Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C@H:19]([NH:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:20][OH:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].Cl[C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56]>C(Cl)(Cl)Cl.CO.CCOC(C)=O>[CH2:58]([O:57][C:55]([NH:22][C@@H:19]([CH2:18][NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH2:20][OH:21])=[O:56])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=S(=O)(NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@H](CO)CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
(S)-3-(4-phenoxybenzenesulfonamido)-2-(tritylamino)propanol (2.26 g, 4.0 mmol) was dissolved in a mixture of chloroform and methanol (1:1, 8 mL) and cooled to 0° C. in an ice bath. The reaction mixture was stirred at 0° C. for 2.5 h, after dropwise addition of trifluoroacetic acid (5.2 mL, 70 mmol). Solvents were removed and the resulting residue was azeotroped 5 times with diethyl ether (5×2 mL) and partitioned between diethyl ether (50 mL) and water (25 mL). The ether layer was washed with water (10 mL) and the combined aqueous fractions are basified with NaHCO3 (1.34 g, 16 mmol). Aqueous fraction was diluted with EtOAc (100 mL) and the mixture was cooled to 0° C. in an ice bath. Then benzyl chloroformate (0.57 mL, 4.0 mmol) was added to the reaction mixture and stirred vigorously at RT for 1.5 h. The layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organic fractions were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated and column purified (silica gel, 5% MeOH in EtOAc) to provide (S)-2-(benzyloxycarbonyla-mino)-3-(4-phenoxybenzenesulfonamido) propanol in 76% (1.38 g, 4.0 mmol) yield as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Oc1ccc(Br)nc1
Product: Oc1ccc(-c2ccc(F)cc2)nc1
Yield: 51 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 2-bromo-5-hydroxypyridine and 4-fluorophenylboronic acid to afford the title compound as an off-white solid (270 mg, 51%)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13](Br)=[C:12]([F:19])[C:11]=1[F:20].B(O)(O)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1>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>[CH3:7][O:8][C:9]([C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)=[C:12]([F:19])[C:11]=1[F:20])=[O:21]
Reactant: COC(=O)c1c(F)c(F)c(Br)c(F)c1F
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(F)c(F)c(-c2ccc(C=O)cc2)c(F)c1F
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A toluene/Water (175 mL+25 mL) mixture was degassed with nitrogen for 30 minutes. Cesium carbonate (14.9 g, 43.55 mmol) was added followed by 4-bromo-2,3,5,6-tetrafluoro-benzoic acid methyl ester (5.0 g, 17.42 mmol), 4-formyl boronic acid (3.4 g, 22.64 mmol) and dichlorobis(triphenylphosphine)-palladium(II) catalyst (0.611 g, 0.87 mmol). The reaction mixture was refluxed for 15 h. TLC shows completion of the reaction. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 5% ethyl acetate in hexane to get colorless solid (3.0 g, 55.24%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18]O)[C:13](=[O:20])[CH2:12]1)=[O:10])[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.N1C=CN=C1.[I:45]I>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][I:45])[C:13](=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCI

Procedure:
4-(Benzyloxycarbonyl)-1-(2-hydroxyethyl)-piperazin-2-one, prepared as described in EXAMPLE 94, part A. (0.26 g, 0.94 mmol) in methylene chloride (6 mL) is treated with triphenyl phosphine (0.60 g, 2.3 mmol), imidazole (0.16 g, 2.3 mmol), and iodine (0.47 g, 1.9 mmol) for 0.5 h at 0° C. The reactin mixture is partitioned between water and methylene chloride; the organic layer is concentrated and the residue is chromatographed (15% EtOAc/methylene chloride) to give 4-(benzyloxycarbonyl)-1-(2-iodoethyl)-piperazin-2-one (0.24 g, 0.62 mmol). Pyrrolo[3,2-c]pyridine (0.073 g, g, 0.62 mmol) is dissolved in DMF (3 mL) and treated with 60% sodium hydride (0.03 g, 0.74 mmol) and all of the 4-(benzyloxycarbonyl)-1-(2-iodoethyl)-piperazin-2-one from the previous step; the reaction mixture is stirred at r.t. for 16 g. The reaction mixture is concentrated to dryness and the residue is partitioned between water and methylene chloride. The organic layer is concentrated and subjected to chromatography (2-5% MeOH/methylene chloride) to yield the title compound (0.028 g, 0.074 mmol) Ion Spray MS m/z: 379, [M+1]+.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][C:20]4[N:19]5[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:12]=4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Br)cncc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cncc(N3CCc4c(cc5n4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A sealed tube was charged with 112e (200 mg, 0.53 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl) piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one 101l (240 mg, 0.51 mmol), PdCl2(dppf) (42 mg, 0.05 mmol), K3PO4 (230 mg, 1 mmol), and NaOAc (80 mg, 1 mmol) in CH3CN (5 mL) and H2O (1.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 112f (138 mg, 40%) as a pale yellow solid. MS: [M+H]+ 635.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([S:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])(=[O:17])=[O:16])[CH:10]=[C:11]([CH:13]=O)[CH:12]=1.CO.[CH3:28][NH2:29].[BH4-].[Na+].[ClH:32].C(=O)([O-])O.[Na+]>CO>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([S:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])(=[O:17])=[O:16])[CH:10]=[C:11]([CH2:13][NH:29][CH3:28])[CH:12]=1
Reactant: N#Cc1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1F
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccccc2C#N)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
2-{[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile (370 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (811 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (120 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in methanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 280 mg, 66%).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:23][C:22]=3[Cl:36])=[CH:11]2)(=O)=O)C=CC=CC=1.CO.[OH-].[K+]>C(O)(=O)C>[Cl:36][C:22]1[N:23]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[S:25][C:21]=1[CH2:20][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[NH:10][CH:11]=1
Reactant: COc1ccc(CNc2nc(Cl)c(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)s2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(Cl)c(Cc3c[nH]c4ncc(Cl)cc34)s2)cn1
Temperature: 80 °C

Procedure:
[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-6-methoxy-pyridin-3-ylmethyl)-amine 619 was combined with methanol:potassium hydroxide (1M) (1:1, 0.5 mL). The mixture was heated at 80° C. for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID) eluting with 0.1% trifluoroacetic acid in water and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to) provide the desired compound P-0190. MS (ESI) [M+H+]+=419.9.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Solvent: CS(C)=O
Product: CC(=O)c1cc2c(cc1OCc1ccccc1)C(C)(C)CCC2(C)C
Yield: 75.4 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-ethanone (0.103 g, 0.418 mmol) in DMSO (1 mL) was alkylated with benzylbromide (0.100 g, 0.585 mmol, 0.070 mL) as described in Example 21. Aqueous workup gave 1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone 0.106 g (75% crude) as a yellow oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, ArH), 7.45 (m, 5H, ArH), 6.88 (s, 1H, ArH), 5.12 (s, 2H, OCH2), 2.59 (s, 3H, CH3), 1.66 (br s, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[N:24]=[C:25]2[N:29]([C:30]=1[S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:27][S:26]2>>[Cl:22][C:23]1[N:24]=[C:25]2[N:29]([C:30]=1[S:31]([N:1]1[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]1)(=[O:33])=[O:32])[CH:28]=[CH:27][S:26]2
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(S(=O)(=O)c3c(Cl)nc4sccn34)CC1)O2

Procedure:
Compound 77 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl chloride and conditions outlined in procedure P. M.p.=265-267° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.08-8.05 (m, 1H), 7.87-7.84 (m, 1H), 7.61-7.50 (m, 3H), 7.33-7.29 (m, 1H), 3.66-3.60 (m, 2H), 3.11 (s, 2H), 3.02-2.95 (m, 2H), 2.12-2.06 (m, 2H), 1.95-1.84 (m, 2H); LCMS: 522 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([N:20]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:19])=[CH:7]2.O.NN>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2
Reactant: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N2C(=O)c3ccccc3C2=O)s1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)s1
Temperature: 90 °C

Procedure:
To a stirred solution of 2-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)-quinolin-3-yl)ethyl)isoindoline-1,3-dione (30 mg, 69 μmol) in THF (1.0 mL) and ethanol (3.0 mL) was added hydrazine monohydrate (69 μl, 1380 μmol). The reaction was heated to 90° C. for 40 minutes and then cooled to room temperature and evaporated in vacuo. The resulting residue was diluted with ethyl acetate (60 mL) and water (40 mL) and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine and then dried (MgSO4), filtered and evaporated in vacuo to give (1S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethanamine. 1H NMR (500 MHz, choroform-d) δ ppm 8.62 (1H, s), 7.79-7.84 (2H, m), 7.49-7.52 (1H, m), 5.61 (1H, d, J=6.4 Hz), 2.86 (3H, s), 1.57 (3H, d, J=6.6 Hz). Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([F:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1F
Reactant: COC(=O)C(C=O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(CCOc3nc(=O)c(Cc4cncnc4)c[nH]3)cc2)cc1F
Temperature: 115 °C
Yield: 3.7 %

Procedure:
To the solution of 2-{4-[(3-fluoro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (100 mg, 0.249 mmol) and methyl 2-formyl-3-(5-pyrimidinyl)propanoate (58 mg, 0.299 mmol) in NMP (2 mL) was added K2CO3 (138 mg, 0.997 mmol). The mixture was heated with a microwave reactor at 115° C. for 2 h. Purification via MDAP then afforded the title compound (4 mg, 3.71% yield). LCMS: rt=3.19 min, [M+H+]=433
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30]([OH:32])=O)=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:72][C@@H:73]([C:75]1[O:76][CH:77]=[C:78]([CH2:80][OH:81])[N:79]=1)[CH3:74]>CN(C=O)C>[OH:81][CH2:80][C:78]1[N:79]=[C:75]([C@H:73]([NH:72][C:30]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:15]4[C:14]5[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=5)[N:17]([CH3:20])[N:16]=4)[N:22]=3)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[CH:28]=2)=[O:32])[CH3:74])[O:76][CH:77]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)c1nc(CO)co1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CO)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
In a round-bottomed flask, [2-((R)-1-amino-ethyl)-oxazol-4-yl]-methanol trifluoroacetate (crude from Step 5) was dissolved in DMF (1.5 ml) and N,N-diisopropylethylamine (0.70 ml, 4.0 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (140 mg, 0.32 mmol was added followed by HATU (133 mg, 0.35 mmol). The reaction was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) to afford 118 mg (66%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amide as a light brown foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(Br)ccn1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Product: Brc1ccnc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-2-fluoropyridine (1 eq.), benzyl alcohol (1.2 eq.) and dibenzo-18-crown-6 (0.05 eq.) in toluene (0.4 M) was added potassium hydroxide (2 eq.). A Dean-Stark apparatus was then attached and the reaction suspension was heated at reflux for 3 h. After cooling to RT, the reaction mixture was diluted with hexanes and then filtered through a pad of celite. Concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of column chromatography (SiO2, 97:3 (v/v) Hex:Et2O) afforded the title compound as a colorless oil.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.CCCCCC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2c(sc3ccccc32)c1O
Solvent: CCCCCC
Product: N#Cc1cnc2c(sc3ccccc32)c1Cl
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1.01 g (4.47 mmol) of 4-hydroxybenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 7 mL of phosphorous oxychloride is heated at reflux temperature for 40 minutes, then cooled to room temperature. Hexane is added and the solid is collected by filtration, dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to a small volume. The solids are collected by filtration to give 696 mg (64%) of product, mp 305–308° C.
Reaction SMILES: C1(C=CC=C(O)C=1)O.[OH-].[Na+].S([O:16][CH3:17])(OC)(=O)=O.C[C:19]1[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][CH:24]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:16][CH3:17])[CH:20]=1
Reactant: COc1cccc(C)c1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Oc1cccc(O)c1
Agent: [Br-]
Solvent: O
Product: COc1cccc(OC)c1

Procedure:
An aqueous phase consisting of resorcinol (2.20 g, 20 millimoles, Lancaster, 99%), tetrabutyl-ammonium bromide (1.30 g, 50% w/w solution in water, 2 millimoles, Sachem 821 East Woodward, Austin, Tex. 78704), sodium hydroxide (5.01 g, 50% w/w solution in water, 60 millimoles, Aldrich), and water (248.83 g) was treated with a mixture of dimethyl sulfate (12.63 g, 100 millimoles, Aldrich, 99+%) and 3-methylanisole (GC standard, 0.750 g, 6 millimoles, Aldrich, 99%). The excess molar concentration of sodium hydroxide was 0.5. The organic phase:aqueous phase weight ratio was 1:18. The two phase system was stirred mechanically (600 rpm, a calibrated photo-tachometer) at room temperature (25° C.). Aliquots were taken after 0, 1, 3, 5, 8, 12, and 18 minutes after the addition of the alkylating agent. When aliquots were taken the pH of the reaction mixture was checked to determine if the hydrolysis of dimethyl sulfate caused the system to become acidic. After 5 minutes of the reaction, the pH became acidic and the reaction mixture was treated with an additional amount of sodium hydroxide solution (3.50 g, 50 w/w solution in water). Aliquots were briefly centrifuged, the phases were separated and the organic phase was injected into the GC column. The yield of 1,3-dimethoxybenzene based on the limiting reactant (resorcinol) was 47% after 12 minutes of reaction.
Reaction SMILES: [Mg].[CH:2]1([CH2:8]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:11].[BH4-].[Na+]>C(OC)(C)(C)C.II.CO>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]([NH2:11])[CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccccn1
Reactant: BrCC1CCCCC1
Agent: II
Agent: [BH4-]
Agent: [Mg]
Solvent: CO
Solvent: COC(C)(C)C
Product: NC(CC1CCCCC1)c1ccccn1
Yield: 74.5 %

Procedure:
To a refluxed stirred mixture of 1.34 kg (55.8 moles) of magnesium in 6 L of t-butylmethyl ether (MTBE) and 4 g (0.016 moles) of iodine, a solution of 10 kg (55.9 moles) cyclohexylmethyl bromide in 22 L (MTBE) was added slowly. After approximately 10% to 25% of the solution was added, heating was discontinued and the remainder of the solution was added at a rate to maintain refluxing temperature. After the addition, the reaction was refluxed for an additional 24 hrs, then cooled to 0° to 5° C. and 3.903 kg (37.1 moles) of 2-cyanopyridine in 22 L MTBE was added at 0°-10° C. After the addition, the greenish thick suspension was stirred without cooling for 18-24 hrs. The Grignard reaction mixture was transferred with stirring to 40 L of methanol at 10° to 15° C. To the clear solution was added 1.4 kg (36.8 moles) of sodium borohydride. The mixture was stirred at room temperature 18 hrs., then quenched by the addition of 16 L of water and 36 L of 4N hydrochloric acid. The organic solvents were removed under vacuum and the remaining aqueous solution was washed twice with 6 L of methylene chloride. The aqueous phase was basified with 15 L of ammonium hydroxide solution and extracted three times with 10 L of methylene chloride. The methylene chloride was dried over 6.5 kg of sodium sulfate and concentrated to yield 5.645 kg (75%) of 1-(R,S)-(2-pyridyl)-2-cyclohexylethylamine.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](=[O:21])/[CH:18]=[CH:19]/[CH3:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH:19]([CH3:20])[C:18]([CH:17]=[O:21])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/C=O
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1Oc2ccc(Oc3ccccc3)cc2C=C1C=O

Procedure:
The starting material is prepared as follows: A mixture of 5-phenoxysalicylaldehyde (6.52 g, 30.4 mmol), crotonaldehyde (3.2 g, 45.7 mmol) and potassium carbonate (8.41 g, 60.9 mmol) in 100 ml of 1,4-dioxane is heated at reflux for 2 hours. The mixture is cooled, diluted with water, and extracted three times with dichloromethane. The combined organic layers are dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 7% ethyl acetate/hexane) yields 6-phenoxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde which is converted to 6-phenoxy-2-methyl-3-(N-hydroxyaminomethyl)-2H-1-benzopyran as described above.