Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].C([O-])(=[O:7])C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C1(CC(O)=O)C=CC=CC=1.N1CC=CN1.N=N.[CH3:35][C@H:36]1[C@:42]2([OH:56])[CH:43]3[C@:48]([OH:54])([CH2:49]C(CO)=[CH:51][C@H:41]2[C@H:40]([C:57]([CH3:59])=[CH2:58])[C:38](=[O:39])[CH2:37]1)[C:46](=[O:47])[C:45]([CH3:55])=[CH:44]3>>[CH3:35][C@H:36]1[C@:42]2([OH:56])[C@H:43]3[C@:48]([OH:54])([CH2:49][C:2]([CH2:1][OH:4])=[CH:51][C@H:41]2[C@@H:40]2[C:57]([CH3:58])([CH3:59])[C@:38]2([OH:39])[C@@H:37]1[OH:7])[C:46](=[O:47])[C:45]([CH3:55])=[CH:44]3
Reactant: C=C(C)[C@@H]1C(=O)C[C@@H](C)[C@]2(O)C3C=C(C)C(=O)[C@@]3(O)CC(CO)=C[C@@H]12
Reactant: CC(=O)[O-]
Agent: C1=CNNC1
Agent: N=N
Agent: O=C(O)Cc1ccccc1
Product: CC1=C[C@H]2[C@@]3(O)[C@H](C)[C@@H](O)[C@]4(O)[C@H]([C@@H]3C=C(CO)C[C@]2(O)C1=O)C4(C)C

Procedure:
Another embodiment is shown in FIG. 8. In this embodiment, the acidic hydrolysis of phorbol produces crotophorbolone, which is then used as the starting material. First, treatment of crotophorbolone with hydrazine in the presence of acetic acid selectively affords the C13 hydrazone (not shown), which without isolation is cyclized to pyrazoline S5a. Oxidation of pyrazalone S5a with lead (IV) tetraacetate gives cyclic diazene S7a, allowing for concomitant direct introduction of a C13 acetate group and a diazene bridge between C13 and C15. Other C13 esters can also be directly introduced with this procedure by using the corresponding lead (IV) carboxylate or related oxidants. Photolysis of cyclic diazene S7a results in the extrusion of nitrogen and reestablishment of the C13-15 cyclopropane bond, providing prostratin in high yield and in a remarkably concise four—step sequence from crotophorbolone, or five steps from phorbol with a 12-16% overall yield, producing over 100 mg of prostratin from a single run. DPP can be made in a similar manner. In this case, the acetate ligands of lead tetraacetate are exchanged by premixing with an excess of phenylacetic acid. The resulting salt induces the oxidative conversion of pyrazoline S5a to diazene S7b. (in 36% yield for three steps from crotophorbolone). Subsequent photolysis affords the natural product and therapeutic lead DPP in 90% yield, or 13% overall yield from phorbol. Details of this embodiment are described below in EXAMPLES 7 and 11.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C2C=[CH:15][C:16]3[CH2:17][C@H:18]4[N:29]([CH:30]=O)[CH2:28][CH2:27][C@@:24]5([C:25]=3[CH:26]=2)[C@H:19]4[CH2:20][CH2:21][CH2:22][CH2:23]5)C=CC=CC=1.[C:32]([O:35][CH2:36][CH3:37])(=O)[CH3:33].O>O1CCCC1>[O:35]([C:36]1[CH:37]=[CH:15][C:16]2[CH2:17][C@H:18]3[N:29]([CH3:30])[CH2:28][CH2:27][C@@:24]4([C:25]=2[CH:26]=1)[C@H:19]3[CH2:20][CH2:21][CH2:22][CH2:23]4)[C:32]1[CH:24]=[CH:25][CH:16]=[CH:15][CH:33]=1
Reactant: CCOC(C)=O
Reactant: O=CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(-c2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 73 %

Procedure:
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenyl-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hq) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:23][C:24]45[CH2:33][CH:28]6[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]6)[CH2:25]4)[CH2:31]5)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Solvent: O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC12CC3CC(CC(O)(C3)C1)C2
Yield: 91.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 3-aminoadamantan-1-ol hydrate (0.129 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(3-hydroxyadamantan-1-yl)acetamide as a white solid (0.275 g, 90.4% yield).
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)CCC.Br[C:15]1[CH2:19][CH2:18][O:17][N:16]=1.COC(=O)[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]=1>>[N:24]1[CH:23]=[CH:28][CH:27]=[C:26]([O:29][C:15]2[CH2:19][CH2:18][O:17][N:16]=2)[CH:25]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1ccc(O)cn1
Agent: CCCCOc1ccc(C=O)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-137a and I-137b were prepared in 3 steps from 4-butoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=370.1 m/z. Activity: A
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][C:3]=1[CH3:16].O.Cl>O1CCCC1>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[CH2:8][OH:9])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(C)(C)CO)cc(C)c1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propionic acid (4.45 g) is dissolved in 50 mL of tetrahydrofurane, borane methylsulfide complex (2.6 mL) is added and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is cooled to 0° C., 10% HCl water solution is added dropwise and the reaction mixture is extracted with dichloromethane. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (hexane/ethyl acetate 100:0→50:50) to give the title compound. Yield: 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Cl)c(Cl)c1

Procedure:
In a three-necked flask fitted with a Nichrome stirrer and a reflux condenser is placed 7.0 g of ethyl 3,4-dichlorophenylacetate, 5.9 g of N-bromosuccinimide, 0.1 g of benzoyl peroxide and 150 ml of carbon tetrachloride. The reaction mixture is heated at reflux for 18 hours, cooled and filtered. The carbon tetrachloride filtrate is concentrated under reduced pressure to give a deep orange liquid. Vacuum distillation at 115°-120° C. (0.5 mm) gives ethyl α-bromo-3,4-dichlorophenylacetate as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13](Br)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.[I:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](I)[N:21]=1>O1CCCC1.CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:22]3[CH:23]=[N:24][CH:25]=[C:20]([I:19])[N:21]=3)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Ic1cncc(I)n1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (1.0 g, 3.03 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (10 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2,6-diiodopyrazine (704 mg, 2.1 mmol, 0.7 equiv), Pd(PPh3)4 (175 mg, 0.2 mmol, 5 mol %) in tetrahydrofuran (2 mL) and dimethyl formamide (0.1 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 140° C. for 20 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 40:60, v/v] to afford 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 7%). MS (M+H)+=455.1, Rt=1.53 min.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([C:25]1[O:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)=[O:24]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:29]3[CH:28]=[CH:27][O:26][C:25]=3[CH:23]=[O:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 26, starting from methyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 40) and 2-formylfuran-3-boronic acid pinacol ester
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][C:14]1[Se:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]1[Se:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Cc1nc2ccccc2[se]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Product: O=[N+]([O-])c1ccc(Cl)c(C=Cc2nc3ccccc3[se]2)c1
Yield: 44 %

Procedure:
This compound was prepared in a similar manner in 44% yield from 2-chloro-5-nitrobenzaldehyde and 2-methylbenzoselenazole, mp 201°-203° C., UV λmaxEtOH nm (ε) 208(31164), 225(31164), 331(34291); 1H-NMR δTMSCDCl3 (ppm) 8.61 (d, J=2.7 Hz, 1H), 8.20-7.26 (complex pattern, 8H); 13C-NMR δTMSCDCl3 (ppm) 169.2, 146.9, 140.2, 135.1, 131.7, 131.1, 130.1, 128.8, 128.5, 126.7, 126.1, 125.1, 124.8, 124.0, 121.9; IR νmaxKBr (cm-1) 1643.4, 1604.3, 1565.8, 1517.9, 1481.0, 1460.6, 1384.3, 1342.7, 1282.2, 1243.8, 1130.7, 1115.4, 1090.0, 910.9, 829.2, 815.2. Anal. Calcd. for C15H9ClN2O2Se: C, 49.53, H, 2.50, N, 7.70. Found: C, 49.66, H, 2.55, N, 7.77.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:35]1[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=[C:34]1[CH:30]1[CH2:31][CH2:32][CH2:33][O:29]1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]c(C3CCCO3)nc2c1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CCCO4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(tetrahydrofuran-2-yl)-1H-benzimidazole were reacted to give 224. LCMS m/z: 561.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7]([CH2:15][CH2:16][NH:17][C@H:18]1[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]1)[N:6]=[CH:5]2.O.[OH-].[Li+:28]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH2:16][NH:17][C@H:18]1[CH:23]3[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]3)[CH2:19]1)[N:6]=[CH:5]2.[Li+:28]
Reactant: COC(=O)c1cc(Cl)cc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cc(Cl)cc2cnn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Yield: 120.5 %

Procedure:
A mixture of (S)-methyl 5-chloro-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate (525 mg, 1.5 mmol) from Step D above and lithium hydroxide monohydrate (183 mg, 4.4 mmol) in tetrahydrofuran/water (14 mL, 1:1) was stirred at room temperature until the reaction was complete by TLC (2-3 h). The solvent was removed under reduced pressure to give lithium (S)-5-chloro-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-7-carboxylate as a green solid (641 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.71 (s, 1H), 7.48 (s, 1H), 4.80 (t, J=6.6 Hz, 2H), 3.10-2.96 (m, 2H), 2.95-2.88 (m, 1H), 2.80-2.58 (m, 5H), 2.33-2.27 (m, 1H), 1.80-1.76 (m, 1H), 1.72-1.60 (m, 2H), 1.60-1.40 (m, 1H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 349 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[C:39]([F:44])[CH:38]=1>C(OCC)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:41][C:40]1[CH:42]=[CH:43][C:37]([Br:36])=[CH:38][C:39]=1[F:44])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.54 g, 4.5 mmol) was dissolved in 50 mL diethyl ether under an Ar atmosphere, cooled in an ice water bath, added dry pyridine (1.4 mL, 17.8 mmol), followed by the dropwise addition of oxalyl chloride (0.58 mL, 6.7 mmol). Reaction was stirred at 0° C. for 1 hour, then at ambient temperature for 1 hour. Diluted reaction with 50 mL diethyl ether, filtered off solids and concentrated filtrates. Redissolved filtrate in 30 mL dry DCM under an Ar atmosphere, cooled in an ice water bath, added 1 mL dry pyridine followed by 4-bromo-2-fluoroaniline (0.85 g, 4.5 mmol). Stirred reaction at ambient temperature for 20 hours. Concentrated solution, redissolved in EtOAc (150 mL), washed with 10% citric acid (3×100 mL), water (2×100 mL), brine, dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluting with an automated system with gradient of 0-60% EtOAc in hexanes over 40 minutes. Combined and concentrated pure fractions to yield title compound as a clear oil. (0.96 g, 42%) APCI (AP−): 515.1, 517.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:11][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: Cc1c(C(N)=O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(N)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
2-Methyl-3-nitrobenzamide (8.85 g) was dissolved in a mixture solvent of ethanol (300 ml) and tetrahydrofuran (200 ml), followed by addition of 10% palladium-carbon (800 mg). The resulting mixture was stirred under hydrogen atmosphere at ambient temperature and atmospheric pressure for 6 hours. After insoluble materials were filtered off, the filtrate was concentrated under reduced pressure and washed with isopropyl ether, to afford the entitled compound as white solid (6.73 g, 91%). The physico-chemical values are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.84–6.88 (dd, 2H), 6.58 (s, 1H), 5.04 (s, 2H), 4.3–4.38 (q, 2H), 3.62–3.80 (m, 4H), 3.02–3.14 (m, 4H), 2.3 (s, 3H), 1.32–1.38 (t, 3H). 13C NMR (400 MHz, CDCl3): 180, 165, 119, 116.2, 116, 109, 61.8, 52, 51.5, 50.8, 45.8, 42.6, 14.4, 10.2.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:33][O:32][C:30](=[O:31])/[CH:29]=[CH:8]/[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/Cc1ccccc1
Yield: 80.5 %

Procedure:
To a solution of phenyl acetaldehyde (5.0 g, 41.61 mmol) in toluene (500 mL) was added methyl (triphenylphosphoranylidene)acetate (13.9 g, 41.61 mmol). The reaction mixture was stirred at reflux for 3 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was added ether/hexane (=1:1, v/v) at 0° C. then stirred for 30 min. The filtrate was concentrated then purified by a silica gel column to produce the title compound (5.9 g, 70˜90%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH3:13])=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:18](Cl)(=[O:20])[CH3:19].Cl>ClCCCl>[CH3:1][O:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(C)CCC2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc2c(cc1C(C)=O)CCCC2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a stirring solution of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene (6.3 g, 35.74 mmol) in 60 mL 1,2-dichloroethane at 0° C. under nitrogen as added aluminium trichloride (5.24 g, 39.32 mmol), followed by acetyl chloride (2.8 mL, 39.32 mmol). The resulting mixture was stirred for 18 hours at room temperature, then was poured into cold 5% aqueous HCl and extracted with methylene chloride. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield 5.1 g of 1-(3-methoxy-5-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone, MP=48-50° C.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([O:5]C(C)(C)C)=O.[C:45]1([CH2:51]C(Cl)=O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([CH2:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:5]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:6]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2cc(Br)ccc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(5-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=4)[N:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([O:34][CH2:33]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[OH:34][C:32]1([CH2:33][O:21][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:8]2[N:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]4=[N:10][N:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:36][CH2:35]1
Reactant: Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1ccn2c(-c3ccc4cccc(OCC5(O)CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 98 °C
Yield: 48.2 %

Procedure:
A mixture of 2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (prepared according to Example 1; 20 mg, 0.72 mmol), tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (178 mg, 0.83 mmol) and cesium carbonate (472 mg, 1.5 mmol) in dimethylacetamide (2.5 mL) was heated to 98° C. overnight. The mixture cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of dichloromethane to 1:9 methanol/dichloromethane to provide 170 mg (48%) of desired product.