Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].BrCCBr.[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH2:26][CH:27]2[C:31](=O)[C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28]2)=[CH:24][CH:23]=1.Cl>C1COCC1.C(O)C>[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH2:26][C:27]2[O:28][C:29]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=3[C:31]=2[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc2c(c1)OC(Cc1ccc(Cl)cc1)C2=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCO
Solvent: BrCCBr
Product: COc1ccc2c(-c3ccc(OCCN4CCCC4)cc3)c(Cc3ccc(Cl)cc3)oc2c1
Temperature: 25 °C

Procedure:
4-[2-Pyrrolidinoethoxy]phenyl bromide (1.41 g, 5.20 mmol) in dry THF (50 ml) was added to magnesium turnings (312 mg, 13.0 mmol) in a dry 3-necked round bottom flask under an oxygen-free nitrogen atmosphere and the mixture was maintained under gentle reflux. 1,2-Dibromoethane (0.22 ml, 2.60 mmol) was added dropwise over a period of 1/2 hour. The mixture was heated gently until the magnesium was nearly consumed (ca. 1/2 hour). 2-(p-Chlorobenzyl)-6-methoxy-3(2H )-benzofuranone (740 mg, 2.60 mmol) in THF (50 ml) was added dropwise to the mixture at 0° C. The reaction mixture was allowed to warm to room temperature and refluxed for 18 hours. The cooled mixture was quenched with saturated ammonium chloride (30 ml), extracted with dichloromethane (3×40 ml), washed with water, dried (anhydrous sodium sulphate) and the solvent evaporated off to yield an oil which was dehydrated with concentrated hydrochloric acid (2 ml) in ethanol (25 ml). The mixture was refluxed for 2 hours, whereupon ethanol was removed. It was then basified with 10% sodium hydroxide (20 ml) and extracted with dichloromethane (3×40 ml). The dichloromethane extract was washed with water (3×20 ml), dried (anhydrous sodium sulphate) and the solvent was evaporated off to give a solid which was chromatographed on silica gel. Elution with (dichloromethene: hexane: triethylamine=1:2:0.3), yielded a colourless solid which was recrystallised from methanol to give 2-(p-chlorobenzyl)-3-[p-(2-pyrrolidinoethoxy)phenyl]-6-methoxybenzo[b]furan (2), m.p. 75° C. Dry hydrogen chloride gas was bubbled through an ethereal solution of the free base for 10 minutes and cooled to 0° C. The hydrochloride salt which preciptated out was filtered off at the pump, rinsed with ether, and recrystallised from isopropanol to yield white crystals of the hydrochloride salt. Yield (22%); m.p. 223°-225° C.; 1H-NMR (CDCl3)δ 1.82 (m, 4H, N(CH2CH2)2), 2.65 (br s, 4H, N(CH2CH2)2), 2.93 (t, 2H, J6.0 Hz, OCH2CH2N), 3.84 (s, 3H, OCH3), 4.16 (distorted t, 4H,J 6.0 Hz, OCH2CH2N, CH2 at C-2), 6.80-7.47 (m, 11H, ArH ); m/z (%) 463 (M+ -HCl, 28), 461 (M+ -HCl, 10), 364 (17), 98 (38), 84 (100). (Found: C, 67.37, H, 5.92, N, 2.56, Cl, 13.95. C28H28ClNO3.HCl required C, 67.47, H, 5.66, N, 2.81, Cl, 14.23).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].O=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[C:3]([CH:5]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.257 g, 6.42 mmol) in tetrahydrofuran (32 mL) at 0° C. under a nitrogen atmosphere was added diethyl cyanomethylphosphonate (1.19 g, 6.72 mmol) (purchased from Aldrich). The reaction was then stirred for 45 minutes at room temperature. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.00 g, 5.84 mmol) (purchased from Alfa Aesar) in tetrahydrofuran (8.8 mL) was introduced dropwise and the mixture was stirred for 16 hours. Brine and ethyl acetate were added and the layers separated. The aqueous layer was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford product, used without further purification in Step 2 (1.12 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[O:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH2:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reactant: CCc1cccc(B(O)O)c1
Product: CCc1cccc(-c2ccccc2NC(=O)OC2CN3CCC2CC3)c1
Yield: 86 %

Procedure:
Using general procedure E, quinuclidin-3-yl 2-bromophenylcarbamate, 3-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (120 mg, 86%). 1H NMR (500 MHz, CDCl3) δ 8.09 (br s, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.26-7.18 (m, 4H), 7.14 (t, J=7.5 Hz, 1H), 6.71 (br s, 1H), 4.79 (m, 1H), 3.25 (m, 1H), 2.90-2.65 (m, 7H), 2.05 (m, 1H), 1.80-1.64 (m, 2H), 1.62-1.52 (m, 1H), 1.40-1.32 (m, 1H), 1.28 (t, J=7.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 153.4, 145.2, 138.1, 134.7, 131.8, 130.2, 129.1, 128.8, 128.4, 127.5, 126.6, 123.5, 120.1, 72.0, 55.3, 47.3, 46.4, 28.9, 25.3, 24.5, 19.4, 15.7 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time 1.55 min; (M+1) 351.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:14][C:13]=2[CH3:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:31][OH:32].C(N(CC)CC)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=3)=[N:14][C:13]=2[CH3:29])[CH:7]=[CH:6][C:3]=1[C:4]([NH:31][OH:32])=[NH:5]
Reactant: NO
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C#N)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C(=N)NO)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 136 %

Procedure:
3.0 g 2-Chloro-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzonitrile were dissolved in a mixture of 20 ml tetrahydrofuran and 20 ml methanol. 9.91 g hydroxylamine hydrochloride were added followed by the addition of 19.9 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.4 g crude 2-chloro-N-hydroxy-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzamidine which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([CH:8]=1)[NH2:7].[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([N:7]=[C:15]=[S:16])[CH:8]=1
Reactant: Nc1cc(F)ccc1N1CCOCC1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(N2CCOCC2)c(N=C=S)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 5-fluoro-2-morpholino aniline (6 g) and thiophosgene (5.2 g) in dioxan (20 ml) and water (40 ml) was stirred at 0° C. for 15 minutes and at room temperature for one hour to yield a residue which was extracted with dichloromethane to give an oil which was purified by chromatography on a silica gel column (mesh 100-200) using a 1:9 mixture of ethylacetate and hexane as eluant to give 5-fluoro-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:40][CH2:39][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH2:37][CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:23][CH2:22]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:22][CH2:23][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH2:37][CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:39][CH2:40]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Reaction time: 18 h
Yield: 200 %

Procedure:
A solution of tert-butyl 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate (limiting reagent) (step d) in DCM (2.8 volumes) was cooled to 5° C. Trifluoroacetic acid (10 molar equivalents) was added over 20 min (exotherm to 15° C.). The reaction mixture was warmed to ambient and stirred for 18 hr. Toluene (3 volumes) was added and the mixture was evaporated. The resulting gum was triturated with toluene (2×1.5 volumes) and evaporated to give a brown gum. Yield: 200% of theoretical. (carried through crude—NMR assay shows ˜45% by weight purity with remaining weight due to TFA trapped in the gum)
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19](CC=C)[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][C:35]([CH3:37])=[O:36].O.C[N+]1([O-])CC[O:43]CC1>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[OH:36][CH:35]([CH2:37][OH:43])[CH2:34][N:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)[C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[CH:12][CH:13]=2)=[N:18]1
Reactant: C=CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nn(CC(O)CO)cc2-c2ccnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of N-phenyl-N′-{4-[1-(2-propen-1-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}urea (0.18 mmol) in 5:1 acetone:water (1.2 mL) was added N-methylmorpholine N-oxide (0.276 mmol) followed by a 2.5% solution of osmium tetroxide in t-butanol (93.5 mg). The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous sodium sulfate (11 mL), filtered through a pad of celite (rinsing with ethyl acetate) and concentrated in vacuo. The residue was purified by Gilson reverse phase HPLC to afford the title compound as a white solid (14%). ESMS [M+H]+: 469.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:23]1[CH2:26][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24]1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:25]2[CH2:26][O:23][CH2:24]2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)cc1Cc1ccc(OC2COC2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of crude 4-(5-bromo-2-chlorobenzyl)phenol (3.0 g, 10 mmol) and cesium carbonate (4.9 g, 15 mmol) in N,N-dimethylformamide (77.5 mL) at room temperature was added a solution of toluene-4-sulfonic acid oxetan-3-yl ester (3.5 g, 15 mmol) in N,N-dimethylformamide (8 mL). The mixture was heated to 65° C. for 22 hours whereupon an additional aliquot of cesium carbonate (3.3 g, 10 mmol) was added. The reaction mixture was stirred for a further 12 hours at 120° C., cooled to room temperature whereupon water and ethyl acetate were added and the mixture was carefully acidified with 1N aqueous hydrochloric acid solution. The organic layer was separated, washed with brine (3 times), and concentrated in vacuo. Purification via Biotage MPLC (silica gel, eluting with a gradient of 0 to 25% ethyl acetate in heptane) afforded 3-(4-(5-bromo-2-chlorobenzyl)phenoxy)oxetane (2.5 g, 70% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([N:10]1[CH2:11][CH2:12][C:7]2[NH:6][C:5]3[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH2:9]1)=[O:33]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccccc1Cl)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 2-Chlorophenyl isocyanate (0.03 mL, 0.26 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 42 (52 mg, 55% yield). LC-MS (M+H=361, obsd.=361).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[NH:16][N:15]=[CH:14][C:12]=2[N:13]=1.IC>O1CCCC1>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[N:16]([CH3:1])[N:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Clc1ncc2[nH]ncc2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ncc2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Potassium t-butoxide (1.68 g, 14.67 mmol, 1.14 equiv) was added to a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (2.1 g, 12.91 mmol, 1.00 equiv, 95%) in tetrahydrofuran (50 mL) at 0° C. After the reaction mixture was stirred at 0° C. for 30 min, iodomethane (3 g, 20.71 mmol, 1.60 equiv, 98%) was added dropwise at 0° C. The resulting solution was stirred for 4.5 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/ethyl acetate (10/1) to give 300 mg (14%) of 5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1)[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=1)[CH3:8]
Reactant: CCOC(=O)Cc1cccc(CN)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(CNS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Methanesulfonyl chloride (2.6 mL, 34 mmol) was slowly added to a solution of (3-aminomethyl-phenyl)-acetic acid ethyl ester hydrochloride (7.31 g, 34 mmol) and triethylamine (9.8 mL, 70 mmol) in CH2Cl2 (100 mL) at 0° C. The mixture was stirred for 1 h and 1N aqueous HCl solution was added. The aqueous solution was extracted with CH2Cl2 (3×) and the combined organic extracts were washed with brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1:1 hexanes:EtOAc) provided the title sulfonamide (8.56 g) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.21 (m, 4H), 4.70 (broad, 1H), 4.29 (d, 2H), 4.12 (q, 2H), 3.60 (s, 2H), 2.86 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:17]1([CH3:27])[CH2:22]C[CH:20]([CH:23](C)[CH3:24])[CH:19](O)[CH2:18]1>CCO.CCO.CCO.CCO.[Ti]>[CH:23]1([CH3:24])[CH2:20][CH2:19][CH:18]([CH:17]([CH3:27])[CH3:22])[CH:9]([O:8][C:6](=[O:7])[CH:5]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15]2)[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:10]1
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Agent: [Ti]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OC1CC(C)CCC1C(C)C)n1cccc1
Temperature: 110 °C
Reaction time: 19 h
Yield: 31.8 %

Procedure:
To a mixture of 2-(pyrrol-1-yl)malonic acid diethyl ester (300.0 g) and (-)-menthol (417.0 g) was added tetraethyl titanate (10.0 g), and the resulting mixture was stirred at 110° C. for 19 hours. After removal of the (-)-menthol under reduced pressure, the residue was chromatographed on silica gel using n-hexane/ethyl acetate (50:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure to give the title compound (142.0 g, 31.8%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)c1ccc(NCCc2ccccc2)cc1
Temperature: -20 °C

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 10.3 g. of (2-bromoethyl)benzene and 50 ml. of hexamethylphosphoramide is heated in an oil bath at 115°-120° C. for 17 hours. The mixture is put into ice and water and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oil is combined with 200 ml. of ethanol-water (9:1) and 20 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. After chilling the mixture is made acidic with concentrated hydrochloric acid, diluted with 150 ml. of water, chilled, diluted with water and extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulfate and concentrated in vacuo to a gum. Ethanol is added, the mixture is chilled and filtered to give yellow crystals. The mother liquors are chilled at -20° C. to give a second crop of crystals. Recrystallization of the combined crops of crystals from hexane-ethanol gives yellow crystals, m.p. 123°- 125° C. Recrystallization from ethanol gives pale yellow crystals, m.p. 124°-126° C.
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:19])[C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[C:13]2[C:12]([CH3:19])=[CH:11][S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: N#Cc1ccno1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)csc1N
Product: Cc1csc2nc(-c3ccno3)nc(Cl)c12

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-4-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)[C@@H:10]([CH3:35])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:15]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH3:35])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:24]([OH:26])=[O:25])[CH:21]=3)[N:16]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of methyl 3-[(2S)-4-[(tert-butoxy)carbonyl]-2-methylpiperazin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (260 mg, 0.54 mmol) in dichloromethane (30 mL) was added CF3COOH (2 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in methanol (15 mL), and sodium hydroxide (20 mg, 0.50 mmol) in water (1 mL) was added. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL), the pH adjusted to 6, and the resulting solution concentrated in vacuo. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC(MS-Directed)): Column, 1#-PrepC-001(XBridge Shield RP18 19*150 186002987 111130103113 03), N; mobile phase, WATER WITH 0.03% NH3H2O and CH3CN (10% CH3CN up to 22% in 7 min, hold 100% in 2 min, hold 10% in 2 min); Detector, UV 220 nm) to afford 2-(4-fluorophenyl)-3-[(2S)-2-methylpiperazin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (31 mg, 59%).
Reaction SMILES: N1C=CN=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(O[N:39]1N=N[C:41]2[CH:42]=[CH:43][CH:44]=C[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)C(N)=CC=CC=1>CN(C=O)C>[NH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:2]=1[NH:6][C:7]([C:9]1[C:17]2[NH:16][C:15]([NH:18][C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)=[O:20])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cccc2nc(NC(=O)c3nccc4ccccc34)[nH]c12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a solution of 0.33 g (1.0 mmol) of -[(isoquinoline-1-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (from Example 58) in DMF (5 mL) was added 0.47 g (1.25 mmol) of HBTU and DIEA (0.5 mL). The mixture was stirred for 5 min, then 0.22 g (2.0 mmol) of benzene-1,2-diamine was added in one portion. The reaction mixture was heated at 50° C. for 1 h, after cooling to room temperature, the coupling product was precipitated by addition of sat. aq. sodium carbonate solution (15 mL). The solid was filtered, washed with water, and dried to provide 0.35 g (80%) of isoquinoline-1-carboxylic acid [7-(2-amino-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 443 (M+1)+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:22][CH:21]([CH3:23])[CH:20]=[C:19]([C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1)[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 65.5 %

Procedure:
A solution of 1-benzenesulfonyl-2-(3-methyl-1-m-tolyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (2.99 g) in ethanol (50 mL) and tetrahydrofuran (100 mL) was treated with 10% aqueous sodium hydroxide solution (20 mL). The reaction was stirred at 85° C. for 14 h. The reaction mixture was cooled to 25° C. and concentrated in vacuo. Water (100 mL) was added to the residue, and the solution was extracted with ethyl acetate (2×100 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. A light yellow solid was obtained and washed with ethanol (20 mL), then dried to afford 2-(3-methyl-1-m-tolylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.30 g, 77.8%) as a white solid: 1H NMR (300 MHz, CDCl3): δ ppm 9.50 (s, 1H), 7.98-7.89 (m, 2H), 7.23-7.01 (m, 5H), 6.50 (s, 1H), 5.64 (d, 1H, J=10.2 Hz), 2.98-2.90 (m, 1H), 2.32 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).