Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([C:11]([CH3:27])([CH3:26])[N:12]([CH3:25])[CH:13]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:30]#[N:31]>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:28])[CH:10]2[C:11]([CH3:27])([CH3:26])[N:12]([CH3:25])[CH:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:30]#[N:31])=[CH:20][CH:19]=3)[CH:14]2[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CN1C(Cc2ccc(Br)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Solvent: CN(C)C=O
Product: CN1C(Cc2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Yield: 63 %

Procedure:
3.45 g (7.82 mmol) of (3aRS,4RS,6aSR)-2-benzyl-4-(4-bromobenzyl)-5,6,6-trimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione and 3.52 g (39.1 mmol) of copper(I) cyanide were suspended in 150 ml of DMF under argon and heated under reflux for 56 hours. After cooling about 100 ml of DMF were removed, then 150 ml of dichloromethane and 60 ml of concentrated aqueous ammonia solution were added. The mixture was stirred vigorously for a few hours. The blue aqueous phase was separated and the organic phase was washed twice with ammonia solution and once with water. The solvent was removed and the residue was purified chromatographically (hexane/ethyl acetate 1:1+1% triethylamine). 1.91 g of (1RS,3aSR,6aRS)-4-(5-benzyl-2,3,3-trimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-ylmethyl)-benzonitrile were isolated as a yellowish oil. FAB-MS: 775 ([2M+H]+, 1); 663 (2); 388 ([M+H]+, 58); 271 (100); 91 (42).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[C:22]([CH3:32])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:33]#[N:34])C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[C:33]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[C:22]([CH3:32])[CH:21]=1)#[N:34]
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1C
Yield: 65.6 %

Procedure:
In the same manner as Production Example 301-2, N-(4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea (0.8 g) was debenzylated in tetrahydrofuran using palladium-carbon, to obtain the title compound (0.42 g) as a solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[CH2:24][CH2:25][OH:26].CN([CH:30]=[O:31])C>C1COCC1>[F:16][C:17]1[C:18]([CH2:24][CH2:25][OH:26])=[C:19]([F:23])[CH:20]=[CH:21][C:22]=1[CH:30]=[O:31]
Reactant: OCCc1c(F)cccc1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c(CCO)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,6,6-Tetramethylpiperidine (5 mL) was added to a solution of butyllithium (1.6M in hexanes, 19 mL) in THF (25 mL) at −70° C. A solution of 2-(2,6-difluorophenyl)ethanol (example 45, step a) (1.6 g) in THF (25 mL) was added dropwise and the resulting mixture stirred for 2 h. DMF (3.9 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ether gradient. The fractions containing product were combined and evaporated. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with HCl solution (2M, 30 mL), brine (30 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 1.1 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:12]=[C:11]([C:13]([O:15]CC)=[CH2:14])[N:10]=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.O.Cl>O1CCOCC1>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[N:8]=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)[N:10]=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=2)[CH2:3][CH2:2]1
Reactant: C=C(OCC)c1cc(COCC2CC2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC3CC3)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of 4-((cyclopropylmethoxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (98 mg, 0.23 mmol) in dioxane (15 mL) were added water (1 mL) and hydrochloric acid (conc., 0.056 mL, 0.68 mmol). The mixture was stirred at 50° C. for 20 min. The solvents were evaporated. Sodium bicarbonate (aq, 50% saturated) was added and the mixture was extracted with DCM. The organic phase was separated on phase separator and the solvents were evaporated to give the title compound 90 mg (98%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Cl.[F:20][C:21]([F:26])([F:25])[C@@H:22]([NH2:24])[CH3:23].[OH-].[Na+]>C(#N)C.C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:24][C@@H:22]([CH3:23])[C:21]([F:26])([F:25])[F:20])=[O:6]
Reactant: C[C@H](N)C(F)(F)F
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cc(F)c(F)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 μL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J=7.6 Hz, 1H), 7.92-7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J=7.0 Hz, 3H) ppm. LCMS cacld. for C10H8F6NO (M+1)+: m/z=272.0. Found: 272.0.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:16]([S:18][CH3:19])=[S:17].[C:20](OC(=O)C)(=[O:22])[CH3:21].Cl>N1C=CC=CC=1>[C:20]([O:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:16]([S:18][CH3:19])=[S:17])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
0.88 g of methyl (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-2-carbodithioate is dissolved in 10 ml of pyridine. 0.43 ml of acetic anhydride is added to the solution, and the mixture is stirred at room temperature for 13 hours. After the reaction, the mixture is poured into 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent, whereby 0.95 g of methyl (3S)-3-acetoxymethyl-1,2,3,4-tetrahydro-β-carboline-2-carbodithioate is obtained as white powder. Yield: 95%
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].Cl>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.O>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccc(-c2ccccn2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)C#Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 95.1 %

Procedure:
A mixture of (15) (128 mg, 0.46 mmol), copper(I) iodide (9 mg, 50 μmol) and triethylamine (10 cm3) was deoxygenated with argon. Tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 μmol) was added, and the mixture was deoxygenated with argon again. Trimethylsilylacetylene (0.15 cm3, 1 mmol) was added, and the reaction was stirred at room temperature for 9 hours. Water (50 cm3), aqueous hydrochloric acid (3 M, 5 cm3) and dichloromethane (50 cm3) were added, and the layers were separated. The organic layer was washed with brine (50 cm3) and dried over magnesium sulfate, and the solvent was removed to leave a black solid. The crude product was purified by column chromatography using dichloromethane: light petroleum 3:2 as eluent, to give (16) as a pale brown oil (110 mg, 96%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([OH:24])[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:26][C:27]1[N:28]=[CH:29][N:30]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=2[O:39][CH3:40])[CH:31]=1>>[Cl:26][C:27]1[N:28]=[CH:29][N:30]([C:32]2[CH:38]=[CH:37][C:35]([NH:36][C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][C:21]([CH3:25])([OH:24])[CH2:20][CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:34][C:33]=2[O:39][CH3:40])[CH:31]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CC1(O)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Product: COc1cc(Nc2nc3c(c(N4CCC(C)(O)CC4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 15.68 %

Procedure:
1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (Preparation He) (374 mg, 1.034 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (301 mg, 1.344 mmol) were combined and purified as per Example 17 to give 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (89 mg, 0.162 mmol, 15.68% yield) as a slightly yellow solid. LC-MS (M+H)+=549.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.82 (1H, s), 7.64 (1H, br. s.), 7.50 (1H, s), 7.27-7.43 (3H, m), 7.20 (3H, t, J=8.70 Hz), 7.06 (1H, dd, J=8.39, 1.68 Hz), 4.36 (3H, br. s.), 3.73 (3H, br. s.), 2.98-3.26 (3H, m), 2.59 (1H, br. s.), 1.88-2.06 (1H, m), 1.62 (4H, br. s.), 1.25 (2H, br. s.), 1.19 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][N:28]=2)[CH:4]=1.C[OH:40]>ClCCl>[CH3:1][S:2]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][CH2:19]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:27]2[N:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:31][N:32]=2)[CH:4]=1)=[O:40]
Reactant: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Reactant: CO
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Yield: 54 %

Procedure:
Obtained from 12c) (300 mg, 0.56 mmol) according to the general procedure 2. The preparative TLC was performed with 3% methanol in dichloromethane as eluent. White solid. Yield: 170 mg (54% yield).
Reaction SMILES: OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCNC(=O)C=12.[CH2:30]([N:37]1[CH2:71][CH2:70][N:40]2[C:41]([CH2:54][C:55]3([C:60]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH:63]=[CH:62][CH:61]=4)[CH2:59][CH2:58][CH2:57][CH2:56]3)=[N:42][C:43](=[O:53])[C:44]([O:45]CC3C=CC=CC=3)=[C:39]2[C:38]1=[O:72])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]1[CH2:71][CH2:70][N:40]2[C:41]([CH2:54][C:55]3([C:60]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH:63]=[CH:62][CH:61]=4)[CH2:59][CH2:58][CH2:57][CH2:56]3)=[N:42][C:43](=[O:53])[C:44]([OH:45])=[C:39]2[C:38]1=[O:72])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1Cc1ccccc1
Agent: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(O)c21
Product: O=C1c2c(O)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1Cc1ccccc1

Procedure:
This compound was prepared following the same method as described for pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (349) from 2-benzyl-9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (372) (110 mg, 0.19 mmol). The yield was 35 mg, 47%, of a light brown solid.
Reaction SMILES: [CH2:1]([N:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)N)[CH:2]=[CH2:3].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH2:31])[CH2:21][C:22]2([CH3:30])[C:27](=O)[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23]2)=[CH:16][CH:15]=1.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([N:4]1[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:26]2[CH2:25][N:24]([CH3:29])[CH2:23][C:22]([CH2:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[CH2:31])([CH3:30])[C:27]1=2)[CH:2]=[CH2:3]
Reactant: C=C(CC1(C)CN(C)CCC1=O)c1ccc(F)cc1
Reactant: C=CCN(N)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CCn1c2c(c3cc(C)ccc31)CN(C)CC2(C)CC(=C)c1ccc(F)cc1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
N-Allyl-N-p-tolyl-hydrazine (600 mg, 3.70 mmol) and 3-[2-(4-fluoro-phenyl)-allyl]-1,3-dimethyl-piperidin-4-one (970 mg, 3.71 mmol) were dissolved in 1,4-dioxane (4 mL). Trifluoroacetic acid (1 mL) was added and the reaction mixture was heated to 100° C. for 3 h. 1,4-Dioxane was removed under reduced pressure, the residue was basified with aqueous sodium bicarbonate, and extracted with EtOAc (2×30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (100-200 mesh, eluent as 5% EtOAc in hexane) to obtain 290 mg of 5-allyl-4-[2-(4-fluoro-phenyl)-allyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][C:11]1[NH:12][C:13]([CH3:29])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH3:10][C:11]1[NH:12][C:13]([CH3:29])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:24][CH:23]=2)[N:17]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(-c2cccc(-c3ccc(Br)cc3)n2)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccc(-c3ccc(-c4cccnc4)cc3)n2)c(C)[nH]1
Reaction time: 2 h

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 271 mg (2.20 mmol) 3-pyridylboronic acid (Rec. Trav. Chim., 93, 21 (1974)), 720 mg (2.20 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-bromophenyl)-pyridine, 933 mg (8.81 mmol) sodium carbonate, 128 mg (0.110 mmol) tetrakistriphenylphosphine palladium, 9 mL ethanol, and 1 mL water. The mixture was refluxed 20 hours 100 mg 3-pyridiylboronic acid added, and refluxing continued for 2 hours. The reaction was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford the product as an oil, 350 mg (49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=O)N3c1cccc(Br)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (0.15 g, 0.40 mmol) (from Example 6, Step B, supra) in 1,2-dichloroethane (50 mL) was added 1,1′-carbonyldiimidazole (0.65 g, 4.0 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalen-2-one as a brown solid. (Yield 0.12 g, 75%).
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:10][C:9]1[C:2]([F:15])=[C:3]([C:6]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: [F-]
Reactant: N#Cc1c(C(F)(F)F)ccc(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 100 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of 0.96 g of 2,3-dichloro-6-trifluoromethylbenzonitrile in 7 ml of N,N-dimethylformamide was added 0.46 g of spray-dried potassium fluoride and 0.1 g of 18-crown-6-ether and the mixture was stirred for 6 hours at 100° C. under a nitrogen atmosphere. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the solvent under reduced pressure, the crude product obtained was purified by using silica gel column chromatography to obtain 0.65 g of the title compound(mp. 43-44° C.).
Reaction SMILES: CC1C=CC(S(C(C2C=CC=C(I)C=2)[N+]#[C-])(=O)=O)=CC=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]([NH:39][CH:40]=O)[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=1.IC1C=C(C(NC=O)S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1>>[CH3:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([CH:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)[N+:39]#[C-:40])(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(Br)c2)cc1
Agent: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Agent: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Product: [C-]#[N+]C(c1cccc(Br)c1)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 53 but using {(3-bromophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 56) in place of {(3-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 52). Light brown solid (3.2 g, 30%);
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]1[O:12][C:11]2[C:2](=[C:3]([CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5])[O:1]1
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1OCO2
Temperature: 105 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
Compound 121 (16.12 g, 0.081 mol) was dissolved in 500 mL of DMF. Then 100 mL of methylene chloride and 26 g (0.464 mol) of potassium carbonate were added. The mixture was heated to 105° C. with vigorous stirring for 6 hours. The potassium carbonate was filtered and the DMF was removed in vacuo. The residue was poured into ice-water and let stand overnight. The precipitated product 122 was filtered and washed with water until neutral. The dried gray white solid weighed 15.60 g (yield 91%) and was recrystallized from methanol as brilliant long needles, m.p. 122°-124° C. IR cm-1 1710 (ester C=O); 1H NMR δ ppm 3.90 (s, 3H, OCH3), 3.95 (s, 3H, ArOCH3), 6.11 (s, 2H, OCH2O), 6.57 and 7.45 (each d, J=9 Hz, 1H, ArH). Anal. (C10H10O5)C, H.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:31]([Cl:33])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[ClH:33].[C:21]1([C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccc2ccccc12
Yield: 67.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio) pyridine dihydrochloride and 2.78 ml (19.9 mmol) of trietylamine in 40 ml of methylene chloride was added 0.75 ml (4.98 mmol) of 1-naphthoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 1.00 g of the desired compound (free base) (74.8%, yellow powder), mp: 113.0°-114.0° C.