Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:13][CH2:14][CH3:15])=[N:8]2.[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=4)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[N:8]2[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[N:23]([C:22]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:24]=[N:25][N:26]=2)=[CH:39][CH:38]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2ncnc(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of NaH (0.016 g of a 60% dispersion in oil, 0.4 mmol) in dry dimethylformamide (1.5 ml) was added 6-Chloro-8-propylpurine (0.044 g, 0.25 mmol) at room temperature. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (0.139 g, 0.25 mmol) was added. The resulting mixture was warmed to room temperature and then stirred at 40° C. for 3 hours. The reaction was cooled, and the content of the flask was poured into ice-water (50 ml) and extracted with ethyl acetate (3×15 ml). The combined organic phase was washed with brine and then dried over anhydrous Na2SO4. Removal of the solvent gave the crude product as a foam which was purified by flash-chromatography on silica-gel using ethyl acetate/hexane (1:3).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:32])[CH2:30][CH3:31])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.369 g, 1.3 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Propionyl chloride (450 μl, 5.2 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. Ethyl acetate was added to the residue and undissolved salts were removed by filtration. The filtrate was then applied to a silica gel column (4.8×13 cm) and eluted with methanol. After evaporation of the solvent, the product was eluted to a Chromatotron plate (4 mm silica gel) with a mixture of hexane:acetone (75:25). The product containing fractions were combined, concentrated, and further chromatographed on the Chromatotron (2 mm silica gel plate) with a mixture of chloroform:acetone (95:5). Product containing fractions were applied to preparative silica gel plates (20×20×0.2 cm) which were then developed in chloroform:acetone (85:15). Final purification was achieved by a third run on the Chromatotron (2 mm silica gel plate) with a mixture of hexane:acetone (80:20). Lyophilization afforded 0.178 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-((propanoyloxy)methyl)-tetrahydro-2-furyl)-9H-purine as an oil (39% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[C:32]1[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([O:24][CH2:23][CH2:22][O:21][CH3:20])=[C:26]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=2)[CH:27]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COCCOc1ccc(N)cc1-c1ccnn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(NC(=O)c2cccc(Br)c2)cc1-c1ccnn1C
Yield: 99.5 %

Procedure:
A solution of 3-bromobenzoyl chloride (0.06 mmol), N,N-diisopropylethylamine (14 μL, 0.08 mmol), and 4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)aniline (0.05 mmol) in 0.28 mL DMF was agitated on a mechanical shaker for 2 hours. The product was isolated by RP-HPLC and lyophilized to give the title compound (21.4 mg, 96%). LCMS m/z (%)=432.3 (M+H, 81Br 100.0), 430.3 (M+H, 79Br 87.6).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][N:16]3[C:9]=2[NH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37]>>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:7]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([F:14])([F:15])[F:13])[N:10]=[C:9]3[N:16]4[CH2:22][CH2:21][CH2:20][N:17]4[C:18](=[O:19])[C:8]=23)=[CH:24][CH:25]=1)=[O:29]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)C1=C(C(F)(F)F)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Product: CCOC(=O)c1c(C(F)(F)F)nc2c(c1-c1ccc(C(=O)NCc3cccc(F)c3)cc1)c(=O)n1n2CCC1

Procedure:
The product from Step A was treated as described in Step E of Example 8 followed by coupling to 3-fluorobenzylamine as described in Step F of Example 8 to provide the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 9.19 (t, 1H, J=6), 7.93 (d, 2H, J=8), 7.45 (d, 2H, J=8), 7.35 (dd, 1H, J=14, 8), 7.14 (m, 2H), 7.05 (t, 1H, J=9), 4.49 (d, 2H, J=6), 3.98 (m, 4H), 3.84 (t, 2H, J=7), 2.60 (quint., 2H, J=7), 0.91 (t, 3H, J=7) ppm; ; ESI-MS m/z 543 (M+H)+; Anal. calcd. for C27H22F4N4O4.⅓H2O: C, 59.12; H, 4.17; N, 10.21; found: C, 59.12; H, 4.14; N, 10.26.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1)[C:10](=[O:12])[CH3:11].BrC1C=C[C:34]([O:37]C)=[CH:33]C=1N(CC1C=CC(OCCN2CCCCC2)=C(F)C=1)C(=O)C.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:10]([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1)[C:3]1[CH:4]=[C:5]([O:8][C:34](=[O:37])[CH3:33])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:12])[CH3:11]
Reactant: COc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Reactant: CC(=O)N(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the total amount of N-(2-bromo-5-hydroxyphenyl)-N-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]acetamide crude product, which was synthesized from N-(2-bromo-5-methoxyphenyl)-N-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]acetamide (380 mg) synthesized according to an analogous synthetic method to Example 364 described below, were added pyridine (2 ml) and acetic anhydride (2 ml), and the solution was stirred for 1 hour at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol system) to provide the title compound (350 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[Br:24]Br.O>C(Cl)(Cl)Cl>[Br:24][CH:11]1[C:10](=[O:14])[C:9]2[CH:15]=[C:16]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[O:13][CH2:12]1
Reactant: BrBr
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
In 300 ml of chloroform was dissolved 33.3 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To this solution being maintained at 25°-30° C. was dropwise added 16.3 g of bromine in 30 minutes. After the completion of the dropwise addition, the mixture was stirred for 30 minutes at 25°-30° C. 100 ml of water was added thereto. The organic layer was separated, washed with a 5% aqueous sodium thiosulfate solution, water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 40.1 g (yield: 97.3%) of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:7]=O)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][C:31]#[N:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[C:30](=[CH:7]/[C:6]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)/[C:31]#[N:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CCOc1cc(C=O)ccc1OCCCCCCO
Reactant: COc1ccc(CC#N)cc1OC
Product: CCOc1cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)ccc1OCCCCCCO
Yield: 96 %

Procedure:
(2Z)-2-(3,4-dimethoxyphenyl)-3-{3-ethoxy-4-[(6-hydroxyhexyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 3-ethoxy-4-[(6-hydroxyhexyl)oxy]benzaldehyde and (3,4-dimethoxyphenyl)acetonitrile according the same procedure following for example 10 in 96% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]([CH3:21])[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC(=O)N(Cc2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1CCNCC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A solution of 1-benzyl-4-tert-butyloxycarbonyl-7-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (160 mg, 0.41 mmol) in chloroform (2 ml) was stirred with trifluoroacetic acid (3 ml) at room temperature for 30 minutes. The mixture was evaporated to dryness and the residue partitioned between chloroform and saturated potassium carbonate solution (30 ml/1:2). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (98 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([OH:16])[C:6]=2[CH:17]=1.[Br:18][CH2:19][CH2:20]O>C1C=CC=CC=1.S(=O)(=O)(O)O>[Br:18][CH2:19][CH2:20][O:16][CH:7]1[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: OC1c2ccccc2CCc2ccc(Cl)cc21
Reactant: OCCBr
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C(OCCBr)c1ccccc1CC2
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 3-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (3.52 g, 0.014 mol, prepared similarly as described in Fr.M. 2165, 1963; Chem.Abstr. 60, 14523 (1963)) and 2bromoethanol (2.5 g, 0.02 mol) in benzene (80 ml), concentrated sulfuric acid (0.85 ml) was added dropwise. The reaction mixture was stirred for 1.5 h, diluted with 50 ml of benzene and washed with water (30 ml), 0.6 N NaHCO3 (20 ml) and 2×30 ml of water. The benzene solution was dried (MgSO4) and the solvent was evaporated under vacuum to give a residue which was crystallised from a mixture of cyclohexane and n-hexane. 3.9 g (77%) of 5-(2-bromoethoxy)-3-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1.[CH3:18]I>C1COCC1.[Cl-].[Na+].O>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([CH3:18])[C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1
Reactant: CI
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c2c(c3cccc(F)c31)C(=O)CCC2
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (80% dispersion in oi; 1.15 g) in dry THF (50 ml) under nitrogen was added 8-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (6.5 g) in dry THF (50 ml), and the mixture was stirred for 1 h. Methyl iodide (4.1 ml) was added, and the mixture was stirred for 3 h. The mixture was then poured into brine (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (5.77 g), m.p. 126°-128°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCCCCCCCCCCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCSc1ccc(O)cc1
Temperature: 80 °C
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, p-hydroxythiophenol (126 g) was dissolved in N,N-dimethylformamide (600 ml) and thereto was added potassium carbonate (152 g). Thereto was added octadecyl chloride (318 g), followed by heating at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water to precipitate a white solid. Thereto was added 5% hydrochloric acid to adjust the pH to acidic state and then, the white solid was filtered off under reduced pressure and then recrystallized from methyl ethyl ketone to obtain the desired product (261 g). Yield 70%; m.p. 95° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: Fc1ccc(Br)cc1
Product: COC(=O)c1cc([C@H]2CCCN2c2ccc(F)cc2)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 14.7 %

Procedure:
Methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate (130 mg, 0.36 mmol) was reacted with 1-bromo-4-fluorobenzene (0.239 ml, 2.18 mmol) to afford methyl 8-[(2R)-(1-(4-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (enantiomer 2, 24 mg, 15%) as a beige solid. Mass Spectrum: m/z [M+H]+=453.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: Oc1ccccc1Cl
Reactant: OCCCc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Clc1ccccc1OCCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a sol. of 3-(4-bromophenyl)propan-1-ol (Glover S. A., et al.; Tetrahearon, 1990, 46, 7247; 24.5 g, 0.114 mol) in toluene (600 mL) under nitrogen were added 2-chlorophenol (17.4 mL, 0.171 mmol), diisopropyl azodicarboxylate (33.1 mL, 0.171 mol) and tri-n-butylphosphine (42.2 mL, 0.171 mol). The sol. was heated to reflux and stirred under reflux overnight. The sol. was allowed to cool to rt and the solvents were removed under reduced pressure. The residue was diluted in EtOAc and washed with aq. 1M HCl (1×) and aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (petroleum ether→Et2O/petroleum ether 1:99→1:19) led to the tide compound (15.1 g, 41%). Rf=0.70 (EtOAc/heptane 1:3).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[OH:23][CH2:22][C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]1[NH:15][S:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A solution of 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (190 mg, 0.78 mmol) in 2 mL dichloromethane was added dropwise to a solution of ((1R,2R)-2-aminocyclohexyl)methanol (100 mg, 0.78 mmol) and triethylamine (320 μL, 2.3 mmol) in 10 mL dichloromethane at 0° C. The reaction was stirred at 0° C. for 1 h, then concentrated and purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)-6-(trifluoromethyl)pyridine-3-sulfonamide (150 mg, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (d, J=2.01 Hz, 1H), 8.37 (dd, J=8.06, 1.76 Hz, 1H), 7.83 (d, J=8.31 Hz, 1H), 5.83 (d, J=6.80 Hz, 1H), 3.77 (ddd, J=11.21, 3.78, 3.65 Hz, 1H), 3.36 (dt, J=11.33, 5.67 Hz, 1H), 2.97-3.15 (m, 1H), 2.37 (t, J=5.41 Hz, 1H), 1.73-1.87 (m, 1H), 1.67 (d, J=2.01 Hz, 1H), 1.56-1.66 (m, 2H), 1.33-1.46 (m, 1H), 1.05-1.30 (m, 4H). MS [M+H]+=339. MS [M+Na]+=361.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:14]Br>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[Br:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2ccccc12
Reactant: BrBr
Product: O=[N+]([O-])c1cccc2c(Br)cccc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-nitronaphthalene (10.0 g, 58 mmol) and FeCl3 (0.066 g, 0.41 mmol) was heated to 90° C. To the solution was added dropwise bromine (3.0 mL, 58 mmol) (no any solvent was used for this reaction). The reaction mixture was stirred at 90° C. for 2 hrs. After cooling down to room temperature, the mixture was recrystallized from ethanol to give compound A as a yellow needle crystal (7.3 g, 50%). mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=8.7 Hz, 1H), 8.34 (d, J=8.7 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.2, 133.6, 132.7, 131.8, 129.6, 126.4, 125.7, 124.6, 123.7, 123.0. EI-MS (m/z) Calcd. for C10H6BrNO2:251 (M+), Found: 251.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:51][CH3:52]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:50]=[CH:49][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][O:46][CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:51][CH3:52])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCOCC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 65.6 %

Procedure:
A mixture of 0.0562 g (0.18 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0514 g (0.27 mmole) of toluenesulfonic acid monohydrate, 0.0451 g (0.18 mmole) of 4-amino-3-methoxy-N-(tetrahydro-2H-pyran-4-yl) benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give 0.0643 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-252) as a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: ICC(c1ccccc1)c1ccccc1
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 68 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 2,2-diphenylethyl iodide, the procedure of Example 48 was otherwise repeated to synthesize the title compound. Yield 68%.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[C:22]([C:23](Cl)=[N:24]O)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:16][C:17]1[C:22]([C:23]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:24]=2)=[C:21]([Cl:27])[CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: ON=C(Cl)c1c(Cl)ccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2c(Cl)ccnc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A solution of methyl isobutyrylacetate (1.37 mL, 10.2 mmol) in THF (2.1 mL) was stirred at 0° C. as a 0.5 N solution of sodium methoxide in methanol (20.3 mL, 10.2 mmol) was added. A solution of 2,4-dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (1.94 g, 8.64 mmol) in THF (19 mL) was added and the resulting solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexanes to 3:7 ethyl acetate:hexanes gradient elution) and fractions containing the product concentrated. The residue was azetroped with methanol then dichloromethane to provide methyl 3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (1.64 g, 66% as 0.15 dichloromethane). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (d, J=5 Hz, 1H), 7.82 (d, J=5 Hz, 1H), 3.79 (septet, J=7 Hz, 1H), 3.63 (s, 3H), 1.34 (m, 6H).