Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:38])[C:19]([C:35](O)=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[CH:16][C:15]=2[F:39])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:42](CC)CC)C.ClC(OC(C)=C)=O.[OH-].[NH4+]>ClCCl.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:38])[C:19]([C:35]([NH2:42])=[O:36])=[CH:20][N:21]3[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])=[CH:16][C:15]=2[F:39])[CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1
Agent: C=C(C)OC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(N)=O)c(=O)c3cc(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1
Reaction time: 0.5 h

Procedure:
A suspension of EXAMPLE 75B (350 mg) and triethylamine (0.098 mL) in dichloromethane (4 mL) and THF (3 mL) at 0° C. was treated with isopropenyl chloroformate (0.077 mL), stirred for 30 minutes, treated with concentrated ammonium hydroxide (0.100 mL), stirred for 18 hours at ambient temperature, loaded onto a flash silica gel column, and eluted with a methanol/dichloromethane gradient.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[CH3:11][N:10]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:22]3[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)=[CH:15][C:6]=2[C:7]([CH3:13])([CH3:14])[O:8][C:9]1=[O:12]
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc([N+](=O)[O-])cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-nitrophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 328 ([M+H]+); MS (ESI) m/z 326 ([M−H]−); Anal. calcd for C17H17N3O4: C, 62.38; H, 5.23; N, 12.84. Found: C, 62.03; H, 5.15; N, 11.41.
Reaction SMILES: [C:1]1([P:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:9]2[C:10]([CH3:31])=[C:11]3[C:15](=[C:16]([CH3:30])[C:17]=2[C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][C:19]=2[O:28][CH3:29])[CH2:14][O:13][CH2:12]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C1C2C(=CC=CC=2)C=CC=1.Cl[SiH](Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C(OCC)C>[C:32]1([P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[C:10]([CH3:31])=[C:11]3[C:15](=[C:16]([CH3:30])[C:17]=2[C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][C:19]=2[O:28][CH3:29])[CH2:14][O:13][CH2:12]3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc2ccccc2c1-c1c(C)c2c(c(C)c1P(=O)(c1ccccc1)c1ccccc1)COC2
Agent: Cl[SiH](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: c1ccc2ccccc2c1
Product: COc1ccc2ccccc2c1-c1c(C)c2c(c(C)c1P(c1ccccc1)c1ccccc1)COC2
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
(−)-5-(Diphenylphosphinoyl)-6-(2-methoxynaphthalen-1-yl)-4,7-dimethyl-1,3-dihydroisobenzofuran (800 mg, 1.59 mmol, 92% ee) was placed into a flask and the atmosphere in the flask was replaced with nitrogen. Triethylamine (4.4 mL, 31.8 mmol) was added to a solution of this naphthalene compound in xylene (40 mL), and cooled to 4° C. Further, trichlorosilane (800 μL, 7.95 mmol) was added dropwise, and the mixture was stirred for 30 minutes and then stirred at room temperature for 15 minutes. Further, the reaction mixture was heated to 110° C. and stirred for 3 hours. After the resulting reaction mixture was cooled to room temperature, diethyl ether (60 mL) and saturated aq. sodium bicarbonate (800 μL) were added, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite, and after the filtrate was dried with sodium sulfate. After silica gel was added, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (694 mg, 89%, 92% ee).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:10](=O)[C:9]2=[O:21])=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>Cl.CO>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:10]3[C:9](=[O:21])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:15]([F:18])([F:17])[F:16])=[N:32]2)=[CH:27][CH:26]=1
Reactant: O=C1C(=O)N(c2ccc(I)cc2)CCC1C(=O)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione from Part C (10.0 g, 24.3 mmol) and 4-methoxyphenylhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in HCl (1N, 200 mL) and methanol (400 mL). The mixture was refluxed overnight. The reaction mixture was cooled to room temperature and quenched with water. It was extracted with ethyl acetate, washed with brine, and dried (Na2SO4). Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent afforded the desired pyrazole 9.28 g (74%). 1HNMR (CDCl3) δ 7.69 (d, 2H), 7.45 (d, 2H), 7.06 (d, 2H), 6.92 (d, 2H), 4.11 (t, 2H), 3.81 (s, 3H), 3.15 (t, 2H) ppm; Mass Spec (M+H)+514.3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][C:15]2[O:19][C:18]([C:20](Cl)=[O:21])=[CH:17][CH:16]=2)=[CH:4][C:5]2[C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[CH3:24][O:25][C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:27]=1[NH2:28].C(N(CC)CC)C>C(OCC)(=O)C>[O:25]([C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:27]=1[NH:28][C:20]([C:18]1[O:19][C:15]([CH2:14][C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]([CH3:13])([CH3:12])[C:5]=3[CH:4]=2)=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: Cc1cc2c(cc1Cc1ccc(C(=O)Cl)o1)C(C)(C)CCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(NC(=O)c2ccc(Cc3cc4c(cc3C)CCCC4(C)C)o2)c(OC)c1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoyl chloride (10 eq, 0.32 mmol, 0.2M) in 2 mL ethyl acetate, the 2,4,6 trimethoxy aniline mono HCl salt (10 eq, 0.32 mmol) was added. Triethyl amine (excess) was added to this mixture and stirred overnight. The crude product was dried under vacuo and purified through plug column chromatography (1:100 crude mass/silicagel ratio) by eluting with 20 and 30 percent ethyl acetate/hexane solution. In some cases, the regio-isomers were separated by recrystallization in twenty five percent ethyl acetate/hexanes (1 g/75 mL compound/volume) to yield N-(2,4,6-trimethoxylphenyl)-5-[(3,8,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furamide (120 mgs, 82% yield). 1H NMR (CDCl3) 7.28 ppm (1H, broad), 7.12 (1H, s), 7.08 (1H, 3=3.40 Hz, d), 6.89 (1H, s), 6.19 (2H, s), 6.00 (1H, J=3.40 Hz, d), 3.97 (2H, s), 3.83 (3H, s), 3.82 (6H, s) 2.73 (2H, J=6.05 Hz, t), 2.25 (3H, s), 1.84-1.76(2H, multiplet), 1.69-1.63 (2H, multiplet), 1.59 (3H, s), 1.26(6H, s) elemental: expected C(72.55), H(7.18), N(3.02); actual C(72.67), H(7.22), N(2.98).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:16][CH:17]=O.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:30]([CH:38]3[CH2:43][CH2:42][N:41]([CH2:17][CH2:16][N:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]4=[O:1])[CH2:40][CH2:39]3)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2ccccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4 mL of a chloroform solution containing methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate, 0.12 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.03 g of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 0.11 g of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 109 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18](O)=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46].O>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH2:17][C:18]([NH:45][OH:46])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1C(=O)c2ccccc2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (1.1 g, 2.6 mmol) in tetrahydrofurane was added carbonyldiimidazole (0.73 g, 4.5 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 2.3 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was purified by silica gel chromatography (ethyl acetate:hexane=2:1) to give 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-hydroxy-propionamide as a white solid (700 mg, 61%): mp 129-131° C.; 1H NMR (DMSO-d6): δ 0.33-0.35 (m, 2H), 0.54-0.57 (m, 2H), 1.15-1.30 (m, 1H), 3.11 (d, J=5 Hz, 2H), 3.87 (d, J=7.5 Hz, 2H), 5.71 (t, J=7.5 Hz, 1H), 6.95-6.98 (m, 1H), 7.03 (t, JH-F=75 Hz, 1H), 7.11-7.17 (m, 2H), 7.85 (s, 4H), 8.80 (s, 1H), 10.60 (s, 1H). 13C NMR (CDCl3): δ 0.7, 3.9, 3.9, 10.8, 35.7, 52.0, 74.6, 112.6, 114.9, 116.7, 120.8, 120.9, 123.6, 124.2, 132.3, 135.00, 137.7, 140.9, 151.3, 169.0; Anal. Calcd. for C22H20F2N2O6: C, 59.19; H, 4.52; N, 6.28; Found: C, 58.98; H, 4.41; N, 6.16.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:23]([N:22]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
12.65 mmol of succinic anhydride (1.266 g), 12.65 mmol of 4-dimethylaminopyridine (1.546 g) and 10.75 mmol of ditetradecylamine (4.407 g) were successively added to 125 ml of dichloromethane in a round-bottomed flask. The reaction mixture was stirred for 18 hours at room temperature. Once the reaction was complete, the mixture was extracted with dichloromethane and hydrochloric acid (1N). The organic phase was then washed with brine and dried over magnesium sulfate, filtered and then concentrated to give 4.21 g of product (3) (yield: 66%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:20]([O:24][C:25](=[O:53])[NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[O:50][CH3:51])[C:34]=2[NH2:52])[CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:20]([O:24][C:25](=[O:53])[NH:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]3[N:40]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=4[O:50][CH3:51])[C:2](=[O:4])[NH:52][C:34]=23)[CH2:28]1)([CH3:22])([CH3:21])[CH3:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CNc2nc(C)cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)[nH]c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Temperature: -10 °C
Yield: 65.1 %

Procedure:
1.42 g triphosgene (4.78 mmol) was dissolved in 10 mL dichloromethane, and cooled to −10° C. 1.77 mL triethylamine (12.72 mmol) was added. A solution of 1.5 g (R)-1-[2-(2,4-dimethoxybenzyl)amino-6-methyl-3-aminopyridin-4-yl]piperidine-3-carbamic acid tert-butyl ester (3.18 mmol) in dichloromethane (20 mL) was slowly added dropwise at −10° C. After they were completely reacted, the reaction solution was adjusted to be basic by adding saturated sodium carbonate solution, and extracted twice with dichloromethane. The combined organic phase was washed with brine, dried with anhydrous sodium sulfate, and evaporated to dryness. The resultant crude product was recrystallized with dichloromethane and ethyl acetate to afford 1.03 g titled product with a yield of 65.2%.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]/[CH2:7][C:8]1[C:13]([O:14]C(=O)C)=[C:12]([CH3:18])[C:11]([CH3:19])=[C:10]([O:20]C(=O)C)[C:9]=1[CH3:24])/[CH2:3][C:4]#[N:5].C=C(CCC1C(OC(=O)C)=C(C)C(C)=C(OC(=O)C)C=1C)CC#N.C[O-].[Na+].O>CO.CCOCC>[OH:20][C:10]1[C:11]([CH3:19])=[C:12]([CH3:18])[C:13]2[O:14][C:2]([CH3:1])([CH2:3][C:4]#[N:5])[CH2:6][CH2:7][C:8]=2[C:9]=1[CH3:24]
Reactant: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(C/C=C(/C)CC#N)c1C
Agent: C=C(CC#N)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A slurry of 500 mg (1.52 mmoles) of the mixture of E-and Z-3-methyl-5-(2,4,5-trimethyl-3,6-diacetyloxyphenyl)-3-pentenenitrile and 3-methylene-5-(2,4,5-trimethyl-3,6-diacetyloxy-phenyl)pentanenitrile in 5 ml of methanol was treated with 0.71 ml (3.34 mmoles) of a 4.7 M methanolic sodium methoxide solution. The resulting mixture was stirred at room temperature for 4.5 hr, then poured into 20 ml of water and worked-up with ether in the usual manner affording 345 mg (93%) of rac. 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a tan solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[BH4-].[Na+].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][O:7][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: O=Cc1nccs1
Reactant: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Product: CS(=O)(=O)OCc1nccs1

Procedure:
Amine preparation: 2-Thiazolecarboxaldehyde was converted to the corresponding alcohol by treatment with sodium borohydride. Reaction with methanesulfonyl chloride yielded methanesulfonic acid thiazol-2-ylmethyl ester. A mixture of methanesulfonic acid thiazol-2-ylmethyl ester (393 mg), (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (described previously, 435 mg), potassium carbonate (309 mg) and tetrabutyl ammonium iodide (827 mg) was heated to reflux in MeCN (10 mL). After 4 days the reaction mixture was cooled, diluted with ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give (R)-3,5-dimethyl-4-thiazol-2-ylmethyl-piperazine-1-carboxylic acid (S)-tert-butyl ester (314 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([NH:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])[N:11]2[C@@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:7][N:6]=1)[CH3:3].CC(NC1N=C2C(N=C(NC3C(F)=CC(F)=CC=3F)N2[C@H](C)CCC(OC)=O)=CN=1)C>>[CH3:3][CH:2]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([NH:21][C:22]3[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=3[F:28])[N:11]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:7][N:6]=1)[CH3:1]
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n([C@@H](C)CCC(N)=O)c2n1
Agent: COC(=O)CC[C@@H](C)n1c(Nc2c(F)cc(F)cc2F)nc2cnc(NC(C)C)nc21
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n([C@H](C)CCC(N)=O)c2n1
Yield: 57 %

Procedure:
The title compound was prepared as (4S)-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}pentanamide with methyl (4R)-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}pentanoate (500 mg, 1.15 mmol) to give the title compound (273 mg, 57%): ES-MS (m/z) 422.3 [M+1]+.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[C:30]#[N:31])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=C(C#N)C=CN=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=3)[C:30]#[N:31])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cc(C#N)ccn2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: N#Cc1ccnc(Cl)c1
Product: N#Cc1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 75 %

Procedure:
2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)isonicotinonitrile. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (110 mg, 0.166 mmol) and 2-chloro-4-cyanopyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (72 mg, 75%): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 1H, J=5.0, 0.9 Hz), 7.84 (s, 1H), 7.74 (s, 1H), 7.43 (dd, 1H, J=5.0, 1.4 Hz), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 4.88 (dd, 1H, J=7.3, 6.6 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.93 (m, 2H), 1.61 (m, 2H), 1.36 (m, 4H), 0.91 (s, 9H), 0.12 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.7, 150.8, 149.0, 148.6, 142.7, 128.3, 128.2, 127.1, 125.5, 123.7, 121.4, 120.2, 116.1, 68.6, 36.4, 35.8, 31.3, 29.0, 25.6, 25.6, 25.0, 18.1, −5.0, −5.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:23](=[O:25])[CH3:24])[CH:8]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccccc1
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1c1ccccc1
Yield: 92 %

Procedure:
1-Nitro-5-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 27 to give 1-nitro-5-phenyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 156°-157° C. Yield: 92%.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[C:17]([O:21][C:22](=[O:33])[CH2:23][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH:24]([C:25](=[O:26])[NH:7][O:6][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:23][C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:33])[CH3:32]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)ON
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)NOC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a stirring solution of O-tert-butyl hydroxylamine hydrochloride (3.67 g, 29.3 mmol) in dry THF (30 mL) at room temperature was added diisopropylethyl amine (3.60 g, 27.9 mmol). To the resulting mixture was transferred the compound of example 58 (6.87 g, 27.9 mmol), as a solution in dry THF (30 mL), followed by HOBt (5.35 g, 27.9 mmol). The mixture was cooled to 0° C. and EDC (5.35 g, 27.9 mmol) was added in one portion. The reaction mixture was then allowed to warm to room temperature and was stirred for 24 h. The solvent was evaporated and the residue was taken-up into 500 ml of ethyl acetate and subsequently washed with a 5% aqueous solution of KHSO4 (2×200 mL), with a 5% aqueous solution of NaHCO3 (2×200 mL), and finally with water. After drying (anhydrous MgSO4) and evaporation, the crude product was purified by flash chromatography (SiO2, 60% hexane-40% ethyl acetate) to afford 5.93 g (66.0% yield) of the desired product: 1H NMR (CDCl3, 400 MHz) 8.61 (s, 1H), 4.20 (q, 2H), 3.55 (t, 1H), 2.93 (d, 3H), 1.43 (s, 9H), 1.28 (s, 9H); 13C NMR (CDCl3, 400 MHz) 195.8, 171.2, 169.7, 83.1, 81.9, 62.4, 46.8, 34.1, 28.4, 26.6, 14.5.