Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)(=[O:21])=[O:20])=[C:14]2[C:10]=1[C:11]([Cl:29])=[CH:12][NH:13]2)(C(C)(C)C)(C)C.F.C(#N)C>O>[Cl:28][C:24]1[CH:23]=[C:22]([S:19]([NH:18][C:15]2[CH:16]=[CH:17][C:9]([OH:8])=[C:10]3[C:14]=2[NH:13][CH:12]=[C:11]3[Cl:29])(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NS(=O)(=O)c2cccc(Cl)c2)c2[nH]cc(Cl)c12
Agent: F
Solvent: CC#N
Solvent: O
Product: O=S(=O)(Nc1ccc(O)c2c(Cl)c[nH]c12)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
220 mg (0.47 mmol) of N-(4-tert-butyldimethylsilyloxy-3-chloro-1H-indole-7-yl)-3-chlorobenzenesulfonamide synthesized in the same manner as in Synthetic Example 1a was added to a mixed solution (2 ml) of an aqueous 40% hydrogen fluoride solution/acetonitrile (1:10). After stirred at room temperature overnight, water was added thereto and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 141 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:55]=[CH:54][C:33]([C:34]([NH:36][C:37]2[C:38]([O:52][CH3:53])=[N:39][CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=2)=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:41]2[CH:42]=[C:37]([NH:36][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([OH:29])=[CH:55][CH:54]=3)[C:38]([O:52][CH3:53])=[N:39][CH:40]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccc(O)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NC(=O)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (84 mg, 0.19 mmol) were added 4-hydroxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide (85 mg, 0.23 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (16 mg, 0.02 mmol) and 191 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1 ® Purification System (0 to 65%, hexane-ethyl acetate) to give 25 mg (22% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[F:17][C:18]1[C:26]([CH3:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([N+:30]([O-:32])=[O:31])[C:19]=1[C:20](Cl)=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:20](=[O:21])[C:19]1[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([F:29])[C:25]([F:28])=[C:26]([CH3:27])[C:18]=1[F:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=CN(C)C
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
1.4 g (0.01 mol) of ethyl 3-dimethylaminoacrylate, 15 mg of ethyl acetate and 0.8 mg (0.01 mol) of pyridine were loaded and cooled below 5° C., and a liquid mixture of 3 g (0.01 mol) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride and 5 ml of ethyl acetate was added dropwise while the temperature was maintained at 0 to 5° C. The resulting mixture was stirred at 5° C. for 1 hour and then stirred at room temperature (25° C.) overnight (12 hours). The precipitated pyridine hydrochloride was filtered off, and the filtrate was concentrated under reduced pressure to give 3.62 g of ethyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate with a 87% purity (in terms of the percentage of the peak area in HPLC) as the residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:15])[CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][CH2:7]2.S(=O)(=O)(O)O.[CH3:21]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:15])[CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]([O:14][CH3:21])=[O:13])[CH2:9][CH2:8][CH2:7]2
Reactant: CO
Reactant: Cc1cc(N)c2c(c1)CCCC2C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCc2cc(C)cc(N)c21

Procedure:
The product from Example 140 was dissolved in methanol (50 ml) and concentrated sulfuric acid (3 ml) was added. The reaction was refluxed for 4 hours and solvent was evaporated to one-half the volume. Following the procedure of Example 136 the desired ester was obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH2:14][C:15]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)([OH:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:14][C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[O:26][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OCC(O)(CCN(Cc2ccccc2)C(=O)CCl)c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CCN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of N-benzyl-2-chloro-N-[(3RS)-3-(3,4-dichlorophenyl)-3-hydroxy-4-(4-methoxyphenoxy)butyl]acetamide (7.41 g) in THF (741 mL) was added sodium tert-butoxide (1.37 g), and the mixture was stirred at 0° C. for 2 hr, and then stirred while warming to room temperature for 14 hr. To the reaction mixture was added water, and the mixture was concentrated. The concentrated residue was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.02 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=1[CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C>[CH2:11]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[C:23]=1[CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(OCCOCc2ccccc2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCCOCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 60 °C
Yield: 74.1 %

Procedure:
A mixture comprising 1.0 g of 2-mercaptobenzimidazole, 2.0 g of 4-(2-benzyloxyethoxy)-2-chloromethyl-3-methylpyridine, 302 mg of sodium hydroxide and 40 ml of ethanol was stirred under heating at 60° C. for 1.5 hours and distilled under a reduced pressure to remove the ethanol. The obtained residue was subjected to silica gel column chromatography. The column was treated with 30 to 60% ethyl acetate in n-hexane to obtain 2.0 g of the title compound as a white crystal.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: ClCCCCOc1ccccc1
Yield: 77 %

Procedure:
A two phase mixture of phenol (5 g, 53 mmol), 1,4-dichlorobutane (30 ml), tetrabutylammonium hydrogen sulphate (0.3 g, 1 mmol), and sodium hydroxide solution (25 ml, 6M) was refluxed for 3 h. The organic layer was separated, dried (MgSO4), and concentrated in vacuo. The residues were purified by flash chromatography (silica (Merck 15111); eluant:petrol) to give the product as a colourless viscous oil (7.57 g 77%) bp 250° C. at 0.2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].I[CH2:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ICCCCI
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12CCCC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.6 g; 0.0035 mol; 1.0 equiv) in anhydrous THF (20 mL) and cool the reaction to −78° C., under an inert atmosphere. Add drop-wise lithium hexamethyldisilazide (8.8 mL; 0.0088 mol; 2.5 equiv; 1M in THF). Stir at −78° C. for 30 min. Add drop-wise 1,4-diiodobutane (0.56 mL; 0.0042 mol; 1.2 equiv), allow the reaction temperature to reach 0° C. slowly, and stir for 2 h. Then allow the reaction to reach RT and stir for additional 1 h. Quench the reaction with saturated ammonium chloride solution and extract with EA. Wash the organic layer with water, brine, and dry over anhydrous sodium sulfate. Evaporate the organic layer and purify over a 10 g silica column with acetone (5%) in DCM. Pool fractions to give the title compound (0.34 g; 43.09%). H NMR (DMSO-d6): 11.68 (1H, s), 8.53 (1H, s), 2.0-2.1 (m, 2H), 1.91-1.99 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1>>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)=[N:7][C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)[nH]n1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cc(C)n[nH]4)n3)cc2CC1

Procedure:
The title compound was prepared from was prepared from (2,5-dichloropyrimidin-4-yl)-(5-methyl-2H-pyrazole-3-yl)amine (137 mg, 0.56 mmol) and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (124 mg, 0.56 mmol) in an analogous manner to Example 946 to afford a white solid (110 mg, 46%). Mp: 198-9° C. LCMS (m/e) 428 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.24 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.46 (br s, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 2.93 (m, 4H), 2.82 (m, 7H), 2.33 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16](O)[CH:17]2[CH2:22][CH2:21][O:20][N:19]([CH2:23][CH3:24])[C:18]2=[O:25])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])[CH:16]=[C:17]1[CH2:22][CH2:21][O:20][N:19]([CH2:23][CH3:24])[C:18]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN1OCCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCN1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 45.2 %

Procedure:
The dihydro-4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-ethyl-2H-1,2-oxazin-3(4H)-one (15 g, 41 mmol) obtained according to Step B was added to 100 ml of benzene and 0.4 g of p-toluenesulfonic acid monohydrate and refluxed for 13 hours. The mixture was concentrated to a solid, taken up in 150 ml of methylene chloride, washed with dilute sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to a brown solid (14.1 g) which was recrystallized from acetone to yield 6.4 g of crystalline dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-2H-1,2-oxazin-3(4H)-one having a melting point of 166°-167° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:25][CH:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[O:23][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:7]2[CH2:8][CH2:9][C:4]3([O:23][CH:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:25][C:2](=[O:1])[CH2:3]3)[CH2:5][CH2:6]2)=[O:11])=[CH:13][C:14]=1[CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(O)CC(c2cccnc2)O3)ccc1OC(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2cccnc2)O3)ccc1OC(C)C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of [8-hydroxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (100 mg, 0.24 mmol) in dichloromethane (3.4 mL) was cooled to 0° C. and treated with Dess-Martin periodinane (100 mg, 0.24 mmol). The reaction mixture was stirred for two hours and was quenched by the addition of saturated aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×25 mL), and the combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel utilizing a gradient of 50-100% ethyl acetate in hexanes to yield 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-8-one (84 mg) ESI-MS m/z calc. 422.22, found 423.3 (M+1)+; Retention time: 1.41 minutes (3 min run).
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[O:10]=[C:11]1[N:20]2[CH2:21][CH2:22][N:23]=[C:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12]1>>[N+:6]([C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11](=[O:10])[N:20]3[CH2:21][CH2:22][N:23]=[C:19]3[C:18]=2[CH:17]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccccc2C2=NCCN12
Agent: O=S(=O)(O)O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCN12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7 ml of concentrated H2SO4 were added, whilst cooling, to 5 ml of 98% strength HNO3. 9.3 g (0.05 mol) of 5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline were added in portions at 0° to 5° C. to this mixture, and the latter was stirred for 2 hours at room temperature. The reaction mixture was then poured into ice water, and the precipitated deposit was filtered off under suction. It was neutralised in water with NaHCO3, the mixture being heated to boiling for a short time. After the mixture had been cooled, the precipitate was again filtered off under suction, washed with ethanol and ether, and dried.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:8]1[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCc2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and benzylamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (CD3CN) δ 7.47-7.42 (m, 1H), 7.40-7.35 (m, 2H), 7.34-7.29 (m, 2H), 7.23-7.18 (m, 3H), 6.88-6.83 (m, 2H), 6.44-6.35 (m, 1H), 4.16 (d, J=6.6 Hz, 2H), 3.68 (t, J=7.3 Hz, 2H), 1.82-1.71 (m, 2H), 1.49-1.38 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); Mass spectrum: M+H+ 371.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](=[O:34])[O:32][CH3:33])[CH:26]=[CH:25]2>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.C1(C)C=CC=CC=1>[C:6]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](=[O:34])[O:32][CH3:33])[CH:26]=[CH:25]2)(=[O:8])[CH3:7]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)N(c1ccccc1)c1ccc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)N(c1ccccc1)c1ccc2cccc(C(C)=O)c2n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of Pd(PPh3)4 (60.8 mg, 0.053 mmol, Strem Chemicals, Newburyport, Mass.), tributyl(1-ethoxyvinyl)stannane (391 μl, 1.158 mmol, Sigma Aldrich), methyl (8-bromoquinolin-2-yl)(phenyl)carbamate (Example 46a; 376 mg, 1.053 mmol), and toluene (5.2 mL) were stirred under N2 at 100° C. for 20 h. Purification by column chromatography (silica gel: 0 to 10% EtOAc/hexanes followed by 70% EtOAc/hexanes) provided methyl (8-acetylquinolin-2-yl)(phenyl)carbamate, which was used without further purification in the next step. m/z (ESI, +ve) 349.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(Cl)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol (Chen, L.; et al., US 20060004045) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 68%): mp 94-97° C.; 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.11 (d, J=6.8 Hz, 2H), 8.01 (d, J=6.9 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.3 Hz, 3H), 7.32-7.38 (m, 3H), 5.59 (s, 1H), 3.84-3.87 (m, 2H) (NH, OH not observed); ESIMS m/z 534 ([M+H]+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Br:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][C:20]=2[NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[C:4]([OH:3])=[O:16])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl ester hydrochloride and 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1, Part C. Hydrolysis of the methyl ester as in EXAMPLE 2, Part E, provided the title compound. HPLC: RT=9.80 min. MS (ESI−): mass calcd. for C24H17BrCl2N4O5S, 624.29; m/z found, 621/623/625 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.04 (s, 1H), 8.98 (d, J=1.6, 1H), 8.90 (d, J=1.6, 1H), 8.54 (dd, J=7.3, 1.0, 1H), 8.28 (dd, J=8.4, 0.9, 1H), 7.91-7.86 (m, 1H), 7.71 (d, J=1.9, 1H), 7.43 (d, J=1.8, 1H), 7.33 (d, J=8.2, 1H), 7.13 (d, J=8.4, 1H), 7.05 (dd, J=8.2, 1.9, 1H), 6.86 (dd, J=8.4, 1.9, 1H), 6.53 (d, J=7.5, 1H), 4.91 (q, J=6.2, 1H), 3.34-3.09 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[CH:18]=3)[N:6]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=2[C:4](=[O:39])[N:3]1[CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[NH4+].[NH4+].C1C=CC2N(O)N=[N:55]C=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([NH2:55])=[O:26])[CH:18]=3)[N:6]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=2[C:4](=[O:39])[N:3]1[CH2:40][CH2:41][CH3:42]
Reactant: On1nnc2ccccc21
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(C(=O)O)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(C(N)=O)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
A mixture of 3-(3-{4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzoic acid (100 mg, 0.17 mmol), ammonium carbonate (33 mg, 0.34 mmol), HOBT (36 mg, 0.24 mmol), N-methyl morpholine (34 mg, 0.34 mmol) were taken in DMF (2 ml), EDCI (130 mg, 0.68 mmol) was added at cold condition and stirred for 18 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×5 ml), the organic layer was washed with brine (2×10 ml), dried over Na2SO4. The organic solvent was evaporated and the crude product was purified using HPLC to obtain 3-(3-{4-[2,6-Dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzamide (33 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N(C3CCNCC3)C3C(SC=2C=1)=CC=CC=3.CC1(C)C(C)(C)OB([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[NH:64][C:65](=[O:67])[CH3:66])O1.N1C=CC=C(B(O)O)C=1>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.CN1C(=O)CCC1.O.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=4[NH:64][C:65](=[O:67])[CH3:66])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(Cl)ccc32)CC1
Reactant: CC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: OB(O)c1cccnc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2i, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide for 3-pyridyl boronic acid, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 1j was obtained.