 h. After cooling to room temperature, the solid was collected by filtration and washed with toluene, water and dried in air to provide 1-(2-chloro-ethyl)-3-(4-trifluoromethylphenyl)urea [5.28 g, 92.0%, >95% pure by LC/MS MS (ES+) m/z: 267, 269]. The urea (5.27 g, 23.7 mmol) was then stirred in DMF (50.0 mL) with K2CO3 (3.27 g, 11.98 mmol) at room temperature for 12 h. The solid was filtered off and the solvent was removed in vacuum. The crude product was dissolved in dichloromethane and passed through a silica column (50 g) and eluted with dichloromethane:ethyl acetate, 8:2 to give pure cyclic urea intermediate, 1-(4-trifluoromethylphenyl) imidazolidin-2-one, as white crystalline material (3.85 g, 84.7%). MS (ES+) m/z: 231.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.IC>C(#N)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 2.5 °C

Procedure:
55 g (0.19 mol) 4-Iodo-3-nitrobenzoic acid (Compound V), 16.5 g (0.12 mol) potassium carbonate and 550 ml acetonitrile were added into a reaction flask, and started to stir. The mixture was cooled to 0 to 5° C., and 52.9 ml (0.38 mol) triethylamine was added. The temperature was controlled below 10° C., and 71 ml (1.12 mol) iodomethane was added. The mixture was heated to about 40° C. for 8 hours, and concentrated under reduced pressure after completing the reaction until most of the acetonitrile was evaporated. The mixture was then extracted with 500 ml ethyl acetate, washed with water for three times, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to the least amount, and then 300 ml petroleum ether was added, stirred for 30 min, and then filtered. The filter cake was washed with petroleum ether, and dried to obtain methyl 4-iodo-3-nitrobenzoate (Compound IV), about 41.2 g (0.13 mol), yield 71.5%.