Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)C.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>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2F)C1

Procedure:
A solution of Pd(PPh3)4 (Strem Chemicals Inc., Newburyport, Mass., 0.643 g, 0.557 mmol), 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (1.353 g, 5.57 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.000 g, 5.57 mmol), and potassium carbonate (3.08 g, 22.27 mmol) in 12 mL dioxane and 6 mL water was heated to 120° C. for 3 days. The reaction mixture was diluted with diethyl ether, washed with water, the organics dried over MgSO4 and concentrated to provide tert-butyl 5-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. The resulting residue was dissolved in 10 mL THF and was treated with HCl 4 N in dioxane (9.74 ml, 39.0 mmol), and allowed to stir at room temperature overnight. The reaction mixture was diluted with diethyl ether/heptane, and the resulting solid was filtered and dried yielding 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.930 g, 5.82 mmol). [M+H]+=296.1
Reaction SMILES: Br[CH:2]=[C:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].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>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:2]=[C:3]2/[CH:4]=[CH:5][C:6](=[O:8])[O:7]/2)=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=CBr)O1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(/C=C2/C=CC(=O)O2)cc1

Procedure:
A mixture containing 5-bromomethylene-2(5H) furanone (0.175 g, 1 mmol), 4-methoxyphenylboronic acid (0.182 g, 1.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.035 g, 0.05 mmol), tetrabutylammonium iodide (0.018 g, 0.05 mmol) and cesium fluoride (0.456 g, 3 mmol) in toluene (10 mL) and water (10 mL) were stirred at reflux for 24 hours under nitrogen. After cooling, brine (50 mL) was added and the product extracted with ethyl acetate (50 mL×3). The organic fractions were combined, washed with brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated to dryness to give a brown solid. The resulting solid was chromatographed (silica gel: eluent 50:50 dichloromethane/light petroleum) giving the desired product 33 as a yellow powder. Yield 0.163 g (80%), m.p. 118-120° C., 1H NMR (CDCl3) δ 7.76-7.71 (m, 2H, H3′ and H5′), 7.45 (d, J=5.2 Hz, 1H, H4), 6.93-6.88 (m, 2H, H2′ and H6′), 6.14-6.12 (m, 1H, H3), 5.97 (bs, 1H, H6), 3.83 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 170.5 (C), 160.5 (C), 147.0 (C), 145.0 (C), 132.4 (CH), 125.6 (CH), 116.8 (CH), 114.3 (CH), 114.2 (CH), 55.3 CH3). IR (Nujol) 1789, 1737, 1604, 1551, 1509, 1458, 1376, 1302, 1258, 1175, 1119, 1025, 931, 893, 813 cm−1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>>[NH:18]([C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])=[CH:4][CH:3]=1)[NH2:19]
Reactant: OCc1ccccc1Oc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: NNc1ccc(Oc2ccccc2CO)cn1
Temperature: 120 °C

Procedure:
A mixture of [2-(6-chloro-pyridin-3-yloxy)-phenyl]-methanol (235 mg, 1 mmol) and hydrazine monohydrate (5 mL) was heated at 120° C. for 4 hours. The reaction was then cooled and concentrated in vacuo to an oil. The residue was then diluted with saturated NaHCO3, and the aqueous extracted with methylene chloride. The organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the above named compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[N:7]#[C:8][NH2:9].[ClH:10]>O1CCOCC1>[ClH:10].[F:1][C:2]1[CH:3]=[N:4][N:5]([C:8]([NH2:9])=[NH:7])[CH:6]=1
Reactant: Fc1cn[nH]c1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)n1cc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-fluoro-1H-pyrazole, 28-d, (2 g, 23 mmol) and cyanamide (0.97 g, 23 mmol) in dioxane (5 mL) was added 4N HCl in dioxane (15 mL). The mixture was gently refluxed with stirring for 2 h under nitrogen. During the course of the reaction the product crystallizes. After cooling to room temperature, 10 mL of anhydrous ether was added and the mixture was allowed to stand for 30 min. The white solid was collected by filtration, washed with anhydrous ether and dried to constant weight in vacuuo providing the product, 28-e, (3 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:12]=2)[CH:3]=1
Reactant: NCCCO
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Cl)cc1Oc1cccc(CNCCCO)c1
Yield: 100.4 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.21 g, 0.81 mmol), 3-aminopropan-1-ol (65 μL, 64 mg, 0.85 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(3-hydroxypropylamino)methyl]phenoxy}benzonitrile fumarate (352 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][CH:22]([O:24][C:25](=[O:42])[NH:26][C@H:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](Br)[CH:35]=2)[N:30]([C:38](=[O:40])[CH3:39])[C@@H:29]([CH3:41])[CH2:28]1)[CH3:23].C(=O)(O)[O-].[Na+]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(Cl)Cl.O1CCOCC1>[C:38]([N:30]1[C:31]2[C:36](=[CH:35][C:34]([C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[CH3:1])=[CH:33][CH:32]=2)[C@H:27]([NH:26][C:25]([O:24][CH:22]([CH3:23])[CH3:21])=[O:42])[CH2:28][C@@H:29]1[CH3:41])(=[O:40])[CH3:39]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A flask was charged with methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.449 g, 1.625 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 100) (0.5 g, 1.354 mmol), sodium bicarbonate (saturated solution) (1.5 mL, 1.354 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM adduct (0.111 g, 0.135 mmol) then filled with 1,4-dioxane (7 mL). The resulting mixture was degassed by bubbling nitrogen in to it, stirred at 100° C. for 1 hr under microwave irradiation then cooled to room temperature. The reaction mixture was filtered through celite and concentrated in vacuovacuo. The residue was partitioned between EtOAC (30 mL) and water (30 mL) and the layers were separated. The organic phase was washed with brine (25 mL) dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:0 to 60% AcOEt in Hexanes) gave methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (337 mg, 0.769 mmol, 56.8%) as a light yellow solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48](Cl)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[N:41]=[N:40][CH:39]=1.C(O)(=O)C>C1COCC1.CO.O>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])=[CH:45][CH:46]=2)[N:41]=[N:40][CH:39]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(S(=O)(=O)Cl)ccc12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1cnnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a flask containing an ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (40.2 mg, 0.182 mmol) in THF (668 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (191 μl, 0.191 mmol) drop wise over 10 min. The mixture was stirred for 15 min prior to the drop wise addition of a solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)cinnoline-7-sulfonyl chloride (70 mg, 0.174 mmol) in THF (0.7 ml). The solution was allowed to stir for 1 hr (ice melt) providing a brown solution. To the mixture was added acetic acid (about 100 μl) and the mixture dried under reduced pressure. To the crude material was added DCM (1 ml) followed by TFA (0.3 ml) and the mixture stirred at room temperature for 2 hrs. The mixture was dried under reduced pressure and the crude material purified with a 25 g spherical silica column (15 μm spherical, Interchim) ramping EtOAc in heptane (0 to 70%, 10% DCM isocratic throughout) providing product which was lyophilized from MeOH/H2O to afford 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)cinnoline-7-sulfonamide (34 mg, 0.073 mmol, 41.9% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) μ ppm 3.79 (s, 3H) 6.91 (d, J=4.50 Hz, 1H) 7.32 (d, J=4.60 Hz, 1H) 7.51-7.60 (m, 2H) 7.66 (d, J=7.53 Hz, 1H) 7.77-7.84 (m, 1H) 8.08 (dd, J=8.90, 1.86 Hz, 1H) 8.87 (dd, J=1.81, 0.54 Hz, 1H) 9.45 (s, 1H) 13.03 (br. s., 1H). m/z (ESI) 467.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:28]([S:30]([O-:32])=[O:31])[CH3:29].[Na+]>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: CCS(=O)[O-]
Agent: [Na+]
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(=O)(=O)CC)cc3)CC2)nc1

Procedure:
This compound was prepared from the product of example 54 (step A), and sodium ethanesulfinate according to the procedure from example 56. MS (ESI) m/z 444 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(C#N)cc3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-bromomethyl benzonitrile whereby the product was isolated as free base, 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as a brown solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated for C22H21N3O: 344).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:14]=2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=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]>[CH3:33][N:32]([CH3:34])[C:30]([C:29]1[CH:35]=[CH:36][C:26]([NH:25][C:2]2[CH:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:14]=3)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:27][CH:28]=1)=[O:31]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: NC(=O)c1cnc(Cl)cc1NCc1cccc(-c2ccncc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(Nc2cc(NCc3cccc(-c4ccncc4)c3)c(C(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 6-chloro-4-(3-(pyridine-4-yl)benzylamino)nicotinamide (56 mg, 0.1 mmol) in p-Dioxane (2 mL) was added 4-amino-N,N-dimethylbenzamide (41 mg, 0.244 mmol), Pd(OAc)2 (7.5 mg, 0.033 mmol), BINAP (21 mg, 0.033 mmol) and Cs2CO3 (162 mg, 0.498 mmol). After stirred at 80° C. for 15 h, it was concentrated and purified by preparative HPLC to give 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide. MS found for C27H26N6O2 as (M+H)+ 467.3. UV: λ=217.6, 272.7, 294.9 nm. 1H NMR: (CD3OD) δ 8.78 (dd, J=5.2, 1.2 Hz, 2H), 8.22 (s, 1H), 8.14 (dd, J=5.6, 1.2 Hz, 2H), 7.89 (bd, J=3.6 Hz, 1H), 7.85 (bs, 1H), 7.63 (t, J=3.6 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.37 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.02 (s, 1H), 4.65 (s, 2H), 3.09 (s, 3H), 2.97 (s, 3H) ppm.
Reaction SMILES: CN(C1C=CC=CC=1)[C:3]([N:5]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:6]1(=[O:8])=[O:7])=O.C[O-].[Na+].[CH3:26][N:27]([CH3:30])[CH:28]=[O:29]>>[OH:16][C:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:6](=[O:7])(=[O:8])[NH:5][C:3]=1[C:28]([N:27]([CH3:30])[C:26]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:29]
Reactant: CN(C)C=O
Reactant: CN(C(=O)N1C(=O)c2ccccc2S1(=O)=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CN(C(=O)C1=C(O)c2ccccc2S(=O)(=O)N1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 9.9g (0.03 mole) of 2-[(N-methyl-N-phenylcarbamoyl)]saccharin in 125ml of dimethylformamide at 35° C. is added all at once 4.9g (0.09 mole) of sodium methoxide. A considerable amount of heat is evolved and the mixture turns purple in color. Stirring is continued for one hour and it is poured into ice-water containing excess hydrochloric acid to cause precipitation of 5.5g of a tan solid, mp. 138°-144° C. This is dissolved in dichloromethane and extracted with aqueous sodium carbonate solution. Neutralization of the alkaline layer gives a precipitate which is collected and recrystallized from methanol to give 4.0g of product, mp. 148°-152° C. dec.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2O.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2ncnc(O)c2cc1OCCCCl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Cl)c2cc1OCCCCl
Yield: 86 %

Procedure:
The intermediate 6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline (3.5 g, 13.0 mmol) was reacted with POCl3 in the manner described in Example 4A Step 2 to give 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (3.2 g, 11.2 mmol, 86%). LC-MS (ESI) m/z 287 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.CO.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.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2cc(-c3ncccn3)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 400 mg 6-tert.-butoxycarbonylamino-naphthalene-2-boronic acid, 258 mg 2-bromo-pyrimidine, 100 mg tetrakis(triphenylphosphine)palladium and 4 ml 1 M sodium carbonate solution in 15 ml dioxane and 5 ml of methanol is refluxed for four hours in an argon atmosphere. After cooling to ambient temperature the reaction mixture is divided between ethyl acetate and water. The organic phase is dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (75:25 to 50:50) as eluant.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[OH:14][CH:15]1[C:20]2([CH3:25])[CH2:21][N:22]([CH3:24])[CH2:23][C:16]1([CH3:26])[CH2:17][NH:18][CH2:19]2>>[OH:14][CH:15]1[C:16]2([CH3:26])[CH2:23][N:22]([CH3:24])[CH2:21][C:20]1([CH3:25])[CH2:19][N:18]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:17]2
Reactant: CN1CC2(C)CNCC(C)(C1)C2O
Reactant: N#Cc1ccc(F)c2ccccc12
Product: CN1CC2(C)CN(c3ccc(C#N)c4ccccc34)CC(C)(C1)C2O
Yield: 7.6 %

Procedure:
The title compound (3 mg, 8% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane (86 mg, 0.468 mmol).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([C:24]1[CH:34]=[CH:33][C:27](OCC(O)=O)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(N(C)C)=O>[C:16]([C:24]1[CH:34]=[CH:33][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
8 g of a hyperbranched polyglycidol with an average molecular weight 2000, prepared according to W02000/37532 (Bayer A.-G.) and Sunder A. et al, Macromolecules, 32, 4240-4246 (1999), was dissolved in 200 mL dimethyl acetamide at 40° C. 12.9 g (62 mmol) DCC was added and the mixture was stirred for 30 minutes. 13.3 g (52 mmol) 2-(4-benzoylphenoxy)-acetic acid was added and the reaction was allowed to continue for 16 hours at 60° C. The precipitated DCU was removed by filtration and the solvent was evaporated under reduced pressure. The residue was treated with 150 mL dichloromethane and the mixture was cooled to 0° C. After one hour, precipitated DCU was removed by filtration and the solvent was evaporated under reduced pressure. The benzophenone substituted hyperbranched polyglycidol was purified by preparative size exclusion chromatography on a 60×2.5 cm column, PL-gel 10 micron, pore size=500 A, Mw range: 500-30000, supplied by Polymer Laboratories, using tetrahydrofurane, 5% acetic acid as eluent at a flow rate of 10 mL/min and a product load of 200 mg per run. The pooled fractions were evaporated under reduced pressure. The residue was redissolved in 1000mL methylene chloride, extracted with 500 mL brine, dried over MgSO4 and the solvent was removed under reduced pressure. 6.5 g of the benzophenone substituted polyglycidol was isolated. 1H-NMR-analysis showed that the isolated polymer was substituted with 7 benzophenone moieties on average.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)C3CC3)cc2Cl)C1=O
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To a stirred solution of 3.0 grams (0.012 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone and 1.2 grams (0.012 mole) of triethylamine in 30 ml of tetrahydrofuran was added dropwise 1.4 grams (0.013 mole) of cyclopropanecarboxylic acid chloride in 20 ml of tetrahydrofuran. During the addition the reaction mixture was cooled in an ice-water bath. Upon completion of addition the reaction mixture stirred for 16 hours; then was concentrated under reduced pressure to a residual solid. The solid was dissolved in 250 ml of methylene chloride. The solid was washed with water, which caused the precipitation of a solid that was insoluble in the liquid phases. The solid was removed by filtration. The organic phase was separated and washed with three 100 ml portions of water. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual solid. Both solids collected were subjected to thin layer chromatography and were determined to be the same material. The solids were combined and recrystallized from ethyl acetate/acetonitrile to give 2.5 grams of 2-[2-chloro-4-(cyclopropylcarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 191°-193° C.