Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:9]=2[S:8](=[O:22])(=[O:21])[CH:7]=1)C.[OH-].[Li+]>CO>[CH3:20][S:17]([NH:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][S:8](=[O:21])(=[O:22])[C:9]=2[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of (7-methane sulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (prepared as described in US patent application US 2008/0031852, 600 mg, 1.666 mmol) in methanol (30 mL) was cooled to 0° C. in an ice-water bath and treated with 2.0M aqueous lithium hydroxide solution (4.17 mL, 8.332 mmol). The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. The methanol was removed in vacuo and the reaction mixture was poured into 0.5M aqueous hydrochloric acid solution (20 mL) on ice, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford an orange solid. The crude solid was triturated with diethyl ether to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (409 mg, 1.232 mmol, 73.9%), as a yellow solid. LC-MS calcd for C11H12N2O6S2 332.4, found 333.0 [M+H+].
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([O:6][Si:7]([O:16][CH:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])([O:9][CH:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:11])[OH:8])[CH3:5].C(N(CC)CC)C.[CH3:31][C:32]1C=C(O)C=C[C:33]=1[OH:34].C(Cl)(=O)C=C>C1(C)C=CC=CC=1>[C:33]([O:8][Si:7]([O:6][CH:4]([CH2:3][CH:2]([CH3:23])[CH3:1])[CH3:5])([O:16][CH:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])[O:9][CH:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[CH3:11])(=[O:34])[CH:32]=[CH2:31]
Reactant: CC(C)CC(C)O[Si](O)(OC(C)CC(C)C)OC(C)CC(C)C
Reactant: Cc1cc(O)ccc1O
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](OC(C)CC(C)C)(OC(C)CC(C)C)OC(C)CC(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.23 moles of tris(4-methyl-2pentoxy)silanol, 0.23 moles of triethylamine, 0.02 gms. of methyl hydroquinone as polymerization inhibitor and 82 cc of toluene were placed in a three necked flask equipped with a stirrer, addition funnel, a thermometer and a condenser. A solution of 0.23 moles of acryloyl chloride in 23 cc of toluene was added slowly to the reaction mixture at 3°-5° C. At the end of the addition, the mass is allowed to stir for 1/2 hour at 5° C. The solid triethylamine hydrochloride was filtered and the solvent was distilled under vacuum. The residual crude product was distilled (bp 148°-162° C./3 mm/Hg) to give 41 gms. of product (G.C. purity 80%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:34]([F:33])[CH:35]=3)[N:7]=2)[CH:16]=1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1
Reactant: Nc1cccc(F)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
The title compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (0.070 g) and 3-fluoroaniline (0.033 g) using the procedure described in Example 30, step E. The title compound was isolated as a white solid (0.048 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 2H), 6.54 (d, 1H, J=5.52 Hz), 6.70 (m, 1H), 6.94 (m, 2H), 7.24 (m, 2H), 7.34-7.45 (m, 3H), 7.60 (m, 1H), 7.68-7.77 (m, 2H), 7.87 (s, 1H), 8.29 (d, 1H, J=5.52 Hz), 8.51 (m, 1H), 9.16 (m, 1H), 9.81 (s, 1H), 10.32 (s, 1H). ES-LC/MS m/z=539 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17]O)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6]2.[S:19](=O)(=[O:22])([OH:21])[OH:20]>>[NH2:1][C:2]1[N:3]([CH2:16][CH2:17][S:19]([OH:22])(=[O:21])=[O:20])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6]2
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1nc2nn(CCO)c(N)c2c(=O)[nH]1
Product: CC(C)(C)c1nc2nn(CCS(=O)(=O)O)c(N)c2c(=O)[nH]1
Reaction time: 3 h

Procedure:
3-Amino-2-(2-hydroxyethyl)-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (5 g) prepared as in Example 52 was added to concentrated sulphuric acid (10 ml). The solution was kept at 130°-135° C. for 3 hours, then cooled and poured onto ice (30 g). The precipitate which formed was filtered off, water washed and dissolved in 2 M sodium hydroxide solution. A trace of solid was filtered off, and the filtrate was acidified with concentrated hydrochloric acid to re-precipitate the title compound (4.4 g), m.p. 307°-309° C. decomp.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:19])[CH3:20])[C:9]=2[S:8][C:7]=1[CH:26]([C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[OH:27])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2C(C)C
Product: CCOC(=O)c1c(C(O)c2ccc(F)cc2)sc2c1c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared by the method of example 15 part a) using 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester and 4-fluorobenzaldehyde.
Reaction SMILES: [C:1]1(=[CH:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([OH:24])=O)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>C1(C)C=CC=CC=1.CN(C=O)C.O>[C:1]1(=[CH:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1C=C1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1C=C1CCCC1

Procedure:
To a magnetically stirred suspension of [4-(3-cyclopentylidenemethyl-4-methoxy-phenyl)piperidin-1-yl]-oxo-acetic acid (1.2 mmol, 0.40 g) in dry toluene (15 mL) at room temperature was added oxalyl chloride (2.0M in CH2Cl2 ; 1.3 mmol, 0.65 mL) dropwise over 10 minutes, followed by DMF (3 drops) to promote gas evolution. The resulting homogeneous solution stirred at room temperature for 45 minutes, at which time saturated NH3 /CH3CN (15 mL) was added dropwise over 15 minutes. A white solid precipitated out of solution as the mixture was stirred for another 3/4 hour. At that time, TLC analysis shows reaction to be complete. The solution was diluted with H2O to dissolve the white precipitate and then the THF was removed in vacuo. The aqueous phase was diluted with saturated aqueous NaHCO3 solution (100 mL) and then extracted with EtOAc (2×200 mL). Each organic phase was washed with H2O (1×100 mL) and then the combined organics were dried (Na2SO4) and concentrated to yield a white solid. This compound was purified via column chromatography (SiO2 : 40% EtOAc/hex) to afford a pure white solid of the title compound as a pure white solid, mp 116°-117° C. (0.7 mmol, 0.231 g, 56%).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](Cl)=[O:5].[NH:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[Cl:1][CH2:2][O:3][C:4]([N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5]
Reactant: O=C(Cl)OCCl
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)OCCl

Procedure:
Using chloroformic acid chloromethyl ester and diethyl iminodiacetate as the raw materials, the same operation as the Example 101(1) gave the title compound as a crude product, and the crude product was used for the next reaction without further purification.
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[N:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1>CO>[N:2]1([C:6]([C:8]2[N:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][OH:34])[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: Cl
Solvent: CO
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
1M Hydrochloric acid (5 mL) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (82 mg, 0.14 mmol) in methanol (5 mL) and stirred at RT for 1 hour. The methanol was removed in vacuo and the residue taken to pH6, extracted into ethyl acetate (3×50 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude yellow oil was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound as a white foam (36 mg). The compound could be crystallised from a mixture of tert-butylmethyl ether and methanol. 1H NMR δ (CDCl3): 1.24 (d, 3H), 1.81 (s, 1H), 2.28 (quin, 2H), 2.48 (s, 3H), 3.67-3.72 (m, 2H), 4.17 (t, 2H), 4.47-4.54 (m, 1H), 4.63 (t, 2H), 6.73 (t, 1H), 7.09 (t, 1H), 7.25 (t, 1H), 7.27-7.30 (m, 1H), 8.01-8.06 (m, 2H), 8.24 (d, 1H), 8.58 (s, 1H), 9.44 (d, 1H); m/z 464 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:16][CH3:25])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1
Yield: 75 %

Procedure:
3-((4-methylpiperidin-1-yl)sulfonyl)benzoic acid (120 mg, 0.424 mmol) was refluxed in the presence of con. Sulfuric acid (2.74 mg, 0.021 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-((4-methylpiperidin-1-yl)sulfonyl)benzoate (100 mg, 0.319 mmol, 75% yield). 1H NMR (CDCl3, 400 MHz): δ 8.39 (m, 1H), 8.25 (m, 1H), 7.94 (m, 1H), 7.62 (t, 1H, J=7.6 Hz), 3.95 (s, 3H), 3.77 (m, 2H), 2.25 (m, 2H), 1.67 (m, 2H), 1.29 (m, 3H), 0.90 (d, 3H, J=4.8 Hz). ESI-MS: 298.1[M+H]+
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[CH:6][CH2:5]1>O.C1COCC1.CO>[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[CH:6][CH2:5]1
Reactant: COC(=O)c1ccc(C2=CCOc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=CCOc3ccccc32)cc1
Temperature: 50 °C
Yield: 89 %

Procedure:
Lithium hydroxide hydrate (0.80 g, 19.0 mmol) dissolved in water (20 mL) was added to a solution of methyl 4-(2H-chromen-4-yl)benzoate from reaction 34b (1.5 gm, 5.7 mmol) in THF (20 mL) and methanol (20 mL) under nitrogen atmosphere at room temperature. The reaction was heated to 50° C. for 2 h, allowed to cool, concentrated then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give 4-(2H-chromen-4-yl)benzoic acid (1.29 g, 89%) as a tan solid. MS found: (M−H)+=251.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=4[S:24][C:23]=3[NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([NH:43][C:44]4[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[CH:54](I)([CH3:56])[CH3:55].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:54]([N:43]([S:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:32](=[O:33])[NH:31][C:23]2[S:24][C:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[C:22]=2[C:20](=[O:21])[NH:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:18][CH:17]=2)[CH:35]=1)(=[O:41])=[O:42])[C:44]1[CH:45]=[CH:46][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=1)([CH3:56])[CH3:55]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Nc5ccc(C(=O)OC)cc5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CC(C)I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(c5ccc(C(=O)OC)cc5)C(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 350 mg of methyl 4-({[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate, 0.070 mL of isopropyl iodide, 193 mg of potassium carbonate, and 3.5 mL of DMF was stirred at 80° C. overnight. Further, 0.14 mL of isopropyl iodide was added thereto, followed by further stirring at 80° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 264 mg of methyl 4-(isopropyl {[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C(O)(=O)C.Cl>COC(C)(C)C.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(O)cc1
Temperature: 190 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A 22-L 4-necked round bottom flask was equipped with a condenser, nitrogen inlet, thermometer lead and overhead stirring apparatus. The flask was charged with 4-(4-methoxyphenyl)butyric acid (2250 g, 11.58 moles) followed by pyridine hydrochloride (5360 g, 46.34 moles, 4 eq). The resulting mixture of the two solids was heated under nitrogen to 185-195° C., with stirring commencing by 50° C. The flask contents were held at 185-195° C., and reaction progress was monitored by TLC (50/50 v/v hexanes/ethyl acetate+1% v/v acetic acid, panisaldehyde stain for visualization). After two hours, TLC analysis indicated complete consumption of starting material. The heat source was removed and the mixture allowed to cool to 90° C., after which 5N HCl (2900 mL, 14.47 moles, 1.25 eq) and H2O (2700 mL) were added sequentially. Stirring was continued until the pot temperature reached 35° C. The mixture was transferred to a 22-L bottom-outlet flask and diluted with t-butyl methyl ether (MTBE, 6000 mL). The layers were separated and the aqueous portion was reextracted with MTBE (3×4000 mL). The organic portions were combined and back-washed with 5N HCl (750 mL). After drying (Na2SO4) and filtration, the solution was concentrated in vacuo to afford the title compound as a white solid (2020 g, 96.7%). 1H NMR (500 MHz, DMSO-d6) δ 1.70 (m, 2H), 2.15 (t, 2H), 2.45 (t, 2H), 3.33 (s, 1H), 6.65 (d, 2H), 6.95 (d, 2H). 13C NMR (DMSO-d6) δ 26.5, 32.5, 33.5, 114.6, 129.0, 131.2, 155.3, 174.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]([F:68])([F:67])[O:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][S:55]([C:58]2[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=2)(=[O:57])=[O:56])=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:61]2[CH:62]=[CH:63][C:58]([S:55](=[O:56])(=[O:57])[NH:54][C:51]3[CH:50]=[CH:49][C:48]([O:47][C:46]([F:67])([F:45])[F:68])=[CH:53][CH:52]=3)=[CH:59][CH:60]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Nc1ccc(OC(F)(F)F)cc1)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C
Temperature: 25 °C

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.10 g, 0.25 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.015 g, 0.055 mmol), palladium (II) acetate (0.006 g, 0.027 mmol), 4-(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)phenyl-boronic acid (0.118 g, 0.33 mmol) and a 2 M aqueous solution of sodium carbonate (0.6 mL, 1.2 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours. The reaction was cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to {6-chloro-3-methyl-4-[4-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 23%) as a solid. MS calcd. for C27H20ClF3NO5S [(M−H)−] 562, obsd. 562.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]S(C)(=O)=O)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][N:32]=[N+:33]=[N-:34])=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CC(CN=[N+]=[N-])=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of {6-[(methane-sulfonyl)methyl]-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 23, (1.62 g, 3.52 mmol) in DMF(10 mL) is added sodium azide at room temperature. The reaction is then heated to 50° C. and stirred 18 hours after which time the solution is diluted with water. The resulting solution is extracted three times with CH2Cl2 (70 mL), the organic layers combined and washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the resulting residue is purified by HPLC to afford 0.46 g (59% yield) of the desired product. 1H NMR (CDCl3) δ 9.49–9.46 (m, 1H), 9.21–9.19 (d, J=6.9 Hz, 1H), 8.48–8.46 (m, 1H), 7.81–7.74 (m, 2H), 7.69–7.60 (m, 2H), 5.83–5.81 (m, 1H), 5.51–5.43 (m, 1H), 4.76–4.69 d, d, J=17.4, 2.4 Hz, 1H), 4.46–4.40 (d, J=17.4 Hz, 1H), 4.20–4.14 (d, J=17.7 Hz, 1H), 3.84–3.76 (d, J=13.2 Hz, 1H), 3.74–3.70 (m, 3H), 3.68–3.64 (d, J=13.2 Hz, 1H), 3.44–3.39 d, J=17.7 Hz, 1H), 2.99–2.92 (d, d, J=18.3, 3.9 Hz, 1H), 2.50–2.40 (d, d, J=15.6, 14.7 Hz, 1H); MS 409 (M+H)+.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:4]([SiH:2]([Cl:3])[Cl:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[SiH2]Cl
Reactant: C=Cc1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl[SiH](Cl)CCc1ccccc1
Yield: 99.2 %

Procedure:
73.2 g (725 millimol) of dichlorosilane, and 92.7 g (890 millimol) of styrene were reacted in the presence of 0.1164 g (1.68×10-4 mol) of chlorotris(triphenylphosphine)rhodium (I) as in example 3 at 100° C. for 16 hours and then the reacted liquid was distilled to obtain 147.6 g of monophenethyldichlorosilane (b.p. 95° C./7 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:8][C:4]1[CH:3]=[C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(Br)ccn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccnc(C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 4-bromo-2-methylpyridine (1.78 mL) in DMF (35 mL) were added ethyl acrylate (8.13 mL), palladium (II) acetate (168 mg), tri-o-tolylphosphine (685 mg) and triethylamine (6.27 mL), and the mixture was stirred at 100° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH:18]=[CH:19][C:9]=3[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=c1c2ccoc2c2cccnc2n1-c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 3,5-dihydro-5-phenyl-furo-[3,2-c][1,8]-naphthyridin-4[2H]-one (2 g.) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 2 g.) in dry toluene (50 ml.) was stirred in an atmosphere of nitrogen and heated to reflux. Refluxing was continued for 20 hrs. After cooling somewhat the mixture was evaporated, dissolved in CH2Cl2, filtered and chromatographed on silica gel eluting with increasing concentrations of ethyl acetate in CH2Cl2 (0-10%). Evaporation of the relevant fractions and recrystallization from acetonitrile yielded the desired product, m.p. 245°-247° C.