Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH3:19])=[C:4]([NH:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>O.CO>[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:2]2[C:3]([CH3:19])=[C:4]([NH:11][C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(Cl)nn2ccnc2c1Nc1cccc(O)c1
Solvent: CO
Solvent: O
Product: Cc1c(N[C@H]2CC[C@H](N)CC2)nn2ccnc2c1Nc1cccc(O)c1
Reaction time: 24 h

Procedure:
In a 2 dram reaction vial was added 3-(6-chloro-7-methylimidazo[1,2-b]pyridazin-8-ylamino)phenol (0.011 g, 0.028 mmol) from 1a and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 24 hrs. The melt was then cooled, diluted with water and MeOH, and then purified by preparative HPLC to give 0.005 g of the title compound as a TFA salt. 1H NMR (400 MHz, MeOD) δ ppm 8.01 (1H, s), 7.73 (1H, s), 7.11 (1H, t, J=8.14 Hz), 6.48 (1H, d, J=7.63 Hz), 6.28 (1H, s), 3.88-4.10 (1H, m), 3.05-3.27 (1H, m), 2.24-2.37 (2H, m, J=8.65 Hz), 2.11-2.23 (5H, m), 1.45-1.70 (4H, m). LC/MS, m/e 353 (M+1). HPLC Rt, 1.20 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [F:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]>C(O)C.C(OCC)(=O)C.[Pd].[C]>[NH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[O:14][CH3:15]
Reactant: COc1c(F)cc([N+](=O)[O-])c(OC)c1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1c(N)cc(F)c(OC)c1F

Procedure:
The nitro group of 3,5-difluoro-2,4-dimethoxynitrobenzene (10.9 g, 49.7 mmol) is reduced by catalytic hydrogenation at 40 psi in ethanol/ethyl acetate over 10% Pd/carbon. Progress is monitored by TLC. When the reaction is complete, the catalyst is collected on a diatomaceous earth pad over a glass frit via filtration. The filtrate is concentrated in vacuo, giving pure 1-amino-3,5-difluoro2,4-dimethoxybenzene (2) as 9.40 g (99.8%) of a clear, pale brown oil: 1H NMR (CDCl3) 6.25 (dd, 1H), 3.89 (two s, 6H), 3.7 (br s, 2H); 19F NMR (CDCl3) 135.5 (d, 1F), 146.9 (s, 1F). Anal. calc. for C8H9NO2F2 : C, 50.80; H, 4.80; N, 7.40. Found: C, 50.61; H, 4.81; N, 7.26. The hydrochloride salt is obtained by treating a dioxane solution of 5 with 4M HCl in dioxane, collecting the precipitate on a Buchner funnel, rinsing with dioxane, and drying in vacuo to give the hydrochloride salt of Compound 2 as a bone-white powder: m.p. 213°-218° C. (dec.); 1H NMR (D2O) 7.1 (br d, 1H), 4.05 (br s, 6H); 19F (D2O) 131.1 (dd, 1F), 141.6 (s, 1F). Anal. calc. for C8 H10NO2F2Cl: C, 42.59; H, 4.47; N, 6.21. Found: C, 42.75; H, 4.47; N, 6.14.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[O:11])=[CH:4][C:3]=2[O:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc2c(c1)OCO2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc5c(c4)OCO5)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
Under argon, 4-hydroxyphenyl 3, 4-methylenedioxyphenyl ketone (202 mg) obtained in Example 136 and 4-dimethylaminopyridine (112 mg) were added to xylene (2 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (187 mg) was added, and the admixture was refluxed with heat for 20 hours. The reaction mixture was treated in the same manner as described in Example 124 to obtain 135 mg of the title compound (yield: 38%).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[N:9]=[C:8]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>C1COCC1>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S:12](=[O:17])(=[O:16])[N:13]([CH3:14])[CH3:15])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(S(=O)(=O)N(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(S(=O)(=O)N(C)C)n1
Reaction time: 8 h

Procedure:
Add 1 N lithium hydroxide (11.4 mL, 11.4 mmol) to a solution of (S)-2-sec-butylamino-6-dimethylsulfamoyl-isonicotinic acid methyl ester (1.43 g, 4.54 mmol) and THF (10 mL) at 0° C. Stir the mixture overnight, acidify the solution to about pH=2 and concentrate solvent to one half volume. Partition the residue between ethyl acetate and water, and extract the aqueous layer with ethyl acetate (2×30 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]1([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11]([C:3]1([NH:2][OH:1])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)=[O:13]
Reactant: CON1CCC(NO)(C(=O)O)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NO)CCN(OC)CC1

Procedure:
To a suspension of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid (1.0 g, 5.26 mmol) in methanol (25 ml) at 0-10° C. was added thionyl chloride (1.14 ml, 1.88 g, 15.77 mmol) and the reaction mixture was heated at reflux for 48 hours. After cooling, the mixture was concentrated, the residue diluted with ice water (20 ml) and neutralised with aqueous sodium bicarbonate. The aqueous phase was extracted with diethyl ether (3×25 ml), the combined organic layers washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Yield: 0.53 g of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P4ii.2) as a viscous, yellowish oil. This material was identical to the compound described above under preparation ‘EXAMPLE 11, Step 3’.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.C[O-].[Na+].[N+:20]([CH3:23])([O-:22])=[O:21].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH:8]2[C:13](=[O:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH2:23][N+:20]([O-:22])=[O:21])[CH:2]=1
Reactant: O=C1C(=Cc2cccnc2)N2CCC1CC2
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1C2CCN(CC2)C1C(C[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (6.4 g, 0.024 mol) in dry methanol (45 mL) was added drop-wise to sodium methoxide (produced in situ, 0.036 mol). Nitromethane (3.7 mL, 0.068 mol) was then added, and the mixture was heated at reflux for 3 h. After cooling to room temperature, 1 N HCl was slowly added to adjust pH to 8. The mixture was concentrated by rotary evaporation to yield a solid brown residue. The residue was purified by column chromatography, using ethyl acetate/hexane (1:1, v/v), followed by chloroform/methanol/ammonia (90:10:1, v/v), as eluent, to obtain a yellow oil (4.2 g, 64%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add 11 g of 4-bromoisoquinoline to 45 ml of sulphuric acid, followed, dropwise, by a solution of 9.1 g of potassium nitrate in 45 ml of sulphuric acid whilst cooling in an ice-bath. The reaction mixture is stirred at room temperature for 2 hours 30, before being poured onto ice. After the resulting solution has been rendered basic with ammonium hydroxide, the crystals are filtered off, washed and dried to yield the expected product.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1

Procedure:
4-cyanobenzoyl chloride (2 g, 12.08 mmol), DIEA (7.3 mL, 42 mmol), and 4-tert-butylaniline (1.9 mL, 11.9 mmol) were stirred in tetrahydrofuran (50 mL) overnight at room temperature. The tetrahydrofuran was removed under reduced pressure and replaced with ethyl acetate. The ethyl acetate was washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluant gradient from 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to afford the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.08–8.12 (m, 2H), 8.01–8.04 (m, 2H), 7.66–7.69 (m, 2H), 7.37–7.41 (m, 2H), 1.28 (s, 9H); MS (ESI+) m/z 279 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2ccc(N)cc2)cc1
Yield: 103.5 %

Procedure:
To a suspension of 2.18 g of methyl α-(p-tert-butylphenoxy)-α-[p-(p-nitrophenoxy)phenyl]acetate in 50 ml of methanol was added 160 mg of 10% palladium on carbon and the mixture hydrogenated with shaking. The mixture was filtered and the filtrate concentrated under vacuum to give 2.1 g of the product as a gum.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]([C:12]3[C:13](=[O:19])[NH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:10]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>>[CH3:1][C:2]1[O:3][C:4]2[CH:11]([C:12]3[C:13](=[O:19])[NH:14][C:15](=[O:18])[N:16]([CH2:26][C:27]4[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=4)[C:30]([O:32][CH3:33])=[O:31])[CH:17]=3)[C:10]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(Cn2cc(C3c4ccc(C)cc4C=Cc4nc(C)oc43)c(=O)[nH]c2=O)c1

Procedure:
The subtitle compound was prepared from the product of step (vii) and methyl 3-(bromomethyl)benzoate (690 mg) by the method of example 1 step (viii).
Reaction SMILES: [BrH:1].Br.[CH3:3][NH:4][CH2:5][CH:6]=[CH:7][CH2:8][NH:9][CH3:10]>CO.CC(O)C.O.[Pd]>[BrH:1].[BrH:1].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH3:10]
Reactant: CNCC=CCNC
Agent: [Pd]
Agent: Br
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CNCCCCNC
Yield: 181.5 %

Procedure:
N,N′-dimethyl-2-butene-1,4-diamine dihydrobromide 73 (35 g) dissolved in a mixture of MeOH (600 ml), i-PrOH (50 ml) and water (100 ml) was hydrogenated in the presence of 10% Pd/C (4 g) at 30 psi for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give N,N′-dimethylputrescine dihydrobromide 74 (32 g) as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[C:44]([CH3:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:36]4[O:37][C:38]5[C:44]([CH3:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:39]=5[N:40]=4)=[CH:33][CH:34]=3)[C:10]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.515 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.235 g, 0.644 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a yellow powder (0.185 g, 72%). 1H NMR (DMSO-d6, 400 MHz) 2.30-2.49 (m, 2H), 2.41 (s, 3H), 2.49 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 3.17 (m. 2H), 3.24 (s, 3H), 3.45 (t, 2H), 5.40 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.85 (s, 1H); RP-HPLC Rt 11.477 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 499 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:8]=[C:4]2[CH:3]=1.[NH2-].[Li+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:11][CH2:10][CH2:9][CH2:20][CH2:19][CH2:22][CH3:23])=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(c2ccccc2)c2ccccc2)c1

Procedure:
The compound prepared in Example 26 is refluxed in toluene in the presence of lithium amide and EXXAL® 8 (mixture of octanols, Exxon-Mobil) for four hours. The title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:33][C:34]1[CH:39]=[C:38]([O:40][C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:35]=1[N+:45]([O-:47])=[O:46].[NH4+].[Cl-]>CC(N(C)C)=O.C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:33][C:34]3[CH:39]=[C:38]([O:40][C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:35]=3[N+:45]([O-:47])=[O:46])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (840 mg, 2.68 mmol) in DMA (25 mL) was added NaHMDS (2.68 mL of a 1M solution in THF, 2.68 mmol). The reaction was stirred at room temperature for 5 minutes, and then 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene (967 mg, 3.22 mmol) was added by cannula in DMA (5 mL). After 15 minutes, the reaction was poured into saturated NH4Cl (50 mL). The mixture was extracted with EtOAc (150 mL) and the organic layer was washed with water and brine (40 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one. Rf=0.10 (15% EtOAc/hexanes). LCMS=533.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.16 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.80 (s, 2H), 7.44 (s, 1H), 7.33 (d, J=8.9 Hz, 1H), 5.78 (d, J=7.8 Hz, 1H), 4.94 (d, J=17.0 Hz, 1H), 4.79 (d, J=16.9 Hz, 1H), 4.25 (m, 1H), 0.81 (d, J=6.7 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH3:89])[C:10]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[CH3:32])[C:17]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:16]=2[N:15]([C:39]([C:41]2[CH:88]=[CH:87][C:44]([C:45]([N:47]3[C:53]4[CH:54]=[C:55]([C:58]#[N:59])[CH:56]=[CH:57][C:52]=4[N:51]([CH2:60][C:61]4[C:70]5[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=5)[CH:64]=[CH:63][C:62]=4[CH3:71])[C:50](=[O:72])[C@@H:49]([NH:73][C:74](=[O:86])[C@@H:75]([N:77](C)[C:78](=O)OC(C)(C)C)[CH3:76])[CH2:48]3)=[O:46])=[CH:43][CH:42]=2)=[O:40])[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:91]>O1CCOCC1>[ClH:91].[ClH:91].[C:37]([C:35]1[CH:34]=[CH:33][C:17]2[N:18]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[CH3:32])[C:19](=[O:20])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:6])[CH3:89])[CH2:14][N:15]([C:39](=[O:40])[C:41]3[CH:88]=[CH:87][C:44]([C:45]([N:47]4[C:53]5[CH:54]=[C:55]([C:58]#[N:59])[CH:56]=[CH:57][C:52]=5[N:51]([CH2:60][C:61]5[C:70]6[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=6)[CH:64]=[CH:63][C:62]=5[CH3:71])[C:50](=[O:72])[C@@H:49]([NH:73][C:74](=[O:86])[C@@H:75]([NH:77][CH3:78])[CH3:76])[CH2:48]4)=[O:46])=[CH:43][CH:42]=3)[C:16]=2[CH:36]=1)#[N:38]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(C)ccc5ccccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)NC)C(=O)N(Cc4c(C)ccc5ccccc45)c4ccc(C#N)cc43)cc2)c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.69 %

Procedure:
To a solution of tert-butyl N-[(1S)-2-[[(3S)-5-[4-[(3S)-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzoyl]-7-cyano-1-[(2-methyl-1-naphthyl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (27 mg, 0.022 mmol) in dioxane (3 mL) at 0° C. was added 4 M HCl in dioxane (2 mL). The mixture was stirred at 0° C. for 10 min, and the cooling bath was removed. After 16 h, the mixture was concentrated and the residue was triturated with diethyl ether to afford the title compound as a white solid (19 mg, 78.69%). LC-MS: 1013.8 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([N:24](CC(O)=O)[CH3:25])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:83])[CH3:82])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43][C:44](=[O:71])[C@H:45](C)NC(=O)CNC(=O)[C@H](CC1C=CC(O)=CC=1)NC(OC(C)(C)C)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:82])[CH3:83])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43][C:44](=[O:71])[CH2:45][N:24]([C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC(=O)O)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN(C)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-L-tyrosylglycylsarcosine is substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine of Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycylsarcosyl-L-phenylalanyl-L-leucine benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.[CH3:22][C@H:23]1[O:28][C@@H:27]([CH3:29])[CH2:26][NH:25][CH2:24]1>CN(C=O)C>[CH3:29][C@H:27]1[O:28][C@@H:23]([CH3:22])[CH2:24][N:25]([CH2:21][C@@H:19]([OH:20])[CH2:18][O:17][C:4]2[CH:5]=[CH:6][C:7]3[C:8]4[N:9]([CH2:14][CH2:15][N:16]=4)[C:10]([NH2:13])=[N:11][C:12]=3[C:3]=2[O:2][CH3:1])[CH2:26]1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Yield: 96.3 %

Procedure:
A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 1.50 g, 5.20 mmol) and cis-2,6-dimethylmorpholine (6.4 mL, 52.0 mmol, 10 equiv.) in DMF (36 mL) was heated in two portions in a microwave reactor for 45 min. at 140° C. The resulting combined mixtures were concentrated under reduced pressure and purified using MPLC to give N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine (2.02 g, 96%): Preparative HPLC ret. time 4.29 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.10 (d, J=7.3 Hz, 3H), 1.14 (d, J=7.3 Hz, 3H), 2.69 (t, J=11.6 Hz, 1H), 2.76 (t, J=11.6 Hz, 1H), 3.23-3.32 (m, 2H), 3.43-3.54 (m, 2H), 3.80 (s, 3H), 3.81-3.87 (m, 1H), 3.88-3.97 (m, 1H), 4.31 (app dd, J=8.6, 12.1 Hz, 2H), 4.35-4.43 (m, 1H), 7.22 (J=9.4 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H); mass spectrum m/z 404 ((M+1)+, 100%).
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4].C1(=O)CCCCC1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: CC(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Solvent: O
Product: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Yield: 75.5 %

Procedure:
Reflux 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol (8 g.) in toluene (450 cc.) containing cyclohexanone (120 cc.) and aluminium isopropoxide (5 g.) under nitrogen for 4 hours. Cool, and add water (15 cc.) dropwise, followed by anhydrous sodium sulphate. Filter the mixture, wash the residue with ether and combine the filtrate and washings, dry and evaporate finally at 90°/1.05 mm. to give 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17-one (6.0 g.), m.p. 124°-128°, (from methanol); infrared absorption peaks at 5.80, 6.02 μ.