Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]([C:39](OC)=[O:40])=[CH:29]2)=[CH:23][CH:22]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]([CH2:39][OH:40])=[CH:29]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cn1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
Lithium aluminium hydride (205 mg) was added gradually to a solution of methyl 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenylpyrrole-3-carboxylate (1.30 g) in tetrahydrofuran (40 ml) at 0° C., and the resultant was stirred for 3 hours. Sodium sulfate decahydrate (2.80 g) was added to the reaction mixture, and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography to obtain [1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]methanol (1.15 g, yield 94%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (3:2, volume ratio).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]([Mg]Br)[CH3:27]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1)[CH3:27]
Reactant: CC[Mg]Br
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a solution of 200 mg (0.55 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF (5 ml) were added 30 mg (0.055 mmol) Ni(dppp)Cl2 and 330 μl (0.66 mmol, 2M in THF) ethylmagnesiumbromide. The RM was heated to 80° C. for 8 h, followed by quenching with a sat. aq. NH4Cl sol. and extraction with EtOAc (3×20 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 50 mg (0.14 mmol, 25%) Ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 22). [M+H]+358.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (103 g, 0.35 mol) and tosyl chloride (66.7 g, 0.35 mol) were dissolved in toluene (517 g) and then cooled to 0° C. To the mixture was added dropwise triethylamine (35.5 g, 0.35 mol) at 0° C. over 90 min. The mixture was further kept at 0° C. for 4 hrs. The reaction mass was washed with 5% hydrochloric acid (255 g) and 5% aqueous sodium bicarbonate (294 g) and then concentrated at 35° C. under reduced pressure until the weight of the toluene layer reached to 243 g. After cooling to −10° C., to the concentrate was added dropwise n-hexane (310 g) over 3 hrs. Deposited crystals was filtered and dried to give N-Boc-O-tosyl L-tyrosine methyl ester 4 (147 g, yield 92%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:21][C:16]1[N:15]=[C:14]([NH:13][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=2)[C:19]([CH3:20])=[CH:18][N:17]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 62.1 %

Procedure:
A mixture of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (259 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane (15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue was purified by HPLC to give an intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl)phenyl)-5-methylpyrimidin-4-amine as brown solid (200 mg, 62%). A mixture of this intermediate (161 mg, 0.5 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (103 mg, 0.5 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as brown solid (75 mg, 31%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][NH:41]1.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:41]2[CH2:42][CH2:43][C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3ccccc3C2)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
A 2 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (60.0 μmol) was added to 1,2,3,4-tetrahydroisoquinoline (9.59 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (150 μL, 5 eq) and the reaction was stirred at room temperature for 60 hr. Some of the deprotections were incomplete so 2-3 drops of concentrated hydrochloric acid was added to these and they were stirred for another 24 hr. The ether and hydrochloric acid were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 42.9% yield. LCMS m/z (%)=392 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (t, J=5-81 Hz, 2 H), 3.09-3.17 (m, 2 H), 3.69 (t, J=5.6 Hz, 2 H), 3.69 (s, 3 H), 4.12 (t, J=5.56 Hz, 2 H), 4.63 (s, 2 H), 6.32 (d, J=2.02 Hz, 1 H), 7.13 (d, J=9.09 Hz, 1 H), 7.19 (s, 3H), 7.43 (d, J=2.53 Hz, 1 H), 7.47 (d, J=1.52 Hz, 1 H), 7.57 (dd, J=9.09, 3.03 Hz, 1 H), 7.87 (s, 2 H), 8.60 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:23][CH2:24]4)[S:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nsc(N4CCNCC4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nsc(N4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 65 mg (0.16 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-thiadiazol-5-yl]piperazine and 36 μl (0.25 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:11][C:12](=[O:31])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1)([CH3:10])([CH3:9])[CH3:8].Br[C:33]1[C:38]2[S:39][C:40]([C:42]3[C:47]([F:48])=[CH:46][N:45]=[C:44]([NH:49][CH2:50][CH2:51][N:52]4[CH:56]=[CH:55][N:54]=[N:53]4)[N:43]=3)=[CH:41][C:37]=2[CH:36]=[CH:35][CH:34]=1>O1CCOCC1.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]>[C:7]([O:11][C:12](=[O:31])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:33]1[C:38]2[S:39][C:40]([C:42]3[C:47]([F:48])=[CH:46][N:45]=[C:44]([NH:49][CH2:50][CH2:51][N:52]4[CH:56]=[CH:55][N:54]=[N:53]4)[N:43]=3)=[CH:41][C:37]=2[CH:36]=[CH:35][CH:34]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: Fc1cnc(NCCn2ccnn2)nc1-c1cc2cccc(Br)c2s1
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 100 °C

Procedure:
Add a solution of 2 M sodium carbonate (1.08 mL, 2.16 mmol) to a suspension of {2-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.5 g, 1.08 mmol), [4-(7-bromo-benzo[b]thiophen-2-yl)-5-fluoro-pyrimidin-2-yl]-(2-[1,2,3]triazol-1-yl-ethyl)-amine (450 mg, 1.08 mmol), and Pd(dppf)Cl2 (45 mg, 53.99 μmol) in 1,4-dioxane (4.32 mL) and heat at 100° C. for 4 h. Cool to RT and concentrate. Suspend the residue in DCM and filter through a 2-cm pad of silica in a 60-mL sintered glass funnel Elute with 50 mL DCM and 50 mL (1:1 ethyl acetate/hexane). Then elute with 200 mL of ethyl acetate to collect the product. Concentrate and purify on silica eluting with 10% ethanol in 1:1 DCM/hexane to give the title compound. MS (ES) m/z 560 [M+1]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)Oc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)Oc1ccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)cc1
Temperature: 70 °C

Procedure:
To 5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (70 mg, 0.236 mmol) in EtOH was added hydantoin (23.6 mg, 0.236 mmol) and piperidine (23.9 μL, 0.236 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to yield 5-((5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=379)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:13]=1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:14]1([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][C:6]=3[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=C1NCCNc2cc(Br)ccc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1NCCNc2cc(C3CC3)ccc21
Yield: 76 %

Procedure:
A mixture of 8-Bromo-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (1.02 g, 4.23 mmol, 1 eq), cyclopropylboronic acid (480 mg, 5.5 mmol, 1.3 eq), tricyclohexylphosphine (121 mg, 0.42 mmol, 0.1 eq), Pd(OAc)2 (48 mg, 0.211 mmol, 0.05 eq), K3PO4 (3.2 g, 14.8 mmol, 3.5 eq) in Toluene (40 mL), water (4 mL), dioxane (10 mL), was degassed with argon and heated to 110 C for 15 hours. The reaction was cooled, diluted with ethyl acetate, washed sat. aq. Sodium bicarbonate solution, brine, and dried over mgso4, filtered, concentrated in vacuo and purified with flash chromatography on a silica gel column eluting with 50% ethyl acetate in hexanes to give 650 mg 8-Cyclopropyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one, 76%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:13][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(F)c1
Agent: Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(F)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) were dissolved in CCl4 (80 ml). HBr (64 ul, 0.56 mmol) was added, and the mixture was stirred under reflux overnight. The mixture was cooled at room temperature, diluted with DCM, and washed with sat. NaHCO3, water and brine. The organic layer was dried (Na2SO4), filtered, and evaporated obtaining intermediate I15 (2.68 g, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:19]=[O:20])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nccc(Cl)c2s1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at −78° C. was added n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 20 min. Dry DMF (0.5 mL, excess) was added and the reaction mixture was stirred for an additional 2 hrs. The reaction mixture was quenched with methanol at −78° C. and water was added. The mixture was extracted with EtOAc and the organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the resultant yellow solid was triturated with hexane to afford 14 (250 mg, 100% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.2 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.61 (s, 1H), 7.78 (d, J=5.1 Hz, 1 H).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]I>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11]2)=[CH:5][C:4]=1[F:9]
Reactant: Fc1ccccc1Cl
Reactant: CCOC(=O)c1cc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(-c2ccc(Cl)c(F)c2)n1
Temperature: 140 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
A 50 mL of flask was charged with 3.00 g of 4-chloro-3-fluorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N′-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2×50 mL), brine (2×50 mL). The organics was dried over MgSO4 and concentrated under reduced pressure. The residued was purified via flash column chromatography on silica gel (0-25% EtOAc in hexanes) to get the desired product (1.2 g, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][OH:17]>>[CH3:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][O:17][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Reactant: CN1CCC[C@H]1CO
Product: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1

Procedure:
A sample of 3,5-dibromopyridine-N-oxide (prepared according to the method of Y. Tamura et al., Heterocycles, 15:871-874 (1981)) is reacted with (S)-(-)-1-methyl-2-pyrrolidinemethanol according to the procedure of Example 3a, and the product is purified by chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Brc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a solution of 2-bromophenol (1 g, 5.84 mmol), phenylboronic acid (1.42 g, 11.69 mmol) and TEA (2.95 g, 29.2 mmol) in DCM (30 mL) was added Cu(OAc)2 (1.05 g, 5.84 mmol) and 4 Å molecular sieves (500 mg). The reaction mixture was stirred at room temperature over air with a dry tube attached for 16 h. The mixture was filtered and the filtrate was washed by water (50 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated with the residue purified by column chromatography to give 612 mg of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[I-].C([NH3+])(C)(C)C.Cl[CH2:29][C:30]([C:32]1[CH:41]=[C:40]2[C:35]([CH2:36][CH2:37][N:38]([C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])[CH2:39]2)=[CH:34][CH:33]=1)=[O:31]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:29][C:30](=[O:31])[C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][N:38]([C:42](=[O:47])[C:43]([F:46])([F:44])[F:45])[CH2:39]3)=[CH:34][CH:33]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: CC(C)(C)[NH3+]
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2

Procedure:
To 600 mg (2.98 mmol) 4-benzyloxy-1H-pyridin-2-one in 6 mL THF is added at 0° C. 368 mg (3.28 mmol) potassium tert-butylate and 55 mg (0.15 mmol) tert-butylammonium iodide. After 5 min 1.00 g (3.28 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone is added. After 2 h additional 600 mg (1.97 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone is added and the mixture is stirred an additional hour. The reaction mixture is diluted with EtOAc and the organic phase is washed with water, filtered, dried over MgSO4 and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond; water (0.15% formic acid)/acetonitrile (0.15% formic acid) 95:5 to 5:95).
Reaction SMILES: Cl.[NH2:2]O.C([O:6][C:7](=O)[CH2:8][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C>>[CH2:10]([C:9]1[O:21][N:2]=[C:7]([OH:6])[CH:8]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCC(=O)CC(=O)OCC
Reactant: NO
Agent: Cl
Product: CCCCCCCCCCCc1cc(O)no1

Procedure:
The above-identified compound was synthesized according to the process of (Example 1) using hydroxylamine hydrochloride and dodecanoylacetic acid ethylester as raw materials.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:14]=[CH:15]/[C:16]([O:18]CC)=O.C>C(O)C.C1(C)C(C)=CC=CC=1>[CH3:8][C:7]1[CH:6]=[C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[CH2:15][CH2:14]2
Reactant: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Cc1cc(-n2cnnn2)cc2c1NC(=O)CC2

Procedure:
A suspension of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol1-yl]phenyl)prop-2-enoate (2.5 g) in ethanol (250 cm3) was hydrogenated at 60° and 15 p.s.i. (1.04×105Pa) pressure over 10% palladised charcoal (1 g) for 11/2 hours. The cooled mixture was filtered through "Solkafloc" (Trade Mark) and evaporated in vacuo to afford a solid. A suspension of this solid in xylene (100 cm3) was heated under reflux for 7 hours. The mixture was then cooled and the product filtered off and washed with dichloromethane:methanol, 5:1, to afford 3,4-dihydro-8-methyl-6-(tetrazol-1-yl)-2-(1H)-quinolone, m.p. 271°-272°, (1.37 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH:10]([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:15][CH2:14][N:13]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:12]2)[CH:10]([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)C12CCNC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)C12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 104 %

Procedure:
An optically-active compound of 3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (6.9 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.3 g), potassium carbonate (7.7 g) and water (65 ml), and stirred for 4 hours with refluxing. The mixture was cooled to room temperature, and thereto was added water (60 ml). The mixture was extracted with chloroform/methanol (10/1, 120 ml). The organic layer was sequentially washed with water, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. To the mixture was added silica gel (4 g), and the mixture was stirred for 10 minutes, filtered through Celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1, followed by chloroform/methanol=50/1 to 20/1) to give the titled compound (10.0 g).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]3[N:17]=[CH:18][CH:19]=[CH:20][C:5]2=3)[CH2:3][CH2:2]1.[BrH:22].O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:22][CH2:3][CH2:2][CH:1]=[C:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]2[N:17]=[CH:18][CH:19]=[CH:20][C:5]1=2
Reactant: Br
Reactant: COc1ccc2c(c1)C(O)(C1CC1)c1cccnc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of step 1 (4.3 g) in acetic acid (30 ml) was added 48% aqueous HBr (25 ml) at 10° C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 5-(3-bromopropylidene)-5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepine (5.6 g).