Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]4[O:22][CH2:21]4)=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:27][CH3:26])=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCC3CO3)cc2C1=O
Reactant: CN
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-chlorophenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone (3.7 g) in ethanol (25 ml) was added methylamine (8 ml) in ethanol (8 ml). The mixture was allowed to stand overnight. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated basified, extracted with ether and the extract dried (MgSO4). Evaporation gave 4(4-chlorophenyl)-7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethyl-1-tetralone as a semi-solid foam.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][N:12]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([CH3:30])[N:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:11][N:12]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([CH3:30])[N:21]=1)[C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH:1]=[O:3])=[CH:17][CH:18]=1
Reactant: O=CO
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(N(C)c2ccc(NC=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of formic acid 1 mL and acetic anhydride 1 mL, stirred at room temperature for 1 h, was added a solution of N-methyl-N-(2-methylquinazolin-4-yl)benzene-1,4-diamine 0.132 g (0.5 mmol) in CH2Cl2 5 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. After concentration, the crude product was purified by recrystallization in EtOAc/MeOH to give the titled compound in 85% yield. The compound was further purified with preparative HPLC for analytical uses. 1H NMR (CD3OD, 400 MHz): δ 7.84-7.79 (m, 2H), 7.71-7.65 (m, 1H), 7.44-7.41 (m, 1H), 7.27-7.28 (m, 2H), 7.02-6.99 (m, 2H), [3.84 (s, 1H), 3.81 (s, 2H)], [2.78 (s, 1H), 2.76 (s, 2H)] (Two isomers were observed in 2:1 ratio.). m/e: 293.1438 (M+1).
Reaction SMILES: Cl[CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:12][C:11]1[CH:18]=[CH:17][C:15]([O:16][CH:2]([CH3:10])[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][O:6]2)=[O:4])=[CH:14][CH:13]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(Cl)C(=O)N1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Temperature: 120 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A mixture of N-[(±)-2-chloropropionyl]isoxazolidine (16.4 g) which was prepared as in Example 1, hydroquinone (13.2 g), anhydrous potassium carbonate (29.0 g) and dimethylformamide (100 ml) was stirred at 120° C. for 2 hours. After cooling, the reaction mixture was filtered through a suction filter to remove solid matters and the filtrate was concentrated in vacuo. The residue was washed with the addition of chloroform and 1 N hydrochloric acid and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (21.6 g) as a pale yellow oil which was purified by silica gel column chromatography to yield a colorless oil. nD20 =1.5412.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([C:16]2([NH:22]C=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:4]1>CO>[ClH:1].[NH2:22][C:16]1([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CNC1(c2ccc(=O)n(Cc3ccccc3)c2)CCCCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ccc(=O)n(Cc3ccccc3)c2)CCCCC1

Procedure:
A solution of N-[1-[1,6-dihydro-6-oxo-1-(phenylmethyl)-3-pyridinyl]cyclohexyl]formamide hydrochloride (13.4 g) in 200 ml of methanol was heated at reflux for 17 hours. The mixture was cooled, and the resultant crystals were collected, affording 5.6 g of analytically pure 5-(1-aminocyclohexyl)-1-(phenylmethyl)-2(1H)-pyridinone hydrochloride, m.p. 248°-250° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[CH3:45][NH2:46].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH2:35][NH:46][CH3:45])=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:38][CH:39]=1
Reactant: CN
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(C=O)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1ccc(-c2nn(C(c3ccc(OC)cc3)c3ccc(OC)cc3)c3c2Cc2cc(CN4CCN(C)CC4)ccc2-3)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Example 331 (1.2 g, 2.0 mmol) in methanol (10 mL) and tetrahydrofuran (5 mL) added a 2M solution of methylamine in tetrahydrofuran (5 mL) and acetic acid (0.6 mL, 10 mmol). Then sodium triacetoxyborohydride (1.25 g, 6 mmol) was added and the mixture was stirred at room temperature for about 5 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium carbonate and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1)+1% ammonium hydroxide as eluent to provide the desired product. MS (ESI): m/z 620 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][C:3](NCCCC)=[CH:2]1.BrC1C=CC(S(O[CH2:26][C@@H:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)(=O)=O)=CC=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[O:1]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:9][C:8]=2[C:7]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][CH2:26][CH:27]2[O:41][C:31]3=[C:32]4[C:37](=[CH:38][CH:39]=[C:30]3[O:29][CH2:28]2)[N:36]=[C:35]([CH3:40])[CH:34]=[CH:33]4)=[CH:6]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: CCCCNc1coc2cccc-2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCCCc1coc2ccccc12)O3
Temperature: 50 °C

Procedure:
To a stirred solution of 4-benzofuran-3-yl-butylamine (770 mg, 4.07 mmol) in 6 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (611 mg mg, 1.36 mmol). The reaction mixture was heated to 50° C. overnight. The reaction was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography on SiO2 (5% MeOH/CH2Cl2) afforded 403 mg (74%) of the (S)-enantiomer of the title compound as a yellow oil. The fumarate salt was prepared, yielding 285 mg of a beige solid, m.p. 127-130° C.; MS (ESI) m/z 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[N+:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc([N+](=O)[O-])c2)cc1-c1c(Cl)cnn1C
Yield: 14.4 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (36 mg, 0.15 mmol) was treated with 3-Nitrophenyl isocyanate (28 mg, 0.17 mmol) in a similar manner to Example 1.53, providing 8.7 mg (15%) of Compound 110: LCMS m/z (%)=402 (M+H35Cl, 100), 404 (M+H37Cl, 38). 1H NMR (400 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 7.83 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.61 (d, J=4 Hz, 1H), 7.58 (s, 1H), 7.58 (t, 1H), 7.41 (d, J=4 Hz, 1H), 7.19 (d, J=12 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[C:21]([Cl:23])[CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH2:9][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:25]2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)=NN1c1cc(Cl)cc(Cl)c1
Yield: 57 %

Procedure:
A solution of ethyl benzoylacetate (0.192 g, 1.00 mmol), 3,5-dichlorophenylhydrazine hydrochloride (0.235 g, 1.10 mmol), and p-toluenesulfonic acid monohydrate (0.019 g, 0.10 mmol) in ethanol (10 mL) was heated at reflux for 24 hours. The reaction solution was concentrated and the resulting residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid solution. The organic layer was further washed with water and brine, dried (sodium sulfate) and concentrated to afford a yellow solid. The crude product was triturated with hexanes and collected by suction filtration. Air drying afforded 0.174 g (57%) of product as a bright yellow solid: 1H NMR (DMSO-d6) δ12.60-12.40 (br s, 1H), 7.92 (s, 2H), 7.87-7.83 (d, 2H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.36-7.31 (m, 1H), 6.02 (s, 1H) ppm.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:5]=1[CH2:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9].S(Cl)([Cl:23])=O>O>[Br:3][C:4]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:5]=1[CH2:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:23])=[O:9]
Reactant: CCC(Cc1ccc(C(C)(C)C)cc1Br)C(=O)O
Reactant: O=S(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(Cc1ccc(C(C)(C)C)cc1Br)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of sodium ethoxide obtained from 13.7 g (0.60 mol) of sodium metal and 375 ml of dry ethanol and 193 g (0.50 mol) of diethyl (2-bromo-4-tert-butylbenzyl)malonate 65.5 g (0.60 mol) of ethyl bromide was added dropwise by vigorous stirring. This mixture was refluxed for 4 hours, then cooled, and a solution of 100 g of KOH in 270 ml of water was added. The obtained mixture was refluxed for 5 hours, then ethanol was distilled off. A mixture of the obtained solution and 1.5 liters of cold water was acidified by 1 M HCl to pH 1. The precipitate was decanted and then dissolved in 500 ml of ether. This solution was evaporated to dryness, and the residue was decarboxilated for ca. 2 hours at 180° C. To the obtained 2-(2-bromo-4-tert-butylbenzyl)butanoic acid 128 ml (209 g, 1.76 mol) of thionyl chloride was added. The resulting mixture was stirred for 12 hours at room temperature. An excess of thionyl chloride was distilled off. Fractional rectification of the residue gave 116 g (70%) of yellowish liquid, b.p. 137° C.-142° C./1 mm Hg. Anal. calc. for C15H20BrClO: C, 54.32; H, 6.08. Found: C, 54.43; H, 6.20. 1H NMR (CDCl3): δ 7.54 (d, J=1.9 Hz, 1H, 3-H in C6H3), 7.25 (dd, J=8.0 Hz, J=1.9 Hz, 1H, 5-H in C6H3), 7.16 (d, J=8.0 Hz, 1H, 6-H in C6H3), 3.24-3.06 (m, 2H, CH2CHCH2Me), 2.93 (dd, J=13.6 Hz, J=6.1 Hz, 1H, CHCH2Me), 1.89-1.69 (m, 2H, CH2Me), 1.28 (s, 9H, tBu), 1.02 (t, J=7.5 Hz, CH2Me). 13C{1H} NMR (CDCl3): δ 176.4, 152.1, 133.9, 130.9, 130.1, 124.7, 124.4, 58.3, 37.1, 34.5, 31.1, 24.9, 11.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([S:24][CH2:16][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: SCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 167, Step 1, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and benzyl mercaptan.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][CH2:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)=[O:10])=[O:6].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][CH:8]([C:9]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)=[O:10])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:6]
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1ccc(Cl)c(Cl)c1)c1ccoc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccoc1
Yield: 91.9 %

Procedure:
7.6 g of N-(3,4-dichlorobenzoyl)-(3-furylcarbonyl)methylamine, 1.2 g of 61% sodium hydride and 4.7 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 9.0 g of ethyl 3-(3,4-dichlorobenzoylamino)-3-(3-furylcarbonyl)propionate are thereby obtained. Yield: 91.9%
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:20][C:21]([C@@H:23]3[CH:38]=[C:37]4[C@@H:26]([CH2:27][C:28]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][C:35]=64)[NH:30][CH:29]=5)[N:25]([CH3:39])[CH2:24]3)=[O:22])([CH3:19])[O:18][C@@:13]2([OH:40])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:3].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43].C(OCC)C>C(O)C>[CH3:3][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:20][C:21]([C@@H:23]3[CH:38]=[C:37]4[C@H:26]([CH2:27][C:28]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][C:35]=64)[NH:30][CH:29]=5)[N:25]([CH3:39])[CH2:24]3)=[O:22])([CH3:19])[O:18][C@@:13]2([OH:40])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:1].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43]
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C)(NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)C(=O)N12
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C)(NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@@H]4N(C)C3)C(=O)N12

Procedure:
Ergosinine (5.48 g; 10 mmoles) was dissolved in absolute ethanol (60 ml), containing methanesulfonic acid (0.72 ml; 11 mmoles). The clear solution was poured into absolute diethylether (600 ml). The precipitated salt was filtered off and dried in vacuo. Ergosinine methanesulfonate (6.05 g; 98.7% of the theory) with a melting point of 190°-192° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[OH-].[Na+]>O.CCO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:19])[O:18][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][C:8]2=[O:17]
Reactant: O=C(C=Cc1ccccc1)c1cc(Br)c(F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Reaction time: 8 h
Yield: 53.5 %

Procedure:
1-(5-Bromo-4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (10.8 g, 33.75 mmol) was dissolved in H2O (252 mL) and EtOH (84 mL). Then NaOH (1.35 g, 33.75 mmol) was added. The mixture was stirred overnight and filtered. The cake was dissolved in EtOAc and washed with H2O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-7-fluoro-2-phenylchroman-4-one (5.8 g, 54%). 1H-NMR (CDCl3): 2.85 (m, 1H), 3.04 (m, 1H), 5.43 (m, 1H), 6.78 (m, 1H), 7.37 (m, 5H), 8.07 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9]O)=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>C(Cl)Cl>[CH3:1][CH2:2][O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9][I:46])=[O:5]
Reactant: II
Reactant: CCOP(=O)(OCC)C(CCCO)P(=O)(OCC)OCC
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCCI)P(=O)(OCC)OCC
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 32 (1.52 g, 4.39 mmol) in CH2Cl2 (50 mL) were added triphenylphosphine (1.32 g, 5.033 mmol) and imidazole (0.45 g, 6.61 mmol). The reaction mixture was cooled to 0° C., before the addition of iodine (1.22 g, 4.81 mmol). The mixture was then removed from the cooling bath, stirred for 2 h, diluted with hexanes (100 mL) and filtered washing the precipitate with further hexanes (2×30 mL). The filtrate was evaporated and purified by flash chromatography on silica gel with gradient elution from 0-10% methanol/ethyl acetate to give pure 33 (1.6 g, 80%). 1H NMR (400 MHz, CDCl3) δ 1.32-1.38 (m, 12H), 1.95-2.15 (m, 4H), 2.28 (tt, J=24.1, 6.1, 1H), 3.18 (t, J=6.6, 2H), 4.12-4.24 (m, 8H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:17]C)[N:6]=1)[CH2:2][CH3:3].[B-](Br)(Br)(Br)[S+](C)C>ClC(Cl)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:17])[N:6]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)c1nc2cccc(OC)c2c(=O)n1C
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: CC(Cl)Cl
Product: CCCN(CCC)c1nc2cccc(O)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of 2-dipropylamino-5-methoxy-3-methylquinazolin-4(3H)-one (130 mg, 0.449 mmol) in dichloroethane (2 ml) was added boron tribromide-methyl sulfide complex (1M solution in dichloromethane, 0.899 ml, 0.899 mmol) under nitrogen atmosphere. The mixture was refluxed for 2 h. The reaction was quenched with water and stirred for 10 min at room temperature. The aqueous phase was extracted with ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum to afford 123 mg (99%) of the title compound. The residue was used for the next reaction without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(S(C)(=O)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(S(C)(=O)=O)ccc2c1=O
Yield: 87 %

Procedure:
A mixture of tert-butyl[2-isobutyl-6-(methylsulfonyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g, 0.33 mmol) and a solution (5 mL) of 4N hydrogen chloride in ethyl acetate was stirred for 1 h and concentrated under reduced pressure. The obtained residue was precipitated from ethyl acetate-diisopropyl ether (1:10) to give, the title compound (0.12 g, 87%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by then method of Example 15a), from 2-fluoro-5-nitrobenzoic acid (2.0 g, 11.0 mmol) and oxalyl chloride (2.89 ml, 33.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][CH:14]=[N:15]N(C)C)=[O:4].C(OC(=O)C)(=O)C.[O:28]=[C:29]1[CH:38]=[CH:37][C:36](=[O:39])[C:35]2[NH:34][C:33](=[O:40])[CH:32]=[CH:31][C:30]1=2>C(#N)C.[Pd]>[OH:40][C:33]1[CH:32]=[CH:31][C:30]2[C:29](=[O:28])[C:38]3[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[NH:5][C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])=[CH:13][CH:14]=[N:15][C:37]=3[C:36](=[O:39])[C:35]=2[N:34]=1
Reactant: O=C1C=CC(=O)c2[nH]c(=O)ccc21
Reactant: CN(C)N=CC=Cc1ccccc1NC(=O)C(F)(F)F
Agent: [Pd]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: O=C1c2nc(O)ccc2C(=O)c2c(-c3ccccc3NC(=O)C(F)(F)F)ccnc21
Yield: 16.4 %

Procedure:
1.9 g (6.5 mmol) of 4-(2-trifluoroacetamidophenyl)-1-dimethylamino-1-aza-1,3-butadiene, 2.2 mL of acetic anhydride and 1.6 g of Pd/C (10%) are successively added to a solution of 5,8-dioxocarbostyril (1.04 g, 5.9 mmol) in 500 mL of acetonitrile. The reaction medium is refluxed for 15 hours under nitrogen. After evaporating off the solvent on a rotary evaporator, the crude product obtained is purified by flash chromatography on silica (CH2Cl2 and then 95/5 CH2Cl2/MeOH) to give 400 mg of a yellow powder of compound CRL 8249 (or of its oxo tautomer in position 8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COC(=O)c1cccc(N)c1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 69 %

Procedure:
A solution of 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (50 mg, 0.178 mmol) and methyl 3-aminobenzoate (17 mg, 0.112 mmol) in aqueous dioxane (900 μL, 8:1 dioxane/water) was stirred at room temperature for 4 days. The reaction mixture was diluted with MeOH (1 mL) and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 69% yield (30.5 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.49 (s, 3 H) 3.85 (s, 3 H) 7.35 (ddd, J=8.12, 7.31, 0.56 Hz, 1 H) 7.38 (ddd, J=8.12, 2.20, 1.58 Hz, 1 H) 7.46 (dd, J=8.65, 2.05 Hz, 1 H) 7.74 (dt, J=7.31, 1.58 Hz, 1 H) 7.82 (ddd, J=2.20, 1.58, 0.56 Hz, 1 H) 7.84 (dd, J=8.65, 0.56 Hz, 1 H) 7.85 (dd, J=2.05, 0.56 Hz, 1 H). MS (ESI+) m/z 396 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:46]([C:42]3[S:41][CH:45]=[CH:44][CH:43]=3)(=[O:48])=[O:47])[N:18]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 100 mg 4-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide was reacted with 2-thiophenesulfonylchloride to give 50 mg 4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide. LC-MS: tR=5.63 min, [M+1]+711.28, [M−1]−=709.36.