Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]([CH3:46])[N:43]=[CH:44][CH:45]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]([CH3:46])[N:43]=[CH:44][CH:45]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cn1nccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K7) (150 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (114 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[CH:7](C(OCC)=O)[C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[CH:7][C:8](=[O:15])[N:9]2[CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1C(=O)c2ccc(Br)cc2N(C(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)n1c(=O)cc(O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A suspension of ethyl 7-bromo-2,4-dioxo-1-(propan-2-yl)-1,2,3,4-tetrahydroquinoline-3-carboxylate (1.5 g, 4.23 mmol) in sodium hydroxide (2M solution, 32 mL, 64 mmol) is heated to reflux. The reaction medium becomes homogeneous and, after 3 hours, a suspension is once again observed. 6 mL of NMP are added to homogenize, and the resulting mixture is than refluxed for 12 hours. The solution cooled to room temperature is poured into 6M hydrochloric acid solution to give a white precipitate, which is filtered off. After rinsing with water and drying the precipitate under vacuum, 1.1 g of a white solid are obtained (yield: 91%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C)C=O>[Cl:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][N:10]([CH2:16][CH:15]=[CH2:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: C=CCBr
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C

Procedure:
Sodium hydride (0.28 g of 60% dispersion in mineral oil) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.96 g) in dry N,N-dimethylformamide (40 ml) with stirring under nitrogen at ambient temperature. The mixture was then stirred for 30 minutes and allyl bromide (0.62 ml) was added dropwise. After stirring for 1 hour at ambient temperature more allyl bromide (0.20 ml) was added and the mixture was left stirring at ambient temperature for 18 hours. The mixture was added to water with stirring and the solid which precipitated was collected by filtration and dried to give 4-chloro-5-iodo-7-(prop-1-en-3-yl)-7H-pyrrolo[2,3-d]-pyrimidine which was used directly in b).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:29]1([CH2:28][N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@H:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:3]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]2=[O:1])[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (190 mg, 0.536 mmol) in dry DMF (2 mL) under nitrogen was added (bromomethyl)cyclopropane (108 mg, 0.800 mmol) and powdered cesium carbonate (264 mg, 0.810 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the combined organic extracts was purified by flash chromatography on silica gel eluting with 6:1 (v/v) hexane:ethyl acetate to afford the title compound (201 mg, 92%) as a white solid. TLC Rf=0.31 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.19 (m, 1H), 0.35-0.62 (m, 3H), 1.15 (m, 1H), 1.37 (s, 9H), 3.50 and 3.55 (dd, 1H, J=7.0 Hz), 4.12 and 4.17 (dd, 1H, J=7.0 Hz), 4.93 (m, 2H), 5.65 (d, 1H, J=7.0 Hz), 7.29 (m, 4H), 7.41 (m, 5H). MS APCI, m/z=309 (M-BOC). LC/MS: 3.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH:20][C:21](=[O:79])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]4[CH2:40][C:39]([F:42])([F:41])[CH2:38][CH2:37][C:36]=4[C:43]4[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=4)[CH2:30][CH2:29]3)=[CH:24][C:23]=2[O:50][C:51]2[CH:59]=[CH:58][CH:57]=[C:56]3[C:52]=2[CH:53]=[N:54][N:55]3C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O>ClCCl>[NH:55]1[C:56]2[C:52](=[C:51]([O:50][C:23]3[CH:24]=[C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]5[CH2:40][C:39]([F:41])([F:42])[CH2:38][CH2:37][C:36]=5[C:43]5[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=5)[CH2:30][CH2:29]4)[CH:26]=[CH:27][C:22]=3[C:21]([NH:20][S:17]([C:4]3[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]4([F:16])[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)(=[O:19])=[O:18])=[O:79])[CH:59]=[CH:58][CH:57]=2)[CH:53]=[N:54]1
Reactant: O=C(NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Cl)c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Cl)c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2[nH]ncc12
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 521I (0.24 g) dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL). After stirring for 1 hour, the reaction was concentrated, dissolved in dichloromethane (5 mL) and quenched with saturated NaHCO3 (5 mL). The reaction was diluted with water (10 mL) and saturated NaHCO3 (15 mL) and the product extracted into dichloromethane (2×25 mL). The combined organics were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (Reveleris 40 g) and eluted using a gradient of 0.5% to 3% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes). The product was collected, concentrated, dissolved in acetonitrile and concentrated, and dried in vacuum oven at 75° C. overnight to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 13.12 (s, 1H), 12.24-11.44 (m, 1H), 8.31 (d, 1H), 7.91 (d, 1H), 7.83 (s, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.13 (d, 4H), 6.81 (dd, 1H), 6.56 (d, 1H), 6.16 (dd, 1H), 4.52 (d, 2H), 3.79 (dt, 2H), 3.70-3.51 (m, 2H), 3.20 (s, 4H), 2.76 (dd, 4H), 2.49 (m, 8H), 2.02-1.71 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.CN(C)S([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=O)=O.Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>C1COCC1>[N+:27]([C:24]1[CH:23]=[N:22][C:21]([CH:15]2[CH2:14][NH:13][CH2:18][CH2:17][NH:16]2)=[N:26][CH:25]=1)([O-:29])=[O:28]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(C2CNCCN2)nc1

Procedure:
Triethylamine (7.2 mL, 51.8 mmol) was added to a solution of piperazine-1-sulfonic acid dimethyl amide (10 g, 51.8 mmol) dissolved in 400 mL of THF. 2-chloro-5-nitropyrimidine (7.7 g, 48.3 mmol) dissolved in 20 mL of THF was added to the stirred mixture. After 24 hours stirring at room temperature (RT), THF was removed under vacuum and 600 mL of CHCl3 was added to the residue. The CHCl3 layer was washed with 0.5 N HCl and brine, dried over Na2SO4, and filtered. Solvent evaporation gave 14.1 g (92%) of straw yellow solid 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine. The structure was confirmed by 1H-NMR. 1H NMR (CDCl3) δ9.08 (s, 2H), 4.09 (appt, J=5.13 Hz, 4H), 3.35 (appt, J=5.13 Hz, 4H), 2.87 (s, 6H). Step 2: NH4Cl (1.43 g, 26.76 mmol) was added to a suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine (14.1 g, 44.6 mmol) in a mixture of EtOH (175 mL) and H2O (48 mL), followed by iron powder (7.5 g, 133.9 mmol). After refluxing 1 hour, the reaction mixture was filtered and concentrated to give a brown solid which was dissolved in 800 mL of CHCl3, washed with NaHCO3 and brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid which after CC with 100:1 CHCl3:MeOH gave 11.5 g (90%) of solid yellow 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine. The structure was confirmed by 1H-NMR and EI-MS. 1H NMR (CDCl3) δ7.98 (s, 2H), 3.76 (t, J=4.88 Hz, 4H), 3.30 (t, J=4.88 Hz, 4H), 2.86 (s, 6H); EI-MS (m/z) 286 (M+). Step 3: A suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine (5.76 g, 20.2 mmol) in 100 mL of 2 M H2SO4 was refluxed for 1.5 hours until the suspension became clear. After cooling to RT, the solution pH was adjusted to 6-7 with 10 N NaOH, and the cloudy mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid, which was purified by CC using 1:1 EtOAc:hexane to yield 3.23 g (56%) of white solid JHX-2, mp 134-135° C. The structure was confirmed by 1H-NMR, 13C-NMR, ESI-MS and elemental analysis. 1H NMR (CDCl3) δ8.08 (s, 2H), 3.78 (appt, J=5.13 Hz, 4H), 3.29 (appt, J=5.13 Hz, 4H), 2.86 (s, 6H); 13C NMR (CDCl3) 156.9, 145.8, 143.5, 46.0, 44.3, 38.1; EI-MS (m/z) 287 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CON=C1CN(Cc2ccccc2)CC12CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Yield: 44 %

Procedure:
4.0 g of t-butyl-6-benzyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate was dissolved in 40 ml of methanol and thereto 4.0 g of 10% Pd-C was added. The resulting mixture was stirred for 2 hours under the pressure of hydrogen at 5° C. filtered and concentrated under the reduce pressure to give 1.3 g of the titled compound(yield: 87.9%).
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH2:22])=[CH:16][C:17]=2Cl)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)=[CH:16][C:15]([NH2:22])=[CH:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cc(Cl)c2c(c1)CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cc2c(c(Nc3ccc(C(F)(F)F)cc3)c1)CCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 79.1 %

Procedure:
Sodium iodide (252 mg, 1.68 mmol) and hydriodic acid (1 mL, 47% aqueous solution) were added to the solution of 2-benzyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-amine (380 mg, 1.4 mmol) and 4-aminobenzotrifluoride (446 mg, 2.8 mmol) in dioxane (10 mL) and the reaction solution was stirred at 100° C. over night before solvent was removed in vacuo. Residue was dissolved in ethyl acetate, washed by water, brine, dried over sodium sulfate and was purified by column chromatography. Product was obtained as brown oil (440 mg, 79%).
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[C:6]2[C:7](=[O:22])[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1.S(Cl)([Cl:26])=O>ClCCl>[Cl:26][CH2:2][C:3]1[CH:23]=[C:6]2[C:7](=[O:22])[NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cn2nc(CO)cc12
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cn2nc(CCl)cc12

Procedure:
82 mg (0.252 mmol) 2-Hydroxymethyl-6-(4-trifluoromethoxy-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one are treated with thionyl chloride in dichloromethane similar to WO2010/043676 (example G02) to give 2-chloromethyl-6-(4-trifluoromethoxy-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one as pale pink crystals; HPLC/MS 1.91 min (C), [M+H] 344;
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][NH2:29])[O:26][CH:27]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[O:26][CH:27]=1
Reactant: COCCNc1nonc1C(Cl)=NO
Reactant: NCc1cc(Cl)co1
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1nonc1C(=NO)NCc1cc(Cl)co1

Procedure:
The desired compound was prepared according to the procedure of Example 20, step C, using N-hydroxy-4-(2-methoxyethylamino)-1,2,5-oxadiazole-3-carbimidoyl chloride and 1-(4-chloro-2-furyl)methanamine trifluoroacetate as the starting material in quantitative yield. LCMS calculated for C11H15ClN5O4 (M+H)+: m/z=316.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=2)=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:8]([C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:16])([F:17])[F:15])[N:10]=1)=[C:19]=[O:21]
Reactant: Cc1sc(N)c(-c2nc(C(F)(F)F)no2)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1sc(N=C=O)c(-c2nc(C(F)(F)F)no2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.8 %

Procedure:
To a solution of 4,5-dimethyl-3-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-thiophen-2-ylamine (165 mg, 0.627 mmol, Int1.22) in THF (4 mL) was added triphosgene (149 mg, 0.501 mmol) and the reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated to yield the desired compound as a colorless solid (178 mg, 98%) which was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([OH:6])[OH:5])[CH3:2].C(O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=CC=1>>[CH2:1]([O:3][CH:4]1[O:6][CH:12]2[CH:11]([CH2:8][CH2:13]2)[O:5]1)[CH3:2]
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(O)O
Product: CCOC1OC2CCC2O1
Yield: 1013.7 %

Procedure:
130.8 g (1.5 mols) of cyclobutane-cis-1,2-diol, 222.6 g (1.5 mols) of orthoformic acid ethyl ester and 15.0 g of benzoic acid are heated from 90° to 120° C. in the course of 3 hours. The ethanol which forms is distilled off continuously. Fractional distillation in vacuo gives 179.5 g (83%) of 3-ethoxy-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture), boiling point11 63°.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].[C:59]([O:62][CH2:63][C:64](Cl)=[O:65])(=[O:61])[CH3:60]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:64](=[O:65])[CH2:63][O:62][C:59](=[O:61])[CH3:60])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1N
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1NC(=O)COC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]([NH:26][NH2:27])=[O:25])[CH:21]=[C:20]([Cl:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].CN([CH:32]=[O:33])C>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[O:25][C:32](=[O:33])[NH:27][N:26]=3)[CH:21]=[C:20]([Cl:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NN)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4n[nH]c(=O)o4)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N,N′-Carbonyldimidazole (0.021 g, 0.13 mmol) was added to a stirred solution of 3,4-dichloro-N-{1-[6-chloro-4-(hydrazinocarbonyl)pyridin-2-yl]piperidin-4-yl}-5-methyl-1H-pyrrole-2-carboxamide (Example 309) (30 mg, 0.06 mmol) in DMF (2 ml). The mixture was stirred at room temperature for 6 h. The mixture was filtered and purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) mixtures to give the title compound (15 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([N:16]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:23][C:22]2[C:17]1=[N:18][C:19]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:20][C:21]=2[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:13]([CH3:15])[CH3:14]>CN1CCCC1=O>[C:8]([N:28]1[CH2:27][CH2:26][N:25]([C:24]2[N:16]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:17]3[C:22]([N:23]=2)=[C:21]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:20]=[C:19]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)[N:18]=3)[CH2:30][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(C)C)CC1
Reaction time: 1 h
Yield: 61 %

Procedure:
Triethylamine (143 μl) and acetyl chloride (50 μl 0.72 mmol) were added to 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (2 ml of solution of 100 mg of this compound in 1 ml of N-methylpyrrolidone) and the resulting mixture was stirred for 1 hour. The resulting mixture was partitioned with ethyl acetate and water and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in methanol (2 ml) followed by the addition of 25% sodium methoxide-methanol solution (1 ml), and the resulting mixture was stirred for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Dimethyl sulfoxide (3 ml) was added to the residue, then the resulting mixture was partitioned with ethyl acetate and water, the organic layer was similarly dried, and then the solvent was evaporated to give the title compound (150 mg, 61%) as a pale yellow solid.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6](OCC)(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:17]1([CH:23]=[C:24]2[C:29](=[O:30])[C:28](=[CH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][S:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[O:13]=[C:6]1[O:30][C:29]2[C:28](=[CH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][S:26][CH2:25][C:24]=2[CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)OC2=C(CSCC2=Cc2ccccc2)C1c1ccccc1

Procedure:
To an ethanolic solution of sodium ethoxide [prepared from 555 mg (24 mg atom) of sodium in 50 ml of ethanol] is added diethyl malonate (3.52 g, 22 mmole) in 50 ml of absolute ethanol. After heating at reflux temperature for 2 hours, tetrahydro-3,5-bis(phenylmethylene)-4H-thiopyran-4-one (5.84 g, 20 mmole) is added. The resulting solution is then heated at reflux temperature for 2 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:24]([NH:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([N:28]([CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Cc1ccc(-c2cncc(Br)n2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
A mixture of 2-bromo-6-(4-methylphenyl)pyrazine (0.25 g, 1 mmol), N,N-diisopropylethylamine (0.35 mL, 2 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.42 g, 1.5 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature and the residue dissolved in CH2Cl2 (30 mL), the organic extract was washed water (15 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 40 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (37 mg).
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[C:16]([CH:20]2[O:24]CCO2)=[CH:17][S:18][CH:19]=1.[Li]CCCC.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:20]([C:16]1[C:15]([B:1]([OH:6])[OH:2])=[CH:19][S:18][CH:17]=1)=[O:24]
Reactant: Brc1cscc1C1OCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1cscc1B(O)O
Temperature: -78 °C
Yield: 95 %

Procedure:
To a 0.5M solution of B(Oi-Pr)3 (1.2 eq) in toluene/THF 4:1 was added a solution of 2-(4-bromo-3-thienyl)-1,3-dioxolane in toluene/THF 4:1, and the mixture was then cooled to −78° C. BuLi (1.5M in hexanes; 1.2 eq) was then added over 1 h, and the solution kept at this temperature for an additional h, then allowed to warm to −20° C. over 3 h; aq 1N HCl was added and the mixture stirred for an additional h at this temperature. Removal of volatiles gave an aqueous solution that was extracted with DCM; the combined organic phases were then washed with brine, dried over Na2SO4 and concentrated in vacuo. Yield: 95%.