Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[OH:12])[CH2:5][CH2:4]1.Cl.[I:15]Cl>O>[ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([I:15])[C:10]=2[OH:12])[CH2:5][CH2:4]1
Reactant: ClI
Reactant: Cc1ccc(O)c2c1CCC2N
Agent: Cl
Solvent: O
Product: Cc1cc(I)c(O)c2c1CCC2N
Reaction time: 2 h

Procedure:
One gram of 1-amino-7-hydroxy-4-methylindane hydrochloride was dissolved in 20 ml of water, then 5 ml of 3N-hydrochloric acid solution containing 0.85 g of iodine monochloride was added dropwise at a room temperature under vigorous stirring condition. The reaction mixture was stirred at the same temperature for 2 hours, then ice-cooled. The crystals precipitated were collected by filtration, and changed them to hydrochloride, washed with ether and dried. 0.70 Grams of 1-amino-7-hydroxy-6-iodo-4-methylindane hydrochloride was obtained in the form of yellow needle-like crystals. Melting point: Over 200° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]=[C:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:35][O:36][NH:37][CH3:38]>C(Cl)Cl>[CH3:35][O:36][N:37]([CH3:38])[C:15]([CH:13]1[CH2:12][C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[CH2:14]1)=[O:17]
Reactant: O=C(C=C1CC(C(=O)O)C1)OCc1ccccc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(=CC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
To an ice cold solution of 3-[2-(benzyloxy)-2-oxoethylidene]cyclobutane-1-carboxylic acid (2.0 g, 8.12 mmol), N-Methyl-morpholine (2.70 ml, 24.36 mmol) in DCM (50 ml) was added isobutyl chloroformate (1.70 ml, 12.99 mmol) drop-wise over 5 min. After an additional 5 min, methoxy(methyl)amine hydrochloride (1.58 g, 16.24 mmol) was added and the mixture was stirred overnight whislt allowing to warm to RT. The reaction mixture was then diluted with DCM (30 ml), washed with 0.1N HCl (50 ml) then sat. NaHCO3 (50 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with EtOAc:heptanes from 1:9 to 3:7 gave the desired product (1.54 g, 65%); MS (ESI+) for C16H19NO4 m/z 290.10 [M+H]+; HPLC purity 100% (ret. time, 1.86 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 2.96 (1H, ddd, J=16.98, 8.79, 1.81 Hz), 3.17-3.30 (4H, m), 3.30-3.48 (2H, m), 3.51-3.63 (1H, m), 3.64-3.75 (3H, m), 5.15 (2H, s), 5.73 (1H, quin, J=2.25 Hz), 7.29-7.42 (5H, m).
Reaction SMILES: C([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH2:12])[C:6]([OH:8])=[O:7])(=O)C.C(SCC(CCCN)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[NH2:12][CH2:11][CH2:10][CH2:9][CH:5]([SH:4])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)SC(CCCN)C(=O)O
Agent: CC(=O)SCC(CCCN)C(=O)N1CCC[C@H]1C(=O)O
Product: NCCCC(S)C(=O)O

Procedure:
By substituting 2-acetylthio-5-aminopentanoic acid for the 1-(2-acetylthiomethyl-5-aminopentanoyl)-L-proline in the procedure of Example 15, 5-amino-2-mercaptopentanoic acid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]3[N:17]([CH:18]=2)[C:16](=[O:19])[C:15]2[CH:20]=[C:21]([O:62][CH3:63])[C:22]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]4[C:59]([O:60][CH3:61])=[CH:58][C:32]5[C:33](=[O:57])[N:34]6[CH:49]=[C:48](S(C(F)(F)F)(=O)=O)[CH2:47][C@H:35]6[C:36](=[O:46])[N:37]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=5[CH:30]=4)=[CH:23][C:14]=2[N:13]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:12]3=[O:72])=[CH:5][CH:4]=1.[NH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>C(O)C.C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[C:48]1[CH2:47][C@@H:35]2[N:34]([CH:49]=1)[C:33](=[O:57])[C:32]1[CH:58]=[C:59]([O:60][CH3:61])[C:29]([O:28][CH2:27][CH2:26][CH2:25][O:24][C:22]3[C:21]([O:62][CH3:63])=[CH:20][C:15]4[C:16](=[O:19])[N:17]5[CH:18]=[C:9]([C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=6)[CH2:10][C@H:11]5[C:12](=[O:72])[N:13]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:69])([CH3:71])[CH3:70])[C:14]=4[CH:23]=3)=[CH:30][C:31]=1[N:37]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:36]2=[O:46]
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(S(=O)(=O)C(F)(F)F)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Reactant: Nc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccccc7N)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Temperature: 40 °C
Yield: 90.3 %

Procedure:
A catalytic amount of tetrakistriphenylphosphinepalladium (0) (11.2 mg) was added to a mixture of the mono triflate 17 (380 mg), the pinnacol ester of 2-aminophenylboronic acid (124 mg) and sodium carbonate (120 mg) in ethanol (5 mL), toluene (5 mL) and water (5 mL). The reaction mixture was allowed to stir over night at room temperature and at 40° C. until the reaction was complete (c. 2 hr). The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The ethyl acetate solution was dried over magnesium sulphate and filtered under vacuum. Removal of ethyl acetate by rotary evaporation under reduced pressure afforded the crude product which was subjected to flash chromatography (silica gel, ethyl acetate/hexane). Pure fractions were collected and combined. Removal of excess eluent by rotary evaporation under reduced pressure afforded the pure product 103 (330 mg, 86% yield). LC/MS RT: 4.17 min, ES+1018.48.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26]C(OCC)=O)=[CH:22][CH:21]=1)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[OH-].[NH4+].Cl>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[CH:35]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 42.7 %

Procedure:
43.20 g (0.081 Mol) of 6-[((2E)-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate are dissolved in 66 ml (0.815 Mol) of pyridine and 400 ml of acetone at room temperature. 61 ml (0.815 Mol) of ammonium hydroxide solution 25% are added dropwise to the solution at room temperature. After 12 h reaction, the mixture is thrown on water and acidified by the addition of HCl 25% (up to pH=3-4). A paste is obtained which is filtrated and dissolved in ethyl acetate and extracted with water. The organic phase is dried with sodium sulfate, filtrated, concentrated by rotary evaporation. Filtration of the residue over silica gel with tert-Butyl methyl ether as eluant and crystallization of the residue in 200 ml of ethyl acetate and 1200 ml of hexane at 0° C. give 15.84 g of 6-[((2E)-{4-hydroxyphenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate as yellow crystals.
Reaction SMILES: N1CCCC(C(O)=O)C1.CN([C:13]([O:17][N:18]1N=NC2C=CC=[N:24][C:19]1=2)=[N+:14](C)C)C.F[P-](F)(F)(F)(F)F.[CH:34]([N:37]([CH2:41][CH3:42])[CH:38]([CH3:40])C)([CH3:36])C>CN(C)C=O>[CH2:42]1[CH:40]2[CH:36]([C:13]3[O:17][N:18]=[C:19]([NH2:24])[N:14]=3)[CH2:34][N:37]([CH2:38]2)[CH2:41]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C1CCCNC1
Solvent: CN(C)C=O
Product: Nc1noc(C2CN3CCC2C3)n1
Temperature: 25 °C

Procedure:
A solution of the appropriate piperidine-3-carboxylic acid in dimethylformamide (10-20 ml/mmol) is admixed under argon at RT with HATU (1.2 eq.), N,N-diisopropylethylamine (2.2 eq.) and the appropriate alkyl N′-hydroxyimidocarbamate (1.1 eq.). The reaction mixture is stirred at RT until the formation of the intermediate is complete and then stirred further at 120° C. until the desired product is formed from this intermediate. The reaction mixture is then purified by means of preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 26.3 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridine-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (75 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.25 mmol) to afford the desired product (24 mg, 26%) as an orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.38 (s, 1H), 8.32-8.18 (m, 3H), 8.07 (d, J=9.3 Hz, 1H), 7.86 (dd, J=9.3, 2.6 Hz, 1H), 7.48 (s, 2H), 7.15 (d, J=9.3 Hz, 1H), 3.91 (t, J=6.1 Hz, 2H), 3.49 (t, J=6.1 Hz, 2H), 2.99 (s, 6H), 2.87-2.78 (m, 1H), 1.24-1.18 (m, 4H); ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 96.5% (AUC), tR=11.28 min.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:24]=[CH:23][C:14]([C:15]([CH:17]([CH3:22])[CH2:18][C:19](O)=[O:20])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6]1>O>[CH3:22][CH:17]1[C:15]([C:14]2[CH:23]=[CH:24][C:11]([N:8]3[CH:9]=[CH:10][C:5](=[O:4])[CH:6]=[CH:7]3)=[CH:12][CH:13]=2)=[N:3][NH:2][C:19](=[O:20])[CH2:18]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1
Reactant: NN
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
Hydrazine hydrate (1.8 g) was added to a suspension of 3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]-butanoic acid (5 g) in water (60 ml). The resulting solution was stirred under reflux for 2 hours and cooled to afford the title compound as a pale yellow solid, 4.45 g. m.p. 255-258° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]([O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].[Cl-].[NH4+]>N1CCCC1.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>[C:5]([O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:3]#[C:2][CH2:1][OH:4])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)CCc1cccc(Br)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)CCc1cccc(C#CCO)c1
Temperature: 77.5 °C
Yield: 16.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.14 mmol), cuprous iodide (0.5 g, 0.25 mmol), and propargyl alcohol (0.29 mL, 4.91 mmol) were added to a solution of 3-(3-bromophenyl)propionic acid tert-butyl ester (2.13 g, 7.08 mmol) in pyrrolidine (8 mL) under an argon atmosphere at room temperature. The mixture was heated at 75-80° C. for 5 hours. After cooling to room temperature, saturated ammonium chloride was added and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate (85:15), gave 3-[3-(3-hydroxyprop-1-ynyl)phenyl]propionic acid tert-butyl ester as a yellow oil (0.21 g, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH:14]=[CH:13][C:12](=O)[NH:11][C:10]=12)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.C(OCC)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:12]1[CH:13]=[CH:14][N:9]2[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[N:11]=1
Reactant: CCOC(=O)c1cnn2ccc(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)c1cnn2ccc(Cl)nc12
Temperature: 90 °C
Yield: 73 %

Procedure:
To a suspension of 5-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (prepared according to Gavrin, L. K. et al, J. Org. Chem. 2007, 72, 1043-1046) (3.00 g, 14.5 mmol, 1 equiv) in phosphorus oxychloride (30 mL) was added diisopropylethylamine (2.00 mL, 11.6 mmol, 0.8 equiv). The mixture was heated to 90° C. for 4.5 hours. After cooling, the mixture was carefully quenched with ice-water and extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to give a solid. Trituration (diethyl ether) afforded 2.38 g (73%) of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as a solid. LCMS (ESI) m+H=226.2 (mono chlorinated isotope pattern); 1H NMR (400 MHz, CDCl3) δ: 8.63 (d, 1H), 8.56 (s, 1H), 6.99 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:40]=[CH:39][C:18]3[N:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]([O:37]C)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Li+].[OH-]>CO.O>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:40]=[CH:39][C:18]3[N:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]([OH:37])=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1ncccc1-c1ccc(Cn2cnc3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)ncn3Cc2ccc(-c3cccnc3C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 3-(4-((5-(1-(3-isopropylphenyl)ethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)picolinate (30 mg, 0.056 mmol) in methanol (5 mL) and water (1 mL) was added LiOH (11 mg, 0.28 mmol), then the mixture was stirred at RT for 2 hrs. The methanol was removed under the reduced pressure. The residue in water was adjusted to pH=7 with 3N HCl, 1.5 then the mixture was concentrated. The residue was purified with prep-TLC (DCM/Methanol=10/1, silica gel) to get the titled compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1C=CC=C[CH:3]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]([CH3:23])[C:12]=1[C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][N:25]=1>>[CH3:23][N:13]1[C:12]([C:24]2[O:28][C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:26][N:25]=2)=[C:11]([O:10][C:1](=[O:8])[CH2:2][CH3:3])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14]1(=[O:21])=[O:22]
Reactant: CN1C(c2nnc(-c3ccccc3)o2)=C(O)c2ccccc2S1(=O)=O
Reactant: O=C(Cl)c1ccccc1
Product: CCC(=O)OC1=C(c2nnc(-c3ccccc3)o2)N(C)S(=O)(=O)c2ccccc21

Procedure:
Following the procedures of Example 5, but substituting propionyl chloride for benzoyl chloride, 4-hydroxy-2-methyl-3-(2-phenyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide was acylated to give the title product.
Reaction SMILES: C([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12](I)[C:7]=2[CH:6]=[CH:5]1)(=O)C.[CH3:14][N:15](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[N:9]1[C:8]2[NH:4][CH:5]=[CH:6][C:7]=2[C:12]([C:14]#[N:15])=[N:11][CH:10]=1
Reactant: CC(=O)n1ccc2c(I)ncnc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ncnc2[nH]ccc12
Yield: 80 %

Procedure:
A mixture of 7-acetyl-4-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.28 g, 4.46 mmol), zinc cyanide (427 mg, 2.45 mmol), tetrakis(triphenylphosphine)palladium(0) (258 mg, 0.223 mmol) and N,N-dimethylformamide (10 mL) was tightly sealed in a vial, and the microwave was irradiated at 150° C. for 20 min. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) to give the title compound (520 mg, yield 80%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[C:25]([CH2:37][C:38]([O:40]C)=[O:39])[CH:26]=[CH:27][C:28]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].Cl>COCCOC.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>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:28]3[CH:27]=[CH:26][C:25]([CH2:37][C:38]([OH:40])=[O:39])=[CH:24][C:23]=3[C:22]([F:21])([F:42])[F:43])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)c1
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3C(F)(F)F)cc2)nc1C(N)=O
Temperature: 85 °C
Reaction time: 17 h
Yield: 55.9 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 278 mg, 1.02 mmol) and methyl 2-(3-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 5-2; 300 mg, 0.82 mmol) and sodium carbonate (0.666 mL, 1.33 mmol), tetrakis(triphenylphosphine)palladium(0) (58.7 mg, 0.05 mmol) and lithium chloride (60.8 mg, 1.43 mmol) in DME (20 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was The reaction mixture was acidified with 2M HCl and evaporated. The precipitate was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid (197 mg, 55.9%) as a brown solid, which was purified by flash silica chromatography, elution gradient 0 to 6% MeOH in DCM. Failed to purify material so was further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid (197 mg, 55.9%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH2:20][CH:21]=[CH:22][CH3:23])C(=O)C(F)(F)F.O>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]([C:21]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=2)[NH:13][CH:20]=1)[CH3:23]
Reactant: CC=CCN(C(=O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A solution of N-(2-bromo-4-trifluoromethoxy-phenyl)-N-but-2-enyl-2,2,2-trifluoro-acetamide (10 g, 24.7 mmol) in DMF (50 mL) is treated with n-Bu4NCl (7.5 g, 27.2 mmol), Pd(OAc)2 (221 mg, 0.98 mmol), and stirred at 100° C. for 1 h. H2O (10 mL) is added, and the mixture is cooled to rt, filtered through a pad of silica gel. The filtrate is extracted with heptane (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-25% EtOAc in heptane to afford 3-ethyl-5-trifluoromethoxy-1H-indole (3.1 g, 55%). MS: 230 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.97 (s, NH, 1H), 7.44 (s, 1H), 7.29 (m, 1H), 7.07 (m, 2H), 2.77 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[N:29]1([CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][N:39]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:41]5[CH:42]=[CH:43][C:38]([NH:37][CH2:36][CH2:35][N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[N:39][CH:40]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(NCCN5CCOCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 120 °C
Yield: 16.6 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), (2-Morpholin-4-yl-ethyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (400 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 273 (97.5 mg, yield: 17%). 1HNMR (DMSO-d6, 400 MHz): δ8.61 (s, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.91-7.87 (m, 2H), 7.67-7.67 (m, 2H), 7.37-7.35 (m, 2H), 7.16 (s, 2H), 7.21 (s, 1H), 6.85 (s, 1H), 6.60 (d, J=8.8 Hz, 2H), 4.27 (s, 2H), 3.28 (s, 6H), 3.32 (s, 4H), 3.11 (s, 4H). ESI-MS: m/z=588 [M+H+]