Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].CC(C)([O-])C.[K+].Br[C:19]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>N1C=CC=CC=1.[Cu]I>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:28][C:27]([F:29])=[CH:26][C:25]=1[O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1c(O)cccc1O
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCCc1c(O)cccc1Oc1cc(F)ccc1C(=O)OC
Temperature: 25 °C
Yield: 14.6 %

Procedure:
To a solution of 2-propylresorcinol (10.0 g, 65.7 mmol) in pyridine (120 mL) was added potassium tert-butoxide (7.00 g, 62.5 mmol) at room temperature with stirring. To this was added a mixture of methyl 2-bromo-4-fluorobenzoate (7.60 g, 32.6 mmol) and copper(I) iodide (12.5 g, 65.7 mmol) in pyridine (120 mL). The resulting mixture was gently refluxed for 4 hours. The reaction was cooled to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the resulting material dissolved in ethyl ether. The solution was washed once with 5N aqueous hydrochloric acid. The aqueous layer was extracted once with fresh ethyl ether and the combined organic layers were washed twice with 5N aqueous ammonium hydroxide. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the resulting residue provided 1.45 g (15%) of the desired intermediate product as a light tan solid: mp 92-94° C.; NMR (CDCl3) 7.95 (m, 1H), 7.04 (t, J=9.5 Hz, 1H), 6.79 (t, J=9 Hz, 1H), 6.65 (d, J=9.5 Hz, 1H), 6.50 (m, 2H), 5.25 (bs, 1H, —OH), 3.88 (s, 3H), 2.60 (t, J=8.7 Hz, 2H), 1.55 (hextet, J=7.8 Hz, 2H), 0.92 (t, J=7.8 Hz, 3H); MS-FD m/e 305 (p+1, 40), 304 (p, 100); IR.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](OCC)=[O:12].[O-]CC.[Na+]>C1COCC1.O>[OH:12]/[CH:11]=[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)\[C:8]([CH3:9])=[O:10]
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)/C(=C\O)c1ccccc1

Procedure:
Phenylacetone (Aldrich Chem. Co. 13,538-0; Beilstein 7, 303), XXVIa (101 g, 0.75 mol) was combined with 100 g (1.35 mol) of ethyl formate was added all at once to a suspension of 50 g (0.75 mol) of sodium ethoxide in 500 ml of THF. After 3 hours at room temperature the brown solution was diluted with 400 ml of H2O. Following extraction with benzene to remove unreacted starting material, the aqueous phase was acidified with dilute HCl. The product was extracted with benzene, washed with H2O, dried over MgSO4, and concentrated to give an oil. Distillation gave 39 g (0.24 mol) of (Z)-1-hydroxymethylene-1-phenylacetone, XXVIIIa, as a colorless oil, bp 65- 69° C (0.3 mm).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[CH2:12][N:13]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][O:31][CH2:32][CH2:33]Br.C(OCC)(=O)C.CCCCCC>COCCOC>[CH2:3]([O:10][C:11]([C:12]1([N:13]=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0° C. is added a solution of the N-(diphenylmethylene)glycine benzyl ester (0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) is then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath is removed and the reaction is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether and washed with water. The aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane provides 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester as a clear yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13](Cl)=[O:14].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:37])[C:28](=[CH:33][C:34]=1[O:35][CH3:36])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13]([NH:37][C:27]1[C:28](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=1)[C:29]([O:31][CH3:32])=[O:30])=[O:14]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
In a mixture of 3.2 g of methyl 4,5-dimethoxyanthranilate in 30 ml of chloroform is dissolved 3 ml of triethylamine, and to this solution is added a solution of 3.45 g of 3,4,5-trimethoxybenzoylchloride in chloroform under cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated under a reduced pressure and to the residue is added water. The precipitated crystals are recrystallized from a mixture of dimethylformamide and ethanol to obtain 4.8 g of methyl N-(3,4,5-trimethoxybenzoyl)-4,5-dimethoxyanthranilate as pale yellow prisms.
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][N:6]([S:29]([CH3:28])(=[O:31])=[O:30])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1C(=O)N(S(C)(=O)=O)CC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 13, step 2,1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 13, step 1) was reacted with sodium hydride and methanesulfonyl chloride to give 3-isopropyl-1-methanesulfonyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one as an off-white solid. MS: 454.4 ([M+NH4]+)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([C:55]3[C:60]([O:61]C)=[CH:59][CH:58]=[CH:57][C:56]=3[O:63]C)=[C:18]3[N:54]=[C:21]([C:22]([C:44]4[C:49]([O:50]C)=[CH:48][CH:47]=[CH:46][C:45]=4[O:52]C)=[C:23]4[NH:43][C:26](=[C:27]([C:33]5[C:38]([O:39]C)=[CH:37][CH:36]=[CH:35][C:34]=5[O:41]C)[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2.B(Br)(Br)Br>ClCCl.C(Cl)(Cl)Cl.O1CCCC1>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[C:11]1[C:12]2[NH:16][C:15]([C:17]([C:55]3[C:56]([OH:63])=[CH:57][CH:58]=[CH:59][C:60]=3[OH:61])=[C:18]3[N:54]=[C:21]([C:22]([C:44]4[C:49]([OH:50])=[CH:48][CH:47]=[CH:46][C:45]=4[OH:52])=[C:23]4[NH:43][C:26](=[C:27]([C:33]5[C:34]([OH:41])=[CH:35][CH:36]=[CH:37][C:38]=5[OH:39])[C:28]5[CH:29]=[CH:30][C:31]=1[N:32]=5)[CH:25]=[CH:24]4)[CH:20]=[CH:19]3)=[CH:14][CH:13]=2
Reactant: COc1cccc(OC)c1-c1c2nc(c(-c3c(OC)cccc3OC)c3ccc([nH]3)c(-c3c(OC)cccc3OC)c3nc(c(-c4c(OC)cccc4OC)c4ccc1[nH]4)C=C3)C=C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Oc1cccc(O)c1-c1c2nc(c(-c3c(O)cccc3O)c3ccc([nH]3)c(-c3c(O)cccc3O)c3nc(c(-c4c(O)cccc4O)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
As the solvent, acetic acid, propionic acid, butyric acid or the like is usable. The reaction temperature can be controlled by considering the kind of the solvent and the other conditions, usually a temperature of 80°-120° C. is selected. The reaction time is 5-12 hours, preferably 5-8 hours. After such condensation of these compounds, the tarry reaction mixture obtained by filtrating the reaction solution is purified by, for example, silica gel chromatography or the like to obtain 5,10,15,20-tetra(2',6'-dimethoxyphenyl)porphyrin. Then, 5,10,15,20-tetra(2',6'-dimethoxyphenyl)porphyrin is dissolved in a suitable dry solvent (dichloromethane, chloroform, tetrahydrofuran or the like), cooled in an ice-water bath 40 times or more of the molar quantity of boron tribromide is added and the mixture is stirred at room temperature for 10-24 hours. The reaction solution is poured dropwise into ice water, the solution is extracted by an organic solvent such as ethyl acetate, the organic layer is evaporated to dryness, and the solid is purified by silica gel chromatography to obtain 5,10,15,20-tetra(2',6'-dihydroxyphenyl)porphyrin (in the above process, the compound represented by H2T2,6-OH PP).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:18]#[CH:19].[C-]#[C-].[Na+].[Na+]>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)([OH:7])[C:18]#[CH:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: C#C
Agent: [C-]#[C-]
Agent: [Na+]
Product: C#CC(O)(c1ccc(F)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-fluoro-4′-methoxy-benzophenone from Step 1 (126.7 grams) and acetylene saturated N,N-dimethylformamide (380 mL) were combined in a reaction flask. Sodium acetylide solution (9% by weight in toluene, 343 grams) was added to the reaction mixture dropwise over 45 minutes. The reaction mixture was stirred at room temperature for 1 hour and then poured into ice water (600 mL). The layers were phase separated and the aqueous layer was extracted with three portions of diethyl ether (200 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (200 mL), saturated aqueous sodium chloride (200 mL), and saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to an amber colored oil yielding 136.6 grams of 1-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol. This material was not purified further but was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([N:9]3[CH2:12][CH:11]([OH:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1>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.O1CCOCC1.C(O)C>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:15]=[CH:14][C:5]3[N:6]=[C:7]([N:9]4[CH2:12][CH:11]([OH:13])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC1CN(c2nc3ccc(Br)cc3s2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCO
Product: Cn1cc(-c2ccc3nc(N4CC(O)C4)sc3c2)cn1
Temperature: 150 °C

Procedure:
A mixture of 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-ol (Reference Example 1, 1.426 g, 5.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS #761446-44-0, 1.248 g, 6.0 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.140 g, 0.20 mmol), and (2-biphenyl)dicyclohexylphosphine (0.070 g, 0.20 mmol) in 1:1 dioxane/ethanol (12 mL) was treated with deoxygenated 1 M aqueous Na2CO3 (6.0 mL). The reaction mixture was then heated under microwave irradiation at 150° C. for 10 minutes. The reaction mixture was then diluted with dichloromethane (30 mL) and filtered through a pad of diatomaceous earth that was subsequently rinsed with 9:1 dichloromethane/methanol. The filtrate was concentrated under reduced pressure and the residue was treated with acetonitrile (20 mL) to provide a slurry that was filtered. The filter cake was treated with 4:1 methanol/water (5 mL) and the resulting slurry was filtered. The filter cake was rinsed with 4:1 methanol/water (3 mL), then dried under vacuum to provide 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82-3.91 (m, 2H), 3.85 (s, 3H), 4.31 (t, J=8 Hz, 2H), 4.62-4.72 (m, 1H), 5.86-5.91 (m, 1H), 7.43 d, J=8 Hz, 1H), 7.48 (dd, J=1, 8 Hz, 1H), 7.82 (d, J=1 Hz, 1H), 7.96 (d, J=1 Hz, 1H), 8.07 (s, 1H); MS (DCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[I:12]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:11]([I:12])=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nc(Cl)c2cc[nH]c2n1
Solvent: ClCCl
Product: Cc1nc(Cl)c2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.4 mmol) in dichloromethane (10 mL) was added N-iodosuccinimide (537 mg, 2.39 mmol). The mixture was stirred at room temperature for 2 hours, then washed with aqueous sodium sulfite solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the product as a brown solid. Yield: 330 mg, 1.12 mmol, 47%. LCMS m/z 293.8[M+H+].
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([F:36])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:29][C:30]=1[F:36])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 17 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Canteilo, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-fluoro-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as colorless foam. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:32])([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)[CH3:9])(=O)=O.[C-:33]#[N:34].[K+]>CN(C=O)C.O>[CH3:32][C:8]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:7][CH2:6][C:33]#[N:34]
Reactant: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CCC#N)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 169.2 %

Procedure:
A mixture of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125° C. followed by additional 30 min at 135° C. The mixture was then diluted with water, and the product was extracted with three portions of MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated to give 61 mg of crude 4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo-[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile, which was used without further purification. MS (ES): 410 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[F:9][C:5]1[CH:6]=[C:7]([OH:8])[C:2]2[N:3]([C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:1]=2)[CH:4]=1
Reactant: Nc1ncc(F)cc1O
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(O)cc(F)cn12

Procedure:
3.2 g of 2-amino-5-fluoropyridin-3-ol (Example 11A; 25 mmol, 1 equivalent) were initially charged in 155 ml of ethanol, 1.5 g of powdered molecular sieve 3 Å and 20.6 g of ethyl 2-chloroacetoacetate (125 mmol, 5 equivalents) were added and the mixture was heated at reflux overnight. The reaction solution was concentrated and chromatographed (Biotage Isolera Four; SNAP Cartridge KP-Sil 50 g; cyclohexane/ethyl acetate gradient; then dichloromethane/methanol gradient). The crude product was partly dissolved in a little methanol, and tert-butyl methyl ether was added. The solid obtained was filtered off and rinsed with tert-butyl methyl ether. This gave 570 mg (10% of theory) of the title compound.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O)C.[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])C=O)([CH3:17])[CH3:16].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+].FC(F)(F)C(O)=O>CO.C1COCC1>[CH3:17][C:15]([C:18]1[CH:19]=[C:20]([CH2:5][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Commercially available (1,1-dimethylethoxy)carbonylpiperazine (12.47 g) and 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde (15.67 g) were dissolved in 1:1 mixture of methanol and THF (200 ml). The solution was cooled in an ice-bath, and sodium cyanoborohydride (6.2 g) was added portionwise over 2 h. The reaction mixture was allowed to warm to room temperature and stirred for 48 h. At this time 50 ml of a saturated solution of NaHCO3 was added, and the mixture was concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane. The organic fractions (3×500 ml) were washed with water, brine and dried over sodium sulphate. After removal of the solvent in vacuo, the viscous material was dissolved in trifluoroacetic acid (100 ml) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to afford a white solid. A small amount of this trifluoroacetic acid salt was converted into the corresponding free base and analysed as the required product. The product can be isolated as its free base by simple modification of the above described procedure.
Reaction SMILES: O=S(Cl)[Cl:3].[OH-].[Na+].[NH2:7][C@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.[CH:22]1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(O)C.CO>[ClH:3].[CH3:22][O:20][C:19](=[O:21])[C@H:8]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[NH2:7]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: Cl
Temperature: 66 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-tryptophan (3d) was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain L-tryptophan methyl ester hydrochloride. Yield: 100%.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CC1(C)[O:14][C:13](=O)[CH:12]=[C:11]([CH3:16])[O:10]1>CC(C)=O>[C:13]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])(=[O:14])[CH2:12][C:11]([CH3:16])=[O:10]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: C[Si](C)(C)CCO
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCC[Si](C)(C)C

Procedure:
A mixture of 6.70 g of 2-trimethylsilylethanol (56.7 mmol) and 8.05 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (56.7 mmol) was placed in a round bottom flask equipped with a short distillation apparatus and heated to to drive off acetone. The calculated amount of acetone was collected, and the residue was distilled under reduced pressure. The fraction boiling at 106°-110° C. (5-10 mmHg) was collected (8.52 g, 74%). The product was used in the next step after spectral characterization.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:8].[Na+:9]>>[OH:8][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:6])=[O:7].[Na+:9]
Reactant: O=C1CCCCO1
Reactant: [OH-]
Agent: [Na+]
Product: O=C([O-])CCCCO
Temperature: 65 °C

Procedure:
A suspension of 800 mg (8.0 mmol) of δ-valerolactone in 8 mL (8.0 mmol, 1.0 equiv) of 1N aqueous sodium hydroxide was heated at 65° C. overnight. The clear solution was cooled and concentrated. Toluene was added and the resultant slurry was concentrated to give a white solid: IR (nujol mull) 1550 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([NH:20][NH:21][C:22](=[O:24])[CH3:23])=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]1[O:24][C:22]([CH3:23])=[N:21][N:20]=1)[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nnc(-c2cc3c(OCc4ccccc4)cccc3[nH]2)o1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
N′-(4-Benzyloxy-1H-indol-2-ylcarbonyl)acetohydrazide (7.5 g) was dissolved in tetrahydrofuran (250 ml) and triphenylphosphine (9.0 g) and triethylamine (6 ml) were added. The mixture was stirred under ice-cooling. Diisopropyl azodicarboxylate (40% toluene solution) (17.7 g) was added and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.0 g) as yellow crystals.