Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34].Cl.C([O-])(O)=O.[Na+]>C(O)C.O>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (80 mg, 0.263 mmol) in a mixture ethanol/water (1/4, 5 mL) were added 4-amino-3-methoxy-N-methylbenzamide (72 mg, 0.394 mmol) followed by a catalytic amount of concentrated HCl (0.04 mL). The reaction mixture was stirred at 90° C. for 24 hours, then cooled to room temperature and basified with saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4) and the residue purified by flash chromatography to give the title compound as a colourless solid (92 mg, 78% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:41]([C:44]1[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=1)=[C:42]=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([NH:41][C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 137.9 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine and 2.7 mL of THF was added 117 mg of ethyl 4-isocyanatobenzoate at room temperature. The reaction vessel was tightly sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was then added thereto, followed by extraction with chloroform. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 357 mg of ethyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a crude product. ESI+: 636
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:16])([CH3:15])[CH3:14])C1C=CC=CC=1.CC(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(O)[C@H]1CCCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(O)[C@H]1CCCN1
Reaction time: 24 h
Yield: 122.4 %

Procedure:
A mixture of (R)-2-(1-benzyl-pyrrolidin-2-yl)-propan-2-ol (582 mg, 2.65 mmol), HOAc (3 mL), and Pd(OH)2/C (200 mg) in MeOH was shaken in a Parr bottle with H2 under 50 psi for 24 h. The reaction mixture was then filtered through celite eluting with MeOH. HCl (g) was passed through the filtrate, and the filtrate was then concentrated to afford the title compound as a gray solid (419 mg, 95%). MS: 130.1 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([O:22][C:20](=[O:21])[CH:19]=[CH:18][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:13]=1[C:14]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])([CH3:25])([CH3:24])[CH3:26]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (1.45 g, 4.09 mmol) in CH2Cl2 (40 mL) was added benzylamine (0.613 g, 5.73 mmol), EDC (1.254 g, 6.54 mmol), and DMAP (1.00 g, 8.18 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (50 mL), and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was then purified using silica gel chromatography (hexanes/EtOAc 8/2) to afford the title compound as an oil (720 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 4.63 (d, 2H, J=5.5 Hz), 5.09 (s, 2H), 5.97 (br s, 1H), 6.22 (d, 1H, J=15.6 Hz), 7.01 (dd, 1H, J=2.7, 8.6 Hz), 7.10 (d, 1H, J=2.8 Hz), 7.28-7.42 (m, 10H), 7.55 (d, 1H, J=9.0 Hz), 7.88 (d, 1H, J=16.0 Hz).
Reaction SMILES: CO.[OH-].[Na+:4].[C:5]1([C:11]2[CH:12]=[C:13]([C:17]([NH:19][C:20]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])[CH:14]=[N:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCOCC1>[C:5]1([C:11]2[CH:12]=[C:13]([C:17]([NH:19][C:20]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:21]=3[C:22]([O-:24])=[O:23])=[O:18])[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[Na+:4]
Reactant: O=C(Nc1cc(-n2cccn2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1cc(-n2cccn2)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1

Procedure:
Methanol (2 mL), dioxane (2 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.083 mL) were added to the obtained 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrazol-1-yl)-benzoic acid (53 mg), and the solvent was evaporated under reduced pressure. Water and acetone were added to the obtained residue, and the solid substance was collected by filtration to obtain 23 mg of sodium 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrazol-1-yl)benzoate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])(=[O:23])=[O:22]>>[C:1]([O:5][C:6]([N:8]([O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[O:11])[S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([CH3:20])(=[O:23])=[O:22])(=[O:32])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COCCOCCOC(=O)ONC(=O)OC(C)(C)C
Product: COCCOCCOC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
1-({[(tert-Butoxy)carbonyl]({[2-(2-methoxyethoxy)ethoxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene (101) is prepared from 1-(2-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}ethoxy)-2-methoxyethane and 2-methylsulfonyl benzene sulfonyl chloride according to Scheme 11. (2.72 g, 70%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (2H, ddd, 12.7, 7.5, 1.5 Hz), 7.86 (2 H, m), 4.37-4.56 (2H, m), 3.71-3.85 (2H, m), 3.62-3.71 (2H, m), 3.50-3.60 (2H, m), 3.43 (3H, s), 3.39 (3H, s), 1.43 (9H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:3][OH:4].Cl.CCN(C(C)C)C(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:5]1([C@@H:2]2[CH2:3][O:4][C:22](=[O:24])[NH:1]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N[C@@H](CO)C1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N[C@H](C2CCCCC2)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-Amino-2-cyclohexyl-ethanol.HCl salt (1.0 g, 5.57 mmol, 1.0 equiv) in CH2Cl2 (30.0 mL) at 0° C. was added DIPEA (1.94 mL, 11.1 mmol, 2.0 equiv) followed by triphosgene (4.95 g, 16.7 mmol, 3.0 equiv) and the resulting solution was stirred at room temperature for 12 hours. The solution was then concentrated and the residue was diluted with EtOAc. The solution was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, (EtOAc 100%) to give product 520 mg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (195 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (19. 5 g). To the mixture was added under ice-cooling 65% sodium hydride (5.3 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodohexane (19.9 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(2-hexyloxyethoxy)benzene (16.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:21]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:14](=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1nc(NC(=O)OC(C)(C)C)cs1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1nc(NC(=O)OC(C)(C)C)cs1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 78.5 %

Procedure:
Ethyl 2-(4-tert-butoxycarbonylaminothiazol-2-yl)-acetate (5.1 g) was added to a solution of selenium dioxide (2.96 g) in dioxane (60 ml) and water (2 ml) at 110° C. and stirred for 4.5 hours at 110° C. The mixture was evaporated and the residue was dissolved in ethyl acetate and water. The separated ethyl acetate layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. After removing the solvent, the residue was subjected to column chromatography on silica gel and eluted with methylene chloride. The fraction containing an object compound was evaporated to give ethyl (4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylate (4.2 g).
Reaction SMILES: [CH3:1][C:2]([Si:17]([CH3:20])([CH3:19])[CH3:18])([O:4][C@@H:5]1[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]1)[CH3:3].[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:24][N:9]([C@H:7]1[CH2:6][C@@H:5]([O:4][C:2]([CH3:1])([Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:3])[CH2:8]1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OC(C)(C)[Si](C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1C[C@@H](OC(C)(C)[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of crude tert-butyl {cis-3-[1-methyl-1-(trimethylsilyl)ethoxy]cyclobutyl}carbamate (108 g) in THF (1 L) was added NaH (60% in oil, 39.6 g, 0.99 mol) in portions and the resulting mixture was stirred at rt for 30 min. The mixture was then cooled to 0° C. and iodomethane (140.58 g, 0.99 mol) was added dropwise. After addition, the mixture was stirred from 0° C. to rt overnight. The mixture was quenched with sat. NH4Cl, and water was added (200 mL), and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, then evaporated to give crude product which was purified via silica gel chromatography to give the title compound (68.9 g, 87% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([NH:30][C:31]([N:13]2[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:8][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:11][CH2:12]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
To a cold (0° C.), stirred solution of COMPOUND 249 (66 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added phenyl isocyanate (30 μL, 0.28 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 45 minutes, the mixture was concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 84 mg (84%) of COMPOUND 270 as a white solid. 1H NMR (CDCl3) δ 1.62-1.78 (m, 2H), 1.95-1.99 (m, 2H), 2.09 (s, 6H), 2.68-2.79 (m, 3H), 3.83 (s, 4H), 4.14 (d, 2H, J=13.5 Hz), 6.39 (br s, 1H), 6.99-7.12 (m, 3H), 7.25-7.39 (m, 6H), 8.34 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.39, 27.45, 44.86, 54.98, 57.83, 120.41, 122.86, 123.17, 129.13, 133.86, 138.50, 139.80, 146.23, 155.40, 157.50; ES-MS m/z 430 (M+H). Anal. Calcd. For C26H31N5O.0.5CH2Cl2: C, 67.43; H, 6.83; N, 14.84. Found: C, 67.77; H, 6.99; N, 14.90.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:26])([F:1])[F:25])[CH:4]=1)=[N:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)#[N:24]
Reactant: NCCc1ccncc1
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Product: N#CNC(=NCCc1ccncc1)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.4 %

Procedure:
By following a procedure analogous to the one described in EXAMPLE 1b, N-(3,5-bis(trifluoromethyl)-phenyl)-N'-cyano-O-phenylisourea (1 mmol, 373 mg) was treated with 4-(2-aminoethyl)pyridine (1.15 mmol, 140.5 mg) to give 110 mg (27%) of the title product;
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]>C(Cl)Cl>[Br:24][CH2:20][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1CCBr
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Triphenylphosphine (39.2 g, 0.150 mol) and carbon tetrabromide (49.5 g, 0.150 mol) were added sequentially to a solution of 2-(2-hydroxyethyl)-nitrobenzene (25.0 g, 0.150 mol) in methylene chloride (400 mL) at 0° C. The reaction was stirred overnight and quenched with saturated sodium bicarbonate solution. The methylene chloride phase was washed with saturated brine and dried over magnesium sulfate. The crude product was treated with ethyl acetate, and the precipitated triphenylphosphine oxide removed by filtration. Further purification by flash chromatography by (silica gel, 0-10% ethyl acetate in hexane gradient elution) produced the title compound (27.9 g).
Reaction SMILES: B.O1CCCC1.[CH2:7]([O:14][CH2:15][CH2:16][C@@H:17]([C:19](O)=[O:20])[NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[NH2:18][C@@H:17]([CH2:16][CH2:15][O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:19][OH:20]
Reactant: N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: N[C@H](CO)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 106.7 %

Procedure:
Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 60 mL, 60 mmol) was added at 0° C. to a suspension of O-benzyl-L-homoserine (5.06 g, 24.1 mmol) in tetrahydrofuran (100 mL). The ice bath was removed, and the reaction mixture was stirred for 72 h at room temperature, then the reaction was stopped by careful addition of methanol (40 mL). After evaporation of volatile material, the residue was taken up in 5% methanolic sulfuric acid solution (50 mL). The solution was heated at reflux for 2 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 M aq. sodium hydroxide solution, the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate three times. The combined organic phases were dried (MgSO4), filtered, and evaporated to afford the title compound (5.02 g), which was directly used in the next step. Colorless oil, MS (ISP)=196.1 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.S(=O)(=O)(O)O>ClC1C=CC=CC=1Cl.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: C=C1CC(=O)OC1=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 20 °C
Yield: 70 %

Procedure:
193.3 g (1.45 mol) of anhydrous aluminum chloride are introduced in 1100 g of o-dichlorobenzene and the mixture is brought to 45° C. with stirring. A solution of 80.9 g (0.72 mol) of itaconic anhydride and 132 g (0.7 mol) of 4-chlorobiphenyl in 700 g of o-dichlorobenzene at 50° C. is added dropwise in the course of three hours. The reaction mixture is stirred at 25° C. for four hours and then added to an ice-cold mixture of 1000 g of water and 25 g of sulfuric acid (96%). The aqueous phase is separated off. The organic phase is washed three times with a mixture of 1000 g of water and 15 g of sulfuric acid (96%) in each case. After washing three times, it is allowed to cool to approximately 20° C. and the colorless product is then filtered off with suction. This is then washed three times with 150 g of ethanol (96%) in each case. The product is dried at 60° C. and about 100 mbar until free of solvent and water. 148 g (0.49 mol) of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid (70%) are obtained as a colorless, finely crystalline powder. By working up the mother liquor, as described in Example 1, the yield is increased to 83%. (HPLC purity 99.6-99.8%)
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][NH:40][C:41]2[C:46]3[CH:47]4[O:55][CH2:54][CH2:53][CH2:52][N:48]4[C:49](=[O:51])[NH:50][C:45]=3[N:44]=[CH:43][CH:42]=2)=[CH:37][C:36]=1[F:58]>CN(C=O)C>[F:58][C:36]1[CH:37]=[C:38]([CH2:39][NH:40][C:41]2[C:46]3[CH:47]4[O:55][CH2:54][CH2:53][CH2:52][N:48]4[C:49](=[O:51])[NH:50][C:45]=3[N:44]=[CH:43][CH:42]=2)[CH:56]=[CH:57][C:35]=1[NH:34][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(CNc2ccnc3c2C2OCCCN2C(=O)N3)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CNc2ccnc3c2C2OCCCN2C(=O)N3)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
Benzoic acid (35 mg; 0.17 mmol), Bop-Cl (39 mg; 0.16 mmol), DIEA (0.04 mL; 0.25 mmol), and 45 (55mg, 0.26 mmol) were suspended in DMF (2 mL), and stirred overnight at room temperature. The crude reaction mixture was purified directly via HPLC to provide 52 (7 mg, 10% yield) as a solid. LC-MS (M+H=448, obsd.=448).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:13][N:12]=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22].Cl>C(OCC)(=O)C>[CH2:21]([NH:23][C:24]([N:13]1[C:9]([CH3:8])=[CH:10][C:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:12]1)=[O:25])[CH3:22]
Reactant: Cc1cc(Oc2ccccc2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) was added to a solution of 5-methyl-3-phenyloxypyrazole (0.20 g, 1.2 mmol) in ethyl acetate (5 ml), and the mixture cooled to 0° C. Then, ethyl isocyanate (0.09 g, 1.3 mmol) was added, and the mixture was stirred for 30 minutes at an ambient temperature. And, the mixture was stirred for 4 hours while it was allowed to have room temperature gradually. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-ethyl-5-methyl-3-phenyloxypyrazole-1-carboxamide (0.16 g, yield: 56.4%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.58 (d, J=0.8 Hz, 3H), 3.38 (dq, J=1.3 and 7.3 Hz, 2H), 5.67 (q, J=0.8 Hz, 1H), 6.99-7.07 (br s, 1H), 7.12-7.19 (m, 3H), 7.33-7.39 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[N:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][CH:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][N:35]=[CH:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: Nc1ccncn1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with perfluorophenyl 4-(4-chloro-2-methoxyphenyl)quinazoline-7-sulfonate (Intermediate AAAAAA; 1.0 g, 1.935 mmol), pyrimidin-4-amine (0.193 g, 2.032 mmol), and THF (19.35 ml) and cooled to 0° C. LHMDS (1.0M in THF) (4.06 ml, 4.06 mmol) was added drop wise and the reaction was stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-10% MeOH:DCM) to afford 4-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=13.28 (br. s., 1H), 9.46 (s, 1H), 8.57 (t, J=1.0 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H), 8.22 (d, J=6.5 Hz, 1H), 8.03 (dd, J=1.9, 8.8 Hz, 1H), 7.83 (d, J=8.7 Hz, 3H), 7.47 (d, J=8.1 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.25 (dd, J=2.0, 8.1 Hz, 1H), 7.00 (d, J=6.7 Hz, 1H), 3.72 (s, 3H). m/z (ESI) 428.2 (M+H)+.