Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[N:12][C:11]([NH:15][C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=[CH:10]2>CN(C=O)C.[Cu](I)I>[CH3:1][O:2][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[N:12][C:11]([NH:15][C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=[CH:10]2
Reactant: C[O-]
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cc(Nc3cnc(C#N)cn3)ncc12
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
Sodium methoxide (55 mg, 0.10 mmol) was added to a pre-stirred mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (33 mg, 0.10 mmol) and copper iodide (19 mg, 0.10 mmol) in DMF in triplicate. The three reaction mixtures were heated at 140° C. for 30 minutes, 110° C. for 18 hours, and 120° C. for 10 minutes, respectively. The combined reaction mixtures were partitioned between ethyl acetate and water and the aqueous layer re-extracted with more ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by preparative HPLC gave the title compound (1.7 mg, 0.006 mmol, 2%). 1H NMR (DMSO, 400 MHz) δ 9.33 (s, 1H), 8.81 (d, 1H, J=1.3 Hz), 8.71 (d, 1H, J=1.3 Hz), 8.43 (s, 1H), 7.64 (t, 1H, J=8.1 Hz), 7.43 (d, 1H, J=8.3 Hz), 6.97 (d, 1H, J=7.6 Hz), 4.01 (s, 3H). LCMS (2) Rt=2.87 min, m/z (ESI+) 278 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][N:23]=2.FC(F)(F)C(O)=[O:33].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][N:23]=2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,8]naphthyridine (compound 401) (76 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (0.5 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 3 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (46 mg, yield 56%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[Mg].[CH:9]([C@@H:11]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][C@@H:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10].[NH4+].[Cl-]>C1COCC1>[OH:10][C@H:9]([C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1)[C@@H:11]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][C@@H:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Cc1ccc(Br)s1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](O)[C@H]2[C@@H](c3ccccc3)CC(=O)N2C)s1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A portion (1 mL) of a solution of 2-bromo-5-methylthiophene (0.56 mL, 5.5 mmol) in THF (20 mL) was added to Mg turnings (135 mg, 5.5 mmol). The mixture was gently heated until the magnesium started to be consumed. The remaining thiophene solution was added in 1 mL increments to maintain a constant gentle reflux. After the addition was complete, the solution was heated at the reflux temperature for 3 min, then was allowed to cool to room temperature. To a −78° C. solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 190 mg, 1 mmol) in THF (7.5 mL) was slowly added the freshly prepared Grignard reagent and the reaction mixture was allowed to warm to room temperature. After 2 h a saturated NH4Cl solution was added and the mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (100% EtOAc) to give (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-methyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-one (156 mg, 52%) as a white powder: mp 185-188° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([NH:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN2CCc3ccccc3C2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN2CCc3ccccc3C2C1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine hydrochloride (1.38 g), suspended in a solution of triethylamine (2 ml) in dichloromethane (10 ml) stirred at room temperature was added methane sulphonyl chloride (0.570 g) in dichloromethane (5 ml). After stirring for 18 hours, the solution was washed with water and the organic phase separated, dried and evaporated to yield the title compound (1.06 g) as an oil, which was converted in ethanolic hydrogen chloride to the hydrochloride (0.395 g) m.p. 244.8° C. C14H20N2O2S.HCl requires C, 53.06; H, 6.68; N, 8.84%. Found: C, 53.07; H, 6.77; N, 8.64%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24]>CN(C=O)C.O>[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][C:20]2[O:21][C:20]3[C:22](=[CH:23][C:17]([Cl:16])=[C:18]([OH:24])[CH:19]=3)[C:11]3([C:6]4[C:7](=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]=4[Cl:13])[C:8](=[O:9])[O:10]3)[C:22]=2[CH:23]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC2(c3cc(Cl)c(O)cc3Oc3cc(O)c(Cl)cc32)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 98.1 %

Procedure:
Treatment of tetrachlorophthalic anhydride (5 g, 17.49 mmol) and 4-chlororesorcinol (6.32 g, 43.73 mmol), according to the procedure described in Example 1 Step 1, provided 10.31 g of crude product. Suspension of a 9.25 g portion of this in DMF:water (1:1) followed by filtration, provided 9.70 g (2:1 DMF complex 17.16 mmol, 92.3% yield) of 2′,4,5,6,7,7′-hexachloro-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one that was isolated as an orange solid. 1H NMR (300 MHz; DMSO d6) δ 11.13 (S, 2H), 7.31 (s, 2H), 6.89 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]=[O:13])=[C:7]([O:14][CH3:15])[CH:6]=[CH:5]2.[CH3:16][O:17][C:18]1[CH:19]=[C:20](OB(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH3:15][O:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=3)[CH:3]=2)[C:8]=1[CH:12]=[O:13]
Reactant: COc1cccc(OB(O)O)c1
Reactant: COc1ccc2cc(Br)ccc2c1C=O
Product: COc1cccc(-c2ccc3c(C=O)c(OC)ccc3c2)c1
Yield: 86 %

Procedure:
The compound is prepared by the reaction of 6-bromo-2-methoxy-1-naphthaldehyde (2 g, 7.55 mmol, 1 eq) with 3-methoxyphenylboric acid (1.3 g, 8.30 mmol, 1.1 eq) according to method A. Purification by column chromatography with hexane/ethyl acetate 1/1 as the eluent yielded the desired compound in a yield of 86%, 1.9 g.
Reaction SMILES: [NH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[NH2:2].Cl.O1CCOCC1.[F:20][C:21]([F:33])([F:32])[C:22](=O)[CH2:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)=O>C(O)C>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:24]1[N:1]([C:3]2[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=2)[N:2]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=1
Reactant: CCOC(=O)c1csc(NN)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To 28 (268 mg, 1.431 mmol) was added 4N HCl in dioxane (3.6 mL, 14.3 mmol) and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.23 mL, 1.6 mmol). The resulting suspension was allowed to stir for 16 h at 100° C. Ethanol (1.4 mL) was added, and the mixture was stirred for 4 h at 100° C. Solvent was evaporated and the residue was purified by silica gel column chromatography with gradient of EtOAc (10-20%) in hexanes to afford 29 (203 mg, 20%) as an orange solid. LRMS (ESI): calc. 357.0; found 358.1 (MH)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.Cl>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([B:27]([OH:28])[OH:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(CCOCc2ccccc2)cc1
Reaction time: 3 h
Yield: 64 %

Procedure:
3.8 g (13.0 mmol) of 4-(2-benzyloxyethyl) phenylbromide and 30 ml of dry THF were cooled to -80° C., and 9.4 ml of n-butyllithium (1.65M) was dripped to it. Stirring at the foregoing temperature was performed for 3 hours, and then mixture solution of 5.68 g (30.2 mmol) of triisopropoxyboron and 15 ml of dry THF was dripped, and stirring at room temperature was performed for 13 hours. After the reactions had been completed, 15 ml of 10% hydrochloric acid was added, and extraction with ethyl acetate was performed. After the extracted solution was dried, the solvent was removed by filtration. Then, refining was performed with a silica gel column chromatography (developing solvent: toluene/ethyl acetate=20/1) so that 3.21 g of 4-(2-benzyloxyethyl) phenyl boronic acid was obtained (yield 64%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]1([OH:16])[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1.Br[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[N:15]1[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][C:8]([C:3]1[N:4]=[CH:5][CH:6]=[CH:7][N:2]=1)([OH:16])[CH2:14]2
Reactant: OC1(c2ncccn2)CC2CCC(C1)N2
Reactant: Clc1ccccc1C(Br)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OC1(c2ncccn2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 22.5 °C

Procedure:
Under N2, a well stirred mixture of 3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (4.5 g, 14 mmol), 1,1′-(bromomethylene)bis(2-chlorobenzene) (5.0 g, 16 mmol) and K2CO3 (10.0 g, 72 mmol) in CH3CN (50 ml) was stirred under reflux and the reaction was followed by HPLC. After complete reaction (36 to 48 h) the mixture was cooled to 20-25° C., water (50 ml) was added and the suspension was stirred for 3 h. The product was filtered off, washed with water (2×25 ml) and dried to constant weight under vacuum and a slight stream of N2 at 50° C. Yield: 5.5 g (87% abs.). Assay (HPLC): 97% pure vs. standard.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:8]12[CH:23]([O:24]CC3C=CC4C(=CC=CC=4)C=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:36])[CH2:9]2)([CH3:4])([CH3:3])[CH3:2].O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:8]12[CH:23]([OH:24])[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:36])[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2OCc1ccc2ccccc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2O
Reaction time: 0.08 h

Procedure:
To a solution of compound 53 (1 mmol) in anhydrous CH2Cl2 (10 mL) was added water (0.8 mL) and the biphasic solution was stirred for 5 minutes. To this solution is added DDQ (2.2 mmol). The reaction mixture was stirred for 8 hours when the reaction was complete. It was diluted with CH2Cl2 (100 mL) and washed with 2% sodium bisufite solution. The aqueous layer was extracted until all the compound was in organic layer. The organic layer was washed with saturated bicarbonate followed by brine then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified on silica gel to give compound 54 in nearly quantitative yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH:3]=O.[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:15]([N+:19]([O-:20])=[CH:3][CH:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)NO
Reactant: CC(C=O)Cc1ccc(C(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C=[N+]([O-])C(C)(C)C)Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.18 %

Procedure:
To a mixture of [2-methyl-3-(4-isopropylphenyl)-propionaldehyde] (3.0 g, 15.8 mmol, 1.0 equiv), N-tert-butylhydroxylamine (1.76 g, 19.7 mmol, 1.3 equiv) and toluene (60 ml) was added p-TsOH (50 mg), and the mixture was stirred at rt for 18 h. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography (EtOAc:hexane 1:1) to give N-tert-butyl-C-[2-(4-isopropylphenyl)-1-methyethyl]nitrone (1.04 g, 25.18%) as a white solid: 1H NMR (CDCl3) δ 7.12 (d, J=1.0, 4H), 6.63 (d, J=7.2 1H), 3.47–3.31 (m, 1H), 2.89–2.80 (m, 2H), 2.71–2.63 (dd, 1H), 1.44 (s, 9H), 1.25 (d, J=6.9, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:17])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)OCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 217, 13.7 g, 36.67 mmol) in dichloromethane (20 mL) at 0° C. was added pyridine (5.93 mL, 73.35 mmol) followed by dropwise addition of ethyl chloroformate (3.87 mL, 40.34 mmol). The reaction was allowed to warm to room temperature over 3 hours. Diluted with dichloromethane and washed with saturated NH4Cl. Extracted with dichloromethane three times, combined and dried over Na2SO4. Removed solvent to give title compound as a yellow oil (14.5 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:29])[C:9]2[CH:14]=[C:13]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)[CH:12]=[C:11]([O:21]CC3C=CC=CC=3)[CH:10]=2)=[N:3]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:21][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([O:15][C@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH:12]=1)[C:8]([NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:29]
Reactant: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Temperature: 140 °C
Yield: 97.2 %

Procedure:
N-(1-Methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (453 mg, 1.15 mmol) was dissolved in ethanol (5 mL) and ammonium formate (182 mg, 2.88 mmol) was added in one portion. The reaction was blanketed with argon and 10% palladium on activated carbon (30 mg) was added. This mixture was heated to 140° C. for 10 minutes in a Smith Creator microwave. The catalyst was filtered off and the volatiles removed in vacuo to give the title product as a white solid (339 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12]O)=[C:10]([CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][C:6]([F:18])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[CH2:19]([C:21]1([OH:34])[C:31]2[CH:30]=[CH:29][NH:28][C:27](=[O:32])[C:26]=2[CH2:25][O:24][C:23](=[O:33])[CH2:22]1)[CH3:20]>>[CH2:19]([C:21]1([OH:34])[C:31]2[CH:30]=[C:29]3[N:28]([CH2:12][C:11]4[C:2]3=[N:3][C:4]3[CH:5]=[C:6]([F:18])[C:7]([O:16][CH3:17])=[CH:8][C:9]=3[C:10]=4[CH2:14][CH3:15])[C:27](=[O:32])[C:26]=2[CH2:25][O:24][C:23](=[O:33])[CH2:22]1)[CH3:20]
Reactant: CCC1(O)CC(=O)OCc2c1cc[nH]c2=O
Reactant: CCc1c(CO)c(Cl)nc2cc(F)c(OC)cc12
Product: CCc1c2c(nc3cc(F)c(OC)cc13)-c1cc3c(c(=O)n1C2)COC(=O)CC3(O)CC

Procedure:
(2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinyl)methanol is coupled with compound (M) as described in Stage 11.j. of Example 11. The resultant coupled product is cyclized according to the procedure described in Stage 11.k. A yellow solid is obtained, m.p. >275° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][O:20]CC2C=CC=CC=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][OH:20])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
5% Pd/C (1.85 g, 50% wet) is added to a solution of 4-benzyloxymethylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (1.85 g, 0.0049 mol) in ethanol (20 mL). The reaction mixture is stirred under the positive pressure of hydrogen gas for 16 hrs at room temperature. The reaction mixture is filtered through celite bed and washed with a solution methanol and dichloromethane (1:5, 100 mL). Combine filtrate is concentrated under reduced pressure to give 4-hydroxymethylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:20]([O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:11]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: OC1CCN(c2ccc3cc[nH]c3c2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc3cc[nH]c3c2)C1
Yield: 91.8 %

Procedure:
A homogeneous, colorless solution of 1-(1H-indol-6-yl)pyrrolidin-3-ol (0.1036 g, 0.512 mmol), tert-butylchlorodimethylsilane (0.093 g, 0.615 mmol) and imidazole (0.087 g, 1.281 mmol) in DMF (2.56 mL) was stirred overnight. The mixture was diluted with EtOAc (75 mL), washed with water (4×25 mL) and brine (25 mL) successively, dried over MgSO4, and concentrated in vacuo. The residue was triturated with hexanes to give the desired product (0.1600 g, 0.470 mmol, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc3c(Cl)cccn3c2I)cc1
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(F)c2)cc1
Temperature: 100 °C
Yield: 80.5 %

Procedure:
8-Chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-α]pyridine (0.15 g, 0.4 mmol) was dissolved in N,N-dimethylformamide (5 mL). To this solution was added 2-fluoro-4-pyridinylboronic acid (120 mg, 0.8 mmol), dichlorobis(triphenylphosphine)palladium (II) (60 mg, 0.08 mmol) and aqueous sodium carbonate (170 mg, 1.6 mmol). The resulting solution was heated at 100° C. overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. Purification by silca gel chromatography (1:1 ethyl acetate:hexane) gave 8-chloro-2-(4-fluorophenyl)-3-(2-fluoropyridin-4-yl)imidazo[1,2-α]pyridine (110 mg, 81%) as a white solid. 1H NMR (CDCl3): δ 8.41 (d, 1H), 8.09 (d, 1H), 7.62 (q, 2H), 7.42 (d, 1H), 7.29 (d, 1H), 7.07 (m, 3H), 6.87 (t, 1H); 19F NMR (CDCl3) δ −65.46 and −112.94; MS m/z 342 (M+1).
Reaction SMILES: [CH:1]1([NH:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>O1CCCC1>[CH:1]1([N:9]([OH:10])[C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ONC1CCCCCCC1
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N(O)C2CCCCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A solution containing cyclooctyl hydroxylamine (Compound 36 Part B, 2.0 g, 14 mmol) in tetrahydrofuran (50 mL) was slowly charged with 4-methoxyphenyl isocyanate (2.0 mL, 15 mmol). The reaction mixture was allowed to stir at ambient temperature for 20 hours. A white precipitate was isolated by filtration then washed with cold hexane. A second crop was isolated from the filtrate. The solids were combined and dried to provide 3.2 g of the desired product as a white solid, m.p. 166°-167° C. Analysis: Calculated for C16H24N2O3 : %C, 65.73; %H, 8.27; %N, 9.58; Found: %C, 65.31; %H, 7.98; %N, 9.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.O.[NH2:12][NH2:13]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:12]/[NH2:13]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: NN
Solvent: O
Product: N/N=C/c1c(Br)cncc1Br
Temperature: 120 °C
Yield: 49.1 %

Procedure:
In analogy to GP 1, 54 mg of 3,5-dibromo-pyridine-4-carbaldehyde (0.2 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 1 mL 1-propyl alkohol, treated with 30 μL 80% hydrazine hydrate (0.61 mmol, 3 eq.) and heated to 120° C. for 30 min (employing a Biotage Initiator® microwave oven). The precipitate was filtered and washed with cold 1-propyl alkohol to yield 27 mg of the hydrazone (0.1 mmol, 50% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH2:10])=[O:4].[Cl:11][C:12]([Cl:19])([Cl:18])[C:13]([N:15]=[C:16]=[O:17])=[O:14]>C1COCC1>[Cl:11][C:12]([Cl:19])([Cl:18])[C:13]([NH:15][C:16]([NH:10][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:17])=[O:14]
Reactant: COC(=O)c1ccsc1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-thiophene-3-carboxylic acid methyl ester (1 eq) in anhydrous THF (mL) was added trichloroacetyl isocyanate (1 eq) slowly over a period of 5 min. After the addition was complete, a precipitate formed and the reaction stirred for an additional 1 h. The desired product was obtained by filtration to give methyl 2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (99%) as an off-white solid. The product was used in the next step without any further purification. LC/MS (ES, M+H=345).