Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([Br:15])[CH3:11])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C(C)Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-hydroxy-ethyl)-benzoic acid methyl ester (Step B, 2.12 g, 11.7 mmol) in CH2Cl2 (25 mL) at 0° C. were added carbon tetra bromide (5.07 g, 15.3 mmol) and triphenylphosphine (3.71 g, 14.04 mmol). The reaction mixture was stirred overnight at room temperature, after completion of the reaction, was poured into H2O (50 mL). The aqueous solution was extracted with CH2Cl2 (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography in hexanes/ethyl acetate (5%) to afford 4-(1-bromo-ethyl)-benzoic acid methyl ester as a colorless liquid. (2.45 g, 85%): 1H NMR (300 MHz, CDCl3): δ 8.0 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 5.11 (q, J=6.9 Hz, 1H), 3.91 (s, 3H), 1.83 (d, J=6.9 Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: ClCc1cccnc1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCc1cccnc1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 32, 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-chloromethylpyridine, hydrochloride salt to give 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-pyridylmethoxy)-quinazoline in 18% yield;
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[N:33]=[CH:34][C:35]([C:38]([OH:40])=O)=[N:36][CH:37]=3)=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].CN>ClCCl>[CH3:1][NH:3][C:38]([C:35]1[N:36]=[CH:37][C:32]([O:31][C:29]2[CH:28]=[CH:27][C:24]3[CH2:25][CH2:26][N:20]([C:18]([O:17][C:14]([CH3:13])([CH3:16])[CH3:15])=[O:19])[CH2:21][CH2:22][C:23]=3[CH:30]=2)=[N:33][CH:34]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3cnc(C(=O)O)cn3)cc2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
1,1′-Carbonyldiimidazole (16.6 g, 102 mmol) was added to a solution of 5-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylic acid (D49, Step 2) (37.5 g, 97 mmol) in dry dichloromethane (400 ml) and the resulting mixture was stirred at room temperature for 18 hours. Methylamine (2M solution in tetrahydrofuran) (100 ml) was added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue was purified by column chromatography eluting with a mixture of ethyl acetate:chloroform (1:1) to afford the title compound (25.8 g); MS (ES+) m/e 399 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]\[C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)#[CH:2].I[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.O>CN(C)C=O.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])/[C:6]/3=[CH:13]\[C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Temperature: 70 °C

Procedure:
A solution of (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.43 mmol) (from Example 82) and 4-iodophenol (104 mg, 0.47 mmol) (Aldrich) in N,N-dimethylformamide (2 mL) and triethylamine (2 mL) was degassed by bubbling argon through the solution for 15 minutes. Copper(I) iodide (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (25 mg, 0.021 mmol) (Aldrich) were added, and the reaction was heated at 70° C. for 16 hours. Water (15 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane to give (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 121 mg, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:20][C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:22]=1>C(O)C>[O:30]1[CH2:29][CH2:28][N:27]([C:25]2[N:24]=[C:23]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[C:22]3[CH:6]([C:5]4[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=4)[C:12]([C:11]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:15])[NH:20][C:21]=3[N:26]=2)[CH2:32][CH2:31]1
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2nc(N3CCOCC3)nc(N3CCOCC3)c2C1c1cccc(C#N)c1

Procedure:
0.8 g (6 mmol) of 3-cyanobenzaldehyde, 0.8 g (6 mmol) of ethyl acetoacetate and 1.6 g (6 mmol) of 6-amino-2,4-dimorpholino-pyrimidine were heated together in 20 ml of ethanol for 15 hours under reflux. The reaction mixture was then cooled, and the precipitated product was filtered off with suction and recrystallized from a little ethanol, melting point: 210° C. Yield: 1.8 g (61%).
Reaction SMILES: [OH-].[Na+].C[C@:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:5]([O-:7])=[O:6].Cl>O1CCCC1.CO.O>[C:36]([O:35][C:33]([NH:32][C@@H:4]([CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
1N Sodium hydroxide solution (2.14 mL, 2.14 mmol) was added dropwise to a stirred solution of (2R)-Methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate (552 mg, 1.07 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound has a white solid (486 mg, 90%), m.pt. 171-173° C. Rf: 0.35 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz): δ 7.86 (2H, d, J=8 Hz, Ar—H), 7.68 (6H, m, Ar—H), 7.61 (1H, d, J=8 Hz, Ar—H), 7.43 (2H, d, J=8 Hz, Ar—H), 7.11-7.22 (2H, m, Ar—H), 6.80 (1H, br s, NH), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.06 (1H, m, CHN), 3.80 (2H, s, PhCH2), 2.86 (1H, dd, J=13, 5 Hz, CHHCHN), 2.72 (1H, dd, J=13, 8 Hz, CHHCHN), 1.40 (9H, s, CMe3), ESI-LCMS e/z calcd for C29H30N2O4S: 502.632, found 503 (M+H)+, 525 (M+Na)+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.CN1CCOCC1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=CC#N
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCOCC1
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccc(C=O)cc1
Yield: 8.4 %

Procedure:
3.91 mg (1.6×10-5 mols) of palladium acetate, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 2.63 ml (40 millimols) of acrylonitrile and 4.41 ml (40 millimols) of N-methylmorpholine, in 80 ml of p-xylene, are stirred for 5 hours. Working up as described in the preceding examples affords 0.53 g (8% of theory) of 4-formylcinnamonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]1=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:16])[N:9]1[N:8]=[CH:7]2.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]#[N:8])[C:11]=1[C:10]1[NH:9][C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][C:12]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3cccc(Cl)c3c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cccc(Cl)c1-c1[nH]c(=O)c(-c2ccccc2)cc1C(=O)O
Yield: 99.4 %

Procedure:
A.a) A mixture of 72.9 g of methyl 11-chloro-4-oxo-3-phenyl4H-pyrido[2,1-a]phthalazine-1-carboxylate, 112 g of potassium hydroxide and 1200 ml of methanol was heated to boiling under reflux for 46 hours under argon. The mixture was then concentrated to about 200 ml, the yellow suspension was diluted with 1000 ml of water, filtered and the aqueous phase was extracted three times with 200 ml of methylene chloride each time. The aqueous phase was acidified with 25 percent hydrochloric acid and the separated crystals were filtered off, washed with water and dried in a vacuum. There was obtained 69.7 g of 2-[2-chloro-6-cyanophenyl)-1,6-dihydro-6-oxo-5-phenylnicotinic acid as yellowish crystals with a m.p. of 279°-281°0 (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.OO.CC([OH:29])C>C(O)=O.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:29])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: CC(C)O
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [Pd]
Agent: OO
Solvent: O=CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 16 h

Procedure:
Thebaine (67 g, 0.215 mol) was dissolved in formic acid (98-100%, 120 g) and hydrogen peroxide (30% in water, 24.5 g, 0.216 mol) added at 0° C. The mixture was pumped continuously at 2 ml/min through a 30 ml continuous flow reactor at 80° C. (15 min residence time). An analytical control after the continuous reactor showed less than 1% Thebaine remaining. The continuous stream was added directly to the hydrogenation autoclave that was precharged with 2-propanol (204 g), formic acid (98-100%, 64 g) and 5% Pd/C (7.6 g) and held at 100° C. under H2 (40 bar). The hydrogenation was stirred for 16 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxycodone base, or treated with HCl in 2-Propanol to give the Oxycodone HCl. The yields were 82% for the base and 78% for the HCl salt. The 14-Hydroxycodeinone content of the base was 49 ppm and of the HCl salt 29 ppm.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:26](SCC)(=[S:28])[CH3:27].CN(C=O)C>C(#N)C>[C:26]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:4]1)(=[S:28])[CH3:27]
Reactant: NC[C@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Reactant: CCSC(C)=S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=S)NC[C@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one (1.75 g, 6.9 mmol), triethylamine (2.0 ml, 13.8 mmol) and ethyl dithioacetate (0.87 ml, 7.6 mmol) and DMF (5 ml) in acetonitrile (5 ml) was stirred at r.t. for 48 h. Solvent was removed under vacuum, and the crude material purified by silica gel chromatography (eluent: 10% methanol in ethyl acetate). White crystalline solid (1.3 g, 61%). HPLC Rt=4.5 min. MS (m/z): [M+H]+=312.
Reaction SMILES: [CH:1]([C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5])([CH3:3])[CH3:2].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14]>C(O)(C)C>[CH3:2][CH:1]([C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:12])[CH2:13][OH:14])=[O:5])[CH3:3]
Reactant: CC(C)C(=O)NCCN
Reactant: OCC1CO1
Solvent: CC(C)O
Product: CC(C)C(=O)NCCNCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
To 39 g (0.3 mol) of 2-(isopropylcarbonylamino)ethylamine in 150 ml of isopropyl alcohol was added 22.2 g (0.3 mol) of glycidol. The reaction mixture was stirred at 25° C. for 24 hours and evaporated in vacuo. The residual oil was chromatographed (silica gel/ethanol) to give 18.6 g (30%) of product. This compound was identified by NMR and IR spectroscopy.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=CC=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].C(O)CC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:6][CH2:1][CH3:7])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 62 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-propanol (300 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 85 to 90° C.) to give propyl pyruvate (400 g, yield: 62%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][C@@H:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1)=[O:14].Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]2[N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[N:33]=[CH:34][C:27]=12>C1COCC1.CCOC(C)=O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[N:32]1[C:28]2=[N:29][CH:30]=[N:31][C:26]([O:11][C@@H:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[N:17]=3)=[O:14])=[C:27]2[CH:34]=[N:33]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@H](O)C(=O)Nc1nc(C)ns1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.5 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (0.947 mL, 0.95 mmol) was added dropwise to a stirred solution of (S)-2-hydroxy-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate E1) (187 mg, 0.86 mmol) in anhydrous THF (5 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (228 mg, 0.86 mmol) in dry THF (1.5 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 16 hours. Reaction was cooled, diluted with EtOAc (50 mL), washed with 1M citric acid (25 mL) and brine (25 mL), dried (MgSO4), and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (44 mg, 11%) 1H NMR (400 MHz, CDCl3) δ 2.48 (3H, s), 3.41 (3H, s), 4.01 (2H, ddd), 6.13 (1H, t), 7.38-7.48 (3H, m), 7.56 (1H, dd), 8.34 (1H, s), 8.51 (1H, s), 9.90 (1H, s). m/z (ESI+) (M+H)+=446.08; HPLC tR=2.02 min.
Reaction SMILES: ClCC1([Si](C)(C)C)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH:20]1([Li])[CH:24]=[CH:23][CH:22]=C1.O1C[CH2:29][CH2:28][CH2:27]1>>[CH:14]1([CH2:13][C:12]2[C:11]3[CH2:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:22]=3[CH:23]=[CH:24][CH:20]=2)[CH:15]=[CH:29][CH:28]=[CH:27]1
Reactant: C[Si](C)(C)C1(CCl)c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Reactant: [Li]C1C=CC=C1
Product: C1=CC(Cc2cccc3c2Cc2ccccc2-3)C=C1
Reaction time: 2 h

Procedure:
The 9-(chloromethyl)-9-(trimethylsilyl) fluorene was dissolved in 200 ml tetrahydrofuran and added dropwise to a solution of cyclopentadienyl lithium (0.04m) in 200 ml of tetrahydrofuran. The reaction mixture was stirred for another 2 hours. The yellow solution was washed with 50 ml of an aqueous NH4Cl solution, then washed with 50 ml of water, and then the organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The raw product was dissolved in pentane and was crystallized at -30° C. The recovered product is 1-fluorenyl-1-cyclopentadienyl methane.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1COCO[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[CH3:32][N:11]1[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:15])[CH2:10]1
Reactant: C1OCOCO1
Reactant: O=C(NC1CNCC(c2ccccc2)C1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CC(NC(=O)c2ccc3[nH]nc(-c4ccncc4)c3c2)CC(c2ccccc2)C1
Reaction time: 1 h

Procedure:
In a flask, dichloromethane (1 mL) and acetic acid (1 drop) was added to N-(5-phenylpiperidin-3-yl)-3-(pyridin-4-yl)-1H-indazole-5-carboxamide (0.05 mmol) and 1,3,5-trioxane (0.2 mmol). The reaction was stirred for 60 minutes. Sodium triacetoxyborohydride (1 mmol) was added in one portion. The reaction was stirred for 1 h. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].Cl[CH2:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.[I-].[Na+]>C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)COC(=O)c1ccccc1OC(C)=O
Yield: 70.5 %

Procedure:
To a mixture of acetylsalicylic acid (5.4 g. 0.03 mole) and 2-chloro-N,N-diethylacetamide (4.5 g, 0.03 mole) in 40 ml of ethyl acetate was added triethylamine (4.2 ml, 0.03 mole) and sodium iodide (0.45 g, 0.003 mole). The mixture was refluxed for 4 h. After cooling the mixture was filtered and the filtrate washed with 2M hydrochloric acid, 5% sodium bicarbonate and water. After drying over anhydrous sodium sulphate the solution was evaporated in vacuo leaving an oil which crystallized by trituration with ethanol. Recrystallization from 80% ethanol afforded 6.2 g (70%) of the title compound. Mp 75°-76° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)C1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirring mixture of methyl 1-(6-hydroxy-2-naphthoyl)piperidine-4-carboxylate (500 mg, 1.59 mmol), cis-4-(t-butyl)cyclohexanol (487 mg, 3.18 mmol, 2 equiv) and PPh3 (833 mg, 3.18 mmol, 2 eq) in THF (5 mL) was added DIAD (642 g, 3.18 mmol, 2 eq) at room temperate under N2 atmosphere, then the mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylate (230 mg, yield: 32%) as a yellow solid. ESI-MS (M+1)+: 453.2. 1HNMR (400 MHz, CDCl3) δ: 7.76-7.70 (m, 3H), 7.43 (d, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 4.32-4.26 (m, 1H), 3.71 (s, 3H), 3.08-3.06 (m, 2H), 2.60-2.58 (m, 1H), 2.28-2.26 (m, 2H), 1.91-1.88 (m, 4H), 1.67-1.65 (m, 4H), 1.29-1.26 (m, 2H), 1.12-1.11 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH2:6][CH2:7][CH2:8]N(C)C)[CH3:4].[CH2:12]([N:14](CC)[CH2:15]C)C.[CH3:19][C:20]([O:22][C@H:23]1[C:32]2[C@@:33]3([CH3:48])[C@@H:44]([CH2:45][O:46][CH3:47])[O:43][C:41](=[O:42])[C:35]4=[CH:36][O:37][C:38]([C:39](=[O:40])[C:31]=2[C@@H:26]2[CH2:27][CH2:28][C@H:29]([OH:30])[C@@:25]2([CH3:49])[CH2:24]1)=[C:34]34)=[O:21]>ClCCl>[CH3:12][N:14]([CH3:15])[CH:7]([CH3:8])[CH2:6][N:5]([CH:36]=[C:35]1[C:34]2[C:33]([CH3:48])([C:32]3[CH:23]([O:22][C:20](=[O:21])[CH3:19])[CH2:24][C:25]4([CH3:49])[CH:26]([C:31]=3[C:39](=[O:40])[C:38]=2[OH:37])[CH2:27][CH2:28][CH:29]4[OH:30])[CH:44]([CH2:45][O:46][CH3:47])[O:43][C:41]1=[O:42])[CH2:3][CH3:4]
Reactant: CCN(CC)CC
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCNCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CC(C)N(C)C
Reaction time: 0.17 h

Procedure:
To a solution of the (3-dimethylaminopropyl)-ethyl-carbamic acid benzyl ester trifluoroacetate (0.84 g, 2.2 mmol) in ethanol (30 mL) and concentrated hydrochloric acid (0.5 mL, 6 mmol) was added palladium on carbon (10%, 50 mg). The suspension was shaken under 50 psi hydrogen. When the consumption of hydrogen was observed to have ceased, the mixture was filtered through a pad of diatomaceous earth and then concentrated under reduced pressure to give N′-ethyl-N,N-dimethylpropane-1,3-diamine dihydrochloride (400 mg, 89%) as a white solid. MS (ES+): m/z (M+H)=131.3 To a suspension of the N′-ethyl-N,N-dimethylpropane-1,3-diamine dihydrochloride (0.26 g, 1.3 mmol) in dichloromethane (5 mL) was added triethylamine (0.51 mL, 3.9 mmol). After stirring for 10 minutes, the mixture was treated with 17-hydroxywortmannin (0.28 g, 0.65 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC (employing a gradient elution of 5% acetonitrile/95% water to 95% acetonitrile over 45 minutes). The title compound was obtained as a rust-colored solid (11.6 mg). MS (ES+): m/z (M+H)=561.4.