Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CO.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].C1(C)C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:23][CH2:22]1)[CH3:27]
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: CN(C)CC1CCNCC1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCC(CN(C)C)CC2)cc2c1cnn2C(C)C
Temperature: 115 °C
Reaction time: 15 h
Yield: 11.6 %

Procedure:
To a 10-mL microwave tube were added methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (250 mg, 0.841 mmol), N,N-dimethyl-1-(4-piperidinyl)methanamine (132 mg, 0.925 mmol), Toluene (3 mL), and cesium carbonate (411 mg, 1.262 mmol), and the mixture was degassed for 5 min by bubbling N2 through BINAP (79 mg, 0.126 mmol) and Pd2(dba)3 (38.5 mg, 0.042 mmol) were added. The tube was sealed and the mixture was heated at 115° C. with stirring for 15 h. The mixture was diluted with methanol (5 mL) and filtered. The filtrate was concentrated and the residue was purified using reverse-phase HPLC to give 35 mg of product as a off-white solid. LCMS MH+=359.3
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:15]2[O:14][C:13]([S:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]4[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=4[CH:38]([CH3:40])[CH3:39])=[O:27])[CH2:21][CH2:20]3)=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=O.C(O)(=O)C.O.[NH2:47]N>CO>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[C:15]3[O:14][C:13]([S:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]([NH:28][C:29]5[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=5[CH:38]([CH3:40])[CH3:39])=[O:27])[CH2:23][CH2:24]4)=[N:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[N:47]1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3cccc(C(=O)C=CN(C)C)c3o2)CC1
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3cccc(-c4cc[nH]n4)c3o2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a solution of the enamine (245 mg, 0.4 mmol) in methanol (6 ml) were added acetic acid (123 mg, 2.05 mmol) and hydrazine monohydrate (102 mg, 2.05 mmol) followed by stirring at room temperature for 15 hours. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, hexane:acetone=5:3) to provide 129 mg (yield 58%) of the desired compound as colorless needles.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22]>O>[C:21]([CH2:20][S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:22]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CCSc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of sodium hydroxide (10.4 g, 0.26 mol) in degassed water (600 mL) was added 4-mercaptobenzoic acid (20.0 g, 0.13 mol). This solution was stirred for 30 minutes. To a solution of potassium carbonate (9.0 g, 65 mmol) in degassed water (400 mL) was added chloroacetonitrile (9.8 g, (0.13 mol) portion-wise. These two solutions were mixed and stirred for 48 hours at RT under N2. The mixture was filtered and washed with heptane. The aqueous phase was acidified with 3N hydrochloric acid and the product was filtered off, washed with water and dried, affording 4-cyanomethylsulfanylbenzoic acid (27.2 g, 88%). This compound was used without further purification in the following step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([NH2:30])=[C:28]4[CH2:31][CH2:32][CH2:33][C:27]4=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.Cl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH:18]=[CH:17][N:16]=[CH:15]4)[N:26]=[C:27]3[CH2:33][CH2:32][CH2:31][C:28]=23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1c2c(nn1-c1cccc3cnccc13)CCC2
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c3c(nn2-c2cccc4cnccc24)CCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.075 g, 0.32 mmol) and 2-(isoquinolin-5-yl)-2,4,5,6-tetrahydrocyclopentapyrazol-3-amine (0.050 g, 0.20 mmol) in pyridine (1 mL) was stirred at room temperature for 1 h. The reaction mixture was added 1 N aqueous hydrochloric acid and extracted with in 2:1 CH2Cl2/iPrOH (2×10 mL). The combine organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.056 mmol, 28%). 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.35 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.41-7.37 (m, 3H), 7.18 (d, J=4.8 Hz, 1H), 2.64 (t, J=7.2 Hz, 2H), 2.21 (pent, J=7.2 Hz, 2H), 2.06 (t, J=7.5 Hz, 2H), 1.25 (s, 9H); MS: (ES) m/z calculated for C25H27N4O2S [M+H]+ 447.2. found 447.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>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]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:23]=2)=[CH:27][CH:26]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc(Cl)cc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A mixture of 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 560 (40.5 mg, 10%). 1H NMR (CDCl3, 400 MHz): δ 8.7-8.7 (d, J=2.4 Hz, 1H), 7.96 (s, 1H), 7.90 (s, 1H) 7.57-7.43 (m, 5H), 7.15-7.13 (d, J=8.8 Hz, 1H), 5.94 (m, 1H), 4.56-4.54 (d, J=5.6 Hz, 2H), 4.56-4.54 (d, J=5.6 Hz, 2H), 1.62 (s, 6H). MS (ESI) m/z 406.14 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:9][C:8]=12.I[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:10][N:9]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:8]=12
Reactant: Ic1ccsc1
Reactant: COc1nccc2c(-c3ccccc3)n[nH]c12
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c(-c3ccccc3)nn(-c3ccsc3)c12
Yield: 9.3 %

Procedure:
A solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (225 mg) obtained in Step C of Example 10, 3-iodothiophene (1.05 g), L-proline (46.1 mg), potassium carbonate (691 mg) and copper(I) iodide (38.1 mg) in DMSO (10 mL) was stirred under nitrogen atmosphere at 180° C. for 1 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (28.5 mg).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.N1C=CC(CCCO)=CC=1>>[ClH:28].[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:33][CH:34]=1
Reactant: ClCCCc1ccncc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Agent: Cl
Agent: OCCCc1ccncc1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCc3ccncc3)cc12

Procedure:
6-(3-Pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 10% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 4-(3-Chloro-propyl)-pyridine hydrochloride, prepared from 4-pyridine propanol (U.S. Pat. No. 6,362,336).
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[C@H:27]([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:20]1[CH3:29])=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[C@H:27]([CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@@H:20]1[CH3:29])=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)[C@H](C)c2ccccc2[C@@H]1C
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: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)[C@H](C)c2ccccc2[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), (cis)-2-Amino-1,3-dimethyl-indan-2-carboxylic acid ethyl ester (636 mg, 2.72 mmol), HATU (1.3 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 50-50% EtOAc in heptane) to give a pure product (76) as white solid (79 mg, 9%).
Reaction SMILES: [In].[CH3:2][O:3][CH:4]([O:7][CH3:8])[CH:5]=[O:6].[CH2:9](Br)[CH:10]=[CH2:11]>C(O)C>[OH:6][CH:5]([CH2:11][CH:10]=[CH2:9])[CH:4]([O:7][CH3:8])[O:3][CH3:2]
Reactant: C=CCBr
Reactant: COC(C=O)OC
Agent: [In]
Solvent: CCO
Product: C=CCC(O)C(OC)OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Indium powder (0.52 mol, 1 eq., 60 g, 100 mesh) was added to an ethanol (250 mL) solution containing 2,2-dimethoxyacetaldehyde (0.52 mol, 1.0 eq., 90.62 g, 60 wt % solution in water) and allyl bromide (0.79 mol, 1.5 eq., 66.5 mL). The suspension was stirred at 40° C. for 3 h. The slurry was then centrifuged and the supernatant was decanted. The pellet was suspended and washed 3 times with ethanol (350, 350, and 450 mL). The combined supernatants were mixed with 1500 mL deionized water and 1500 mL saturated sodium chloride. The crude product was extracted with chloroform (1500, 300 mL). The combined organic layers were washed with 1500 mL saturated sodium chloride. The chloroform extract was dried over sodium sulfate, filtered and evaporated at reduced pressure. Yield 40.4 g (53% yield) product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:21])[CH:17]=[N:18][C:19]=1[CH3:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:21][C:16]2[CH:17]=[N:18][C:19]([CH3:20])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)cnc1C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1C
Yield: 16.9 %

Procedure:
The title compound (117 mg, 0.372 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (469 mg, 2.2 mmol), 5-methoxy-6-methylpyridin-3-amine (336 mg, 2.4 mmol) and pyridine (0.54 mL, 7.5 mmol) in DCM (9 mL) at 0° C. to rt using the methods of (IntC1).
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[OH:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (100 mg, 0.29 mmole) in methylene chloride (5 mL) cooled to -78° C., was added dropwise over a period of 5 minutes a lM solution of boron tribromide (0.3mL; 0.3 mmole) in methylene chloride. The temperature was allowed to rise to room temperature and the reaction mixture was stirred for 3 hours. It was then cooled to -78° C. and methanol (2 mL) was added rapidly. The resulting solution was poured into water. The phases were separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 15% ethyl acetate in hexane to yield 63 mg gm (66%) of 2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp. 142°-143° C.
Reaction SMILES: C(=[NH:14])(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:14][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(N)c1=O
Temperature: 95 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with benzophenone imine (0.43 g, 2.4 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (1) (0.51 g, 2.0 mmol), Pd(OAc)2 (0.025 g, 0.040 mmol), rac-BINAP (0.082 g, 0.13 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) in dioxane (15 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude product was dissolved in 1 N HCl/MeOH (3 mL) and stirred for 1 h at room temperature. Then, to the reaction mixture was added sat. NaHCO3 (10 mL) and dichloromethane (10 mL), and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.22 g (54%) of 3-amino-5-bromo-1-methyl-1H-pyridin-2-one (4) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23]>>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: NN
Reactant: Cc1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Solvent: O
Product: Cc1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
12.0 g of 3-chloro-5,6,7,8-tetrahydro-6-(p-toluoyl)pyrido[4,3-c]pyridazine and 50 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 2 hours. The title compound has a M.P. of 207°-210° (decomp., from 95% ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][C@H:10]2[CH:21]=O)=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].[BH4-].[Na+].CO>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][CH:10]2[CH2:21][NH:26][CH2:25][CH2:23][OH:24])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C[C@@H]1COc2c(F)ccc(F)c2[C@H]1Sc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCNCC1COc2c(F)ccc(F)c2C1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-(4-chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-carbaldehyde (2.2 g, 5.9 mmole) and ethanolamine (1.1 g, 18 mmole) were dissolved in 20 ml THF. The reaction was stirred at room temperature overnight. 2 g Sodium borohydride and 10 ml MeOH were added and the reaction was stirred for three hours. 100 ml water and 100 ml EtOAc were added. The organic layer washed with water, dried over sodium sulfate and concentrated. The product was purified by column chromatography (EtOAc/hexane from 25/75 to 100/0 in 45 minutes). Yield, 0.40 g, 17.5%. 1H NMR (CDCl3 400 MHz) δ 7.45 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 6.92-7.00 (m, 1H), 6.54-6.60 (m, 1H), 4.62 (dd, J=8.8 and 2.2 Hz, 1H), 4.48 (br, 1H), 4.38 (dt, J=11.7 and 2.2 Hz, 1H), 3.55 (t, J=5.1 Hz, 2H), 2.67 (dd, J=12.4 and 7.3 Hz, 1H), 2.62 (t, J=5.1 Hz, 2H), 2.48 (dd, J=12.4 and 8.1 Hz, 1H), 2.09 (m, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:11]=[C:10]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]([F:18])=[CH:8][C:6]=1[NH2:7])[CH:2]=[CH2:3].S(=O)(=O)(O)O.[N:24]([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([N:4]1[C:5]2[CH:11]=[C:10]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]([F:18])=[CH:8][C:6]=2[N:7]=[N:24]1)[CH:2]=[CH2:3]
Reactant: C=CCNc1cc(NC(=O)OCC)c(F)cc1N
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: C=CCn1nnc2cc(F)c(NC(=O)OCC)cc21
Reaction time: 1 h
Yield: 21.6 %

Procedure:
A stirred solution of 3.5 grams (0.014 mole) of 2-(2-propen-1-ylamino)-4-ethoxycarbonylamino-5-fluoroaniline in 100 mL of aqueous 1% sulfuric acid was cooled to about -5° C., and a solution of 1.9 grams (0.028 mole) of sodium nitrite dissolved in a minimum of water was added dropwise, while the reaction mixture temperature was held at about 0°-10° C. Upon completion of the addition, the reaction mixture was stirred for one hour and then poured into water. The mixture was made basic to a pH of 8 with potassium carbonate. The mixture was then extracted thoroughly with ethyl acetate. The combined extracts were washed with an aqueous solution saturated with sodium chloride, and then dried with magnesium sulfate. The mixture was filtered, and the filtrate was subjected to column chromatography on silica gel. Elution was accomplished with 1:3 ethyl acetate in hexane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 1-(2-propen-1-yl)-5-fluoro-6-ethoxycarbonylaminobenzotriazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:37][C:38]1[CH:39]=[C:40]([CH:45]=[C:46](Cl)[N:47]=1)[C:41]([O:43][CH3:44])=[O:42]>N1C=CC=CC=1.[Cu]=O>[Cl:37][C:38]1[CH:39]=[C:40]([CH:45]=[C:46]([O:28][C:26]2[CH:25]=[CH:24][C:22]3[NH:23][C:18]([C:3]4[C:4](=[O:17])[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]5[C:11]([C:2]=4[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=5)=[N:19][S:20](=[O:29])(=[O:30])[C:21]=3[CH:27]=2)[N:47]=1)[C:41]([O:43][CH3:44])=[O:42]
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)nc(Oc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4ccccc4n(NCC(C)C)c2=O)N3)c1
Temperature: 125 °C

Procedure:
A mixture of the product of Example 321C (40.0 mg, 0.138 mmol), potassium carbonate (19.1 mg, 0.138 mmol), copper(II)oxide (18.4 mg, 0.23 mmol)and methyl 2,6-dichloroisonicotinate (28.4 mg, 0.138 mmol) in pyridine (0.2 mL) was stirred while heating at 125° C. in a microwave reactor for 100 minutes. After cooling to 25° C., the mixture was loaded directly onto silica gel gel and eluted with a 0-5% methanol in dichloromethane step gradient. The fractions containing the desired product were combined and concentrated. The title compound was isolated by recrystallization of the residue using ethyl acetate/hexane (4.3 mg, 68%). MS (ESI−) m/z 596 (M−H)−. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, J=6.62 Hz, 6H) 2.00 (m, 1 H) 2.84 (br m, 2 H) 3.99 (s, 3 H) 5.73 (br s, 1 H) 7.43 (m, 4 H) 7.62 (d, J=8.46 Hz, 1 H) 7.80 (m, 2 H) 7.96 (d, J=8.46 Hz, 1 H) 8.28 (d, J=8.09 Hz, 1 H) 14.37 (s, 1 H) 15.04 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:8]=2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCCC3)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 36 μl of pyrrolidine and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC). Yield: 30 mg (26%) of [2-amino-6-(2-pyrrolidin-1-ylmethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone; LC-MS retention time: 1.45 min;