Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH2:15][C@H:16]([OH:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].[OH-].[K+].C(O)(C)C>O>[CH3:25][C:24]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[N:9]=[CH:10][N:11]=[C:12]([NH:14][CH2:15][C@@H:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[OH:23])[CH:13]=3)=[CH:7][C:2]=2[O:29][N:28]=1
Reactant: CC(=O)c1ccc(-c2cc(NC[C@H](O)c3ccccc3)ncn2)cc1F
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1noc2cc(-c3cc(NC[C@H](O)c4ccccc4)ncn3)ccc12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A mixture of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenyl-ethyl]amino}-pyrimidin-4-yl)-phenyl]ethanone (88 mg, 0.25 mmol), hydroxylamine hydrochloride (41 mg, 0.60 mmol), KOH (85% aq., 0.158 mL), isopropanol (0.5 mL) and water (0.5 mL) was heated in a sealed tube at 90° C. for 10 h. An additional amount of KOH (85% aq., 2.38 mmol) was added and the temperature increased to 120° C. for an additional 21 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined extracts were dried (Na2SO4), concentrated, and the crude product purified (FCC) to yield the title compound (24 mg, 28%). MS (ESI): mass calcd. for C20H18N4O2, 346.14; m/z found, 347.2 [M+H]+. 1H NMR (CDCl3): 8.70 (d, J=0.8 Hz, 1H), 8.13 (dd, J=1.3, 0.8 Hz, 1H), 7.93 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (dd, J=8.3, 0.8 Hz, 1H), 7.45-7.37 (m, 4H), 7.34-7.30 (m, 1H), 6.80 (d, J=1.0 Hz, 1H), 5.35-5.30 (m, 1H), 5.03-4.99 (m, 1H), 3.94-3.87 (m, 1H), 3.67-3.60 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: C1([O:7][CH:8]2[CH2:12][C:11]([F:14])([F:13])[C:10]([F:16])([F:15])[C:9]2([F:18])[F:17])CCCCC1>S(=O)(=O)(O)O>[F:17][C:9]1([F:18])[C:10]([F:15])([F:16])[C:11]([F:13])([F:14])[CH2:12][CH:8]1[OH:7]
Reactant: FC1(F)CC(OC2CCCCC2)C(F)(F)C1(F)F
Agent: O=S(=O)(O)O
Product: OC1CC(F)(F)C(F)(F)C1(F)F

Procedure:
276 g (1 mol) of 2,2,3,3,4,4-hexafluorocyclopentyl cyclohexyl ether from Step 2 are added dropwise to 300 ml of concentrated sulphuric acid until the evolution of gas has ceased, and the cleavage product is distilled off at 130°-140° C. The mixture of the desired alcohol and cyclohexene is redistilled. In this manner, distillation gives 2,2,3,3,4,4-hexafluorocyclopentanol.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:24]([F:27])([F:26])[F:25])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>>[CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:24]([F:26])([F:27])[F:25])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(Cc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 25.4 %

Procedure:
Following general procedure D, methyl 2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.55 mmol) was reacted with lithium hydroxide (0.055 g) to afford the title compound (0.051 g, 25% over two steps) as a light yellow oil. MW=364.36. 1H NMR (DMSO-d6, 500 MHz) δ 12.27 (s, 1H), 7.72 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 4.17 (s, 2H), 3.52 (s, 2H), 3.41-3.33 (m, 1H), 2.08-1.99 (m, 2H), 1.89-1.60 (m, 6H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[CH2:13]1[CH2:18]CC(N=C=NC2CCCCC2)C[CH2:14]1>C(O)CC.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:9]([O:11][CH2:14][CH2:13][CH3:18])(=[O:10])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CCCOC(=O)/C=C/c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Coumaric acid (0.030 mol) is dissolved in 1-propanol (0334 mol) in a 100 ml round bottom flask. DCC (0.033 mol) is added followed by DMAP (0.003 mol). The mixture is stirred at 50° C. for 24 hours, filtered and the propanol removed under reduced vacuum to leave an oily solid which is taken up in ethyl acetate, washed with saturated aqueous NaHCO3 and distilled water, the ethyl acetate layer dried over MgSO4 to leave after removal of the ethyl acetate the desired product as a pale yellow solid in 71% yield.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:32]>CO>[ClH:32].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCC=CCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCC=CCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-(4-tetradecenyl)propane (450 mg) was dissolved in 27 ml of methanol and 9 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under a nitrogen atmosphere for 8 hours. The reaction mixture was neutralized with hydrochloric acid and concentrated. Water was added to the concentrate and the mixture was subjected to chromatography using Sep-Pak(C18) (trade mark) and elution with methanol. The methanol eluate was concentrated to give 332 mg of pale yellow, oily 2-amino-2-(4-tetradecenyl)1,3-propanediol hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[NH:38][CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4.C(N(CC)CC)C>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[N:38]([C:16]([C:12]4[CH:11]=[C:10]5[C:15](=[CH:14][CH:13]=4)[NH:7][CH:8]=[CH:9]5)=[O:18])[CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)c1ccc2[nH]ccc2c1)CC3
Temperature: 25 °C
Reaction time: 10 h
Yield: 27 %

Procedure:
Oxalyl chloride (15 ul, 0.14 mmol) at RT was added to a solution of indole-5-carboxylic acid (0.02 g, 0.12 mmol) in THF (1 ml). After stirring at RT for 10 h, the mixture was added THF (1 ml) followed by (+)-3-methoxy-morphinan hydrochloride (0.04 g, 0.12 mmol), then triethylamine (0.1 ml, 0.7 mmol) was added and stirred for 18 h. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was washed with saturated Na2CO3 (5 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give a crude pale brown oil. The crude product was purified by column chromatographed eluting with (MeOH: CH2Cl2=1:10) to give a pale yellow oil (0.013 g, 28% yield).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[C:9]3[C:10]4([C:30]5[C:21](=[CH:22][C:23]6[O:28][CH2:27][CH2:26][O:25][C:24]=6[CH:29]=5)[O:20][CH2:19]4)[C:11](=[O:18])[N:12]([CH3:17])[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[O:7])CCC1.Cl[CH2:32]Cl.C(OCC)C>>[CH3:32][N:5]([CH3:1])[C:6]([C:8]1[C:9]2[C:10]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11](=[O:18])[N:12]([CH3:17])[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:7]
Reactant: ClCCl
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)NC3CCC3)cccc21
Solvent: CCOCC
Product: CN(C)C(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Yield: 37 %

Procedure:
Phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (0.30 g, 0.70 mmol), cyclobutylamine hydrochloride (0.23 g, 2.1 mmol), potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0 mL) were added to a microwave reaction vessel. The reaction was heated at 110° C. for 1 h in a microwave reactor, allowed to cool to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 1 M hydrochloric acid (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 20% to 100% gradient of ethyl acetate in hexanes followed by recrystallization from dichloromethane/diethyl ether to afford N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.045 g, 17%) as a colorless solid: mp 128-129° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.41-7.33 (m, 1H), 7.26-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.51 (s, 1H), 6.20 (s, 1H), 5.46 (d, J=6.65 Hz, 1H), 4.96-4.81 (m, 2H), 4.35-4.01 (m, 5H), 3.25 (s, 3H), 2.27-2.09 (m, 2H), 1.70-1.40 (m, 4H); MS (ES+) m/z 407.0 (M+1). N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.12 g, 37%) was isolated as a byproduct from the synthesis of N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide, obtained as colorless solid: mp 218-221° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J=7.8, 7.8 Hz, 1H), 6.91-6.84 (m, 2H), 6.44 (s, 1H), 6.22 (s, 1H), 5.05 (d, J=8.8 Hz, 1H), 4.79 (d, J=8.8 Hz, 1H), 4.20-4.04 (m, 4H), 3.28 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 381.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a mixture of (3-chloropyrazin-2-yl)-(4-phenoxyphenyl)-methanol (12.0 g, 38.4 mmol), phthalimide (11.30 g, 76.8 mmol) and triphenylphosphine (20.10 g, 76.8 mmol) in THF (150 mL) in a flame-dried flask was added diisopropylazodicarboxylate (15.2 mL, 76.8 mmol) drop wise under nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 16 h. TLC (EtOAc/Hexanes, 1:1) showed no starting material left. Solvent was then evaporated to give a crude residue which was purified through column on silica gel using EtOAc/Hexanes (1:1). Yield: 10.5 g (61%); 1H NMR (CDCl3, 300 MHz) δ 6.91 (s, 1H), 7.01-7.22 (m, 5H), 7.39-7.43 (m, 4H), 7.78-7.82 (m, 2H), 7.89-7.94 (m, 2H), 8.40 (d, J=2.4 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: CC[C@H](C)[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H]([C@@H](C)CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 17 (470 mg, 1.59 mmol) and 1-bromopentadecane (0.63 mL, 3.18 mmol), alcohol 71 was obtained as a colorless oil (499 mg, 60% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCn1ccnc1

Procedure:
A mixture of 10.0 g. of N-[4-(1H-imidazol-1-yl)-butyl]isoindole-1,3(2H)-dione, 1.97 ml. of hydrazine hydrate and 100 ml. of ethanol was heated at reflux for 3 hours and then cooled. A 160 ml. of portion of 3N hydrochloric acid was added, the mixture was heated at reflux for one hour and then concentrated. The residue was stirred with 150 ml. of 3N hydrochloric acid and then filtered. The mother liquor was concentrated to dryness, diluted with 10 ml. of ethanol and cooled, giving 1H-imidazole-1-butanamine dihydrochloride (m.p. 132°-146° C.) which was recovered by filtration.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=O)=O)(C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:55][NH:56][C:57](=[NH:85])[C:58]1[CH:63]=[CH:62][C:61]([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[N:71]([CH3:83])[C:72](=[O:82])[CH:73]=[C:74]([C:76]4[CH:81]=[CH:80][N:79]=[CH:78][N:77]=4)[N:75]=3)[C@H:66]([CH3:84])[CH2:65]2)=[CH:60][CH:59]=1>CN(C)C=O.O>[NH2:8][CH2:9][C:10]1[O:55][N:56]=[C:57]([C:58]2[CH:59]=[CH:60][C:61]([N:64]3[CH2:69][CH2:68][N:67]([C:70]4[N:71]([CH3:83])[C:72](=[O:82])[CH:73]=[C:74]([C:76]5[CH:81]=[CH:80][N:79]=[CH:78][N:77]=5)[N:75]=4)[C@H:66]([CH3:84])[CH2:65]3)=[CH:62][CH:63]=2)[N:85]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@@H]1CN(c2ccc(C(=N)NO)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(-c3noc(CN)n3)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of N-tertbutoxycarbonylglycine (94 mg, 0.535 mmol) in N,N-dimethylformamide (2.0 ml) was added [2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (172 mg, 0.535 mmol), 1-hydroxybenzotriazole hydrate (14 mg, 0.107 mmol) and N,N-diisopropylethylamine (0.31 ml, 1.78 mmol), and the reaction mixture was stirred for 30 minutes at room temperature. After the addition of N-hydroxy-4-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzamidine (145 mg, 0.356 mmol), the reaction mixture was stirred for one hour at room temperature, and then heated to 110° C. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was treated with trifluoroacetic acid, and the reaction mixture was stirred for 1 hour. After removal of the solvent, the residue was purified with HPLC to afford 2-{(2R)-4-[4-(5-aminomethyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2-methyl-piperazin-1-yl}-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (44 mg, 0.096 mmol, 27%) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.S1(=O)(=O)[N:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[CH2:11]O1>>[I:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: Ic1cccc(I)c1
Reactant: O=S1(=O)OC[C@@H]2CCCN21
Product: Ic1cccc(C[C@@H]2CCCN2)c1

Procedure:
(S)-2-(3-Iodo-benzyl)-pyrrolidine was prepared from 1,3-diiodobenzene and (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide in analogy to the procedure described for Example 4 in U.S. Pat. No. 5,130,432. LC-MS A: tR=0.57 min; [M+H]+=287.99.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][OH:30])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[C:10]2[NH:9][C:8]([N:26]3[CH2:27][CH2:28][N:23]([C:22]4[N:21]=[CH:20][C:19]([CH2:29][OH:30])=[CH:18][C:17]=4[Cl:16])[CH2:24][CH2:25]3)=[N:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: OCc1cnc(N2CCNCC2)c(Cl)c1
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(Br)c4[nH]3)CC2)c(Cl)c1

Procedure:
4-Bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (180 mg, 0.6 mmol, Example 6b) reacted with (5-chloro-6-piperazin-1-yl-pyridin-3-yl)methanol (228 mg, 1 mmol, Example 60a) under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 490 (M+1).
Reaction SMILES: O=C(C1SC=CC=1)CC(OCC)=O.S1C=CC=C1C1C=CN=C(N)N=1.C[C:27]1([CH3:35])[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])O1.[F:36][C:37]1[CH:45]=[CH:44][C:40](C(O)=O)=[CH:39][CH:38]=1>>[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:29](=[O:34])[CH2:30][C:31]([O:32][CH2:27][CH3:35])=[O:33])=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)CC(=O)c1cccs1
Agent: Nc1nccc(-c2cccs2)n1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1

Procedure:
This material is prepared by a method analogous to that described for preparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D, starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-fluorobenzoic acid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:38]([OH:40])=O)[CH2:13][C:14]2[N:18]=[CH:17][N:16]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.[NH2:52][C@@H:53]([CH2:62][CH:63]([CH3:65])[CH3:64])[CH:54]([OH:61])[C:55]([O:57]C(C)C)=[O:56].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:61][CH:54]([CH:53]([NH:52][C:38](=[O:40])[CH:12]([NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[CH2:13][C:14]1[N:18]=[CH:17][N:16]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=1)[CH2:62][CH:63]([CH3:64])[CH3:65])[C:55]([OH:57])=[O:56]
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A mixture of 12.4 g (23.4 mmol) of N-[(phenylmethoxy)carbonyl]-1-(triphenylmethyl)-L-histidine, (Jones, J. H., et al, Synthesis, page 1110 (1987)) 3.3 g (24.6 mmol) of 1-hydroxybenzotriazole and 50 ml of dimethylformamide is cooled to <0° C. and treated with a mixture of 5.6 g (23.4 mmol) of (3S)-3-amino-2-hydroxy-5methylhexanoic acid, 1-methylethyl ester, monohydrochloride (mixture of isomers at hydroxy center) (Example B), and 2.5 g (25 mmol) of triethylamine in 30 ml of dimethylformamide at -5° C. The solution is stirred for five minutes, treated with 5.1 g (24.6 mmol) of dicyclohexylcarbodiimide in 30 ml of dimethylformamide and stirred for eight hours at -5 to 0° C., kept at -5° C. overnight, allowed to warm to room temperature under a nitrogen atmosphere and stirred for 24 hours. The mixture is treated with 1 g (10 mmol) of triethylamine, stirred at room temperature for 72 hours, filtered and the dimethylformamide evaporated in vacuo. The residue is dissolved in 200 ml of ethyl acetate, extracted with 200 ml of 1N citric acid solution, filtered, extracted with 200 ml of saturated sodium chloride solution, 200 ml of saturated solution of sodium bicarbonate and 200 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and the solvent evaporated in vacuo to give 14.1 g of the title compound as a tan foam.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]/[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C1COCC1>[OH:24][C:23]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:16][N:17]=1
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(O)nnc12
Temperature: 100 °C
Yield: 103.7 %

Procedure:
A solution of (2z)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (200 mg, 0.846 mmol), N,N-carbonyldiimidazole (1.65 g, 10.2 mmol) in THF (10 ml) was stirred at 70° C. overnight. The reaction mixture was then heated in microwave reactor at 100° C. for 10 min. The reaction was completed checked by LCMS analysis. The reaction mixture was concentrated, diluted with EtOAc and washed with sat. NaHCO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated to yield the desired product (230 mg, 98.4%). LCMS calculated for C11H15N6O2 (M+H) 263.1. found: 263.1.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][O:37][CH3:38])[N:30]=[CH:29][N:28]=[C:27]2[S:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>CN(C)C1C=CN=CC=1.C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([S:39][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:41]=2)=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3)c2cc1OC
Yield: 23 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as described in Example 162A (0.089 g, 0.3 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline from the previous step (0.107 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL), to afford 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.038 g, 23%). 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.84 (m, 1H), 7.28-7.54 (m, 5H), 6.78 (s, 1H), 4.72 (s, 2H), 4.56 (s, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s 3H), 1.29 (s, 3H); LC-MS (ESI) m/z 560 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH:21]=1>>[S:24]1[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]1=2
Reactant: BrCc1cc2ccccc2s1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc2ccccc2s1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)benzo[b]thiophene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.86 min.; [M+H]+: 382.22 g/mol.