Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>>[N:32]1([C:30]([C:25]2[CH:24]=[CH:29][CH:28]=[CH:27][C:26]=2[C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=3)=[N:13][CH:14]=2)=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Product: Nc1ncc(-c2ccc(-c3ccccc3C(=O)N3CCOCC3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. for C20H19N5O2, 361.15; m/z found, 362.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 2H), 8.69-8.64 (m, 1H), 7.95-7.87 (m, 2H), 7.64-7.59 (m, 1H), 7.58-7.51 (m, 2H), 7.49-7.42 (m, 1H), 3.69-3.54 (m, 3H), 3.48-3.33 (m, 2H), 3.20-3.07 (m, 1H), 2.97-2.80 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.022 g of product in 70% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[N+:9]([O-])=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH:12]=3)[CH:7]=1.[CH:26]([N:29](CC)C(C)C)(C)C.C[Si](C#N)(C)C>C(#N)C.C(OCC)(=O)C>[C:26]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:25])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2)#[N:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c[n+]1[O-]
Agent: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C#N)n1
Temperature: 100 °C
Yield: 28.9 %

Procedure:
To a slurry of 3-(5-fluoro-2-methylphenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (50 mg, 0.1 mmol) in acetonitrile (0.4 mL) was added N,N-diisopropylethylamine (0.05 mL, 0.3 mmol), followed by trimethylsilyl cyanide (0.06 mL, 0.44 mmol). The mixture was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as a white solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 9.52 (s, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 7.48-7.35 (m, 2H), 7.26 (td, J=8.5, 2.8 Hz, 1H), 2.37 (s, 3H), 2.13 (m, 1H), 0.99-0.83 (m, 4H). LCMS (Method E): RT 5.495 min, M+H+=347.1.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[N:14][CH:13]=[C:12]([CH2:18][CH3:19])[N:11]=1)[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([C:15]1[C:10]([NH:9][C@H:5]2[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:8][N:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]2)=[N:11][C:12]([CH2:18][CH3:19])=[CH:13][N:14]=1)[CH3:17]
Reactant: COC(=O)Cl
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)cnc1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (4.50 g, 17 mmole) in CH2Cl2 (0.1 M, 170 mL) under N2 at 0° C. was added triethyl amine (7.09 mL, 3.0 eq.). Methyl chloroformate (1.44 mL, 1.1 eq.) was added drop-wise over 15 min. After 1 hour, the reaction mixture was poured into saturated aqueous NaHCO3 (150 mL). The aqueous layer was extracted with CH2Cl2 (1×200 ml), dried with MgSO4, filtered and concentrated. Purification with Biotage MPLC (40 g, 10-50% ethyl acetate in heptane gradient) provided 5.35g (98%) of methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2972, 2937, 2877, 2338, 1937, 1708, 1581, 1546, 1499, 1453, 1392, 1189, 1174, 1135, 1103 (s) cm−1 HRMS (ESI) calcd for C16H26N4O3+H1 323.2083. found 323.2089. Anal. Calcd for C16 H26 N4O3: C, 59.61; H, 8.13; N, 17.38. Found: C, 59.23; H, 8.35; N, 17.33.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].C[Sn](C)(C)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: C[Sn](C)(C)c1nccs1
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2nccs2)cc(NC(C)=O)c1Cl
Yield: 29.6 %

Procedure:
A solution of methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (1.0 g, 4.05 mmol), 2-(trimethylstannyl)thiazole (2.9 g, 17.3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.6 mmol) in tetrahydrofuran (75 mL) was heated under reflux for four hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was dried (MgSO4) and concentrated. The crude product was purified by column chromatography (50% ethyl acetate in hexane) to give methyl 4-acetamido-3-chloro-6-(2-thiazolyl)pyridine-2-carboxylate (0.38 g, 1.2 mmol), mp 187-8° C.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:14]2[CH2:13][CH2:12][S:11][C:10]=2[C:9]([O:15]C)=[CH:8][CH:7]=1.OC1C2N=CSC=2C=CC=1>>[F:5][C:6]1[C:14]2[CH2:13][CH2:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c2c1SCC2
Agent: BrB(Br)Br
Agent: Oc1cccc2scnc12
Product: Oc1ccc(F)c2c1SCC2

Procedure:
A BBr3 demethylation of 4-fluoro-7-methoxy-2,3-dihydrobenzo[b]thiophene similar to that described for 4-hydroxy benzothiazole affords the title compound as a brown solid 251 mg: δH (300 MHz, CDCl3) 6.57-6.48 (2H, m, ArH), 4.67 (1H, br. s, OH) and 3.43-3.23 (4H, m, SCH2CH2).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:15]([CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 50 g (0.14 mol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 23.6 g (0.36 mol) of sodium azide, and 250 ml of dimethylformamide was stirred at room temperature for 1.5 hours. The mixture was poured into 1.5 liters of water, and the aqueous solution was made basic with solid sodium carbonate. The resulting precipitate was filtered, washed well with water, and dried, thereby affording 30.6 g (93%) of 2-azido-1-(2-guanidino-4-thiazolyl)-ethanone as a light brown crystalline solid, mp 177° (dec). Analytically pure material can be prepared by recrystallization from absolute ethanol: Calcd. for C6H7N7OS: C, 32.00; H, 3.13; N, 43.53; S. 14.24; found: C, 32.22; H, 3.43; N, 41.93; S, 13.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[C:28]1([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]1)[C:29](=[O:42])[N:30]2[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.BrC1C=CC=C2C=1C1(C3C(=CC4OCCOC=4C=3)OC1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[C:28]2([C:54]4=[CH:53][C:48]5[O:49][CH2:50][CH2:51][O:52][C:47]=5[CH:46]=[C:45]4[O:44][CH2:43]2)[C:29](=[O:42])[N:30]3[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: OB(O)c1cnc2ccccc2c1
Product: COc1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3Cc2ccccn2)cc1

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 4-methoxyphenyl boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (68%) as a colorless solid: mp 205-206° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.59 (d, J=4.7 Hz, 1H), 7.65-7.68 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.84 (m, 2H), 6.78-6.61 (m, 4H), 6.41 (s, 1H), 6.25 (s, 1H), 5.26 (d, J=15.8 Hz, 1H), 4.92 (d, J=15.8 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.36 (d, J=9.0 Hz, 1H), 4.27-4.08 (m, 4H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 158.9, 155.6, 155.5, 149.5, 144.6, 142.6, 140.0, 137.9, 137.1, 130.9, 129.8, 129.0, 128.7, 125.7, 122.9, 122.8, 121.7, 113.2, 111.1, 108.5, 99.4, 64.6, 64.0, 58.5, 55.3, 46.2; MS (ES+) m/z 493.0 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH3:11])=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cn1ccc(C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccn(CC(=O)NN)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (3-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. The mixture was then cooled to rt and the precipitated product was filtered off and crystallized from ethanol. The title compound (>95% purity) was obtained as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.12 (s, 3H), 4.29 (s, 2H), 4.60 (s, 2H), 6.00 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:22]([O:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: O=C(CO)Nc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCC(=O)Nc1ccccc1

Procedure:
4.36 g (28.8 mmol)) of 2-hydroxy-N-phenylacetamide, 0.8 ml (5.74 mmol) of triethylamine and 6.5 ml (84.3 mmol) of diketene were heated at 70° C. under stirring in 50 ml of toluene for 7.5 hours. After the addition of a saturated aqueous sodium hydrogencarbonate solution at room temperature followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[CH3:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH2:27][CH2:26][CH2:25]2>>[CH3:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:9]([C:8]1[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=1)=[O:11])[CH2:27][CH2:26][CH2:25]2
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-(3-trifluoromethyl-phenoxy)-nicotinic acid in analogy to Example 1, Step 2, by replacing 1,2,3,4-tetrahydro-quinoline with 6-methyl-1,2,3,4-tetrahydro-quinoline ([CAS RN 91-61-2]). MS (ISP): 413.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].P.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][SH:32])=[CH:27][CH:26]=1>[Pd]>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=[C:2]([S:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: P
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriate solvent is added base under nitrogen atmosphere, followed by Pd catalyst, phosphine ligand and (4-methoxyphenyl)methanethiol. The reaction is generally carried out at high temperature (80-130° C., prefer 90-110° C.) and normally complete within several hours (8-24 h, prefer 12-18 h). Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH:12]=[CH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9].CC([O-])=O.[Na+]>CC(N(C)C)=O.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1(/[C:13](/[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:20])=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CCOC(=O)C=CCC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C(/CC(=O)OCC)c1ccccc1
Temperature: 130 °C
Yield: 28 %

Procedure:
A solution of iodobenzene (1.08 ml, 9.67 mmol) in DMA (5 ml) was added dropwise to a solution of diethylglutaconate (2 g, 10.74 mmol), Pd(OAc)2 (250 mg, 1.07 mmol), NaOAc (880 mg, 10.74 mmol) in DMA (5 ml) at 115° C. under argon. After heating for 8 hours at 130° C., the reaction was cooled, diluted with CH2Cl2 (60 ml), and washed with water (4×10 ml). The organic layer was washed with sat. aq. NaHCO3 (20 ml), brine (20 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The dark oil was purified by column chromatography using CH2Cl2 as the eluent. The product oil was dried overnight in vacuo giving diethyl (2Z)-3-phenylpent-2-ene-1,5-dioate in 28% yield.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[OH-].[NH4+:16]>C(O)C>[NH2:16][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
5-Chlorosulfonyl-2-oxindole (2.1 g) was added to 10 mL of ammonium hydroxide in 10 mL of ethanol and stirred at room temperature overnight. The mixture was concentrated and the solid collected by vacuum filtration to give 0.4 g (20% yield) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([OH:22])[CH:20]=[CH2:21])[C:3]=1[CH3:23].C(N(CC)CC)C.[Si:31](OS(C(F)(F)F)(=O)=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:22][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:20]=[CH2:21])[C:3]=1[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(O)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(O[Si](C)(C)C(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a stirring 23° C. DCM solution (32 mL) of 1-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)prop-2-en-1-ol (1.47 g, 3.79 mmol) and triethylamine (2.3 mL, 16.5 mmol) was added TBDMS-OTf (2.0 mL, 11.65 mmol) and the reaction was stirred and monitored by TLC. After 45 minutes, an additional 2 mL of TBDMSOTf was added and the mixture allowed to stir overnight. The dark mixture was then quenched 10% NaHCO3 and the color dissipated. The mixture was washed with brine, dried with sodium sulfate and concentrated in vacuo. Column chromatography using silica gel with EtOAc in hexanes gave desired silylated product (1.60 g, 84% yield). 1H-NMR: (400 MHz, CDCl3): δ 8.39 (d, J=8.4 Hz, 1H); 7.55-745 (m, 3H); 7.34-7.30 m, 1H); 7.26-7.24 (m, 1H); 7.24-7.18 (d, J=8.0 Hz, 1H); 7.16-7.14 (m, 1H); 6.09-6.01 (m, 1H); 5.32-5.30 (m, 1H); 5.13-5.03 (m, 2H); 2.77 (s, 3H); 0.87 (s, 6H); 0.83 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([NH:21][C:18]2[C:17]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:43])=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccsc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccsc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-3-yl)pyrazin-2-amine (7g) (450 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.5 mg, 127 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11g (512 mg, 809 μmol, 69.0%) as a yellow solid. Rf=0.22 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.94 (s, 9H), 3.56 (s, 2H), 6.72-6.82 (AA′BB′, 2H), 6.93-7.02 (AA′BB′, 2H), 7.12-7.22 (AA′BB′, 2H), 7.50 (dd, 1H, J=2.9, 5.0 Hz), 7.59 (d, 1H, J=5.0 Hz), 7.81 (d, 1H, J=2.9 Hz), 8.04-8.12 (AA′BB′, 2H), 8.91 (s, 1H), 10.50 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.90, 17.95, 25.50 (3C), 25.54 (3C), 41.9, 119.6 (2C), 120.3 (2C), 125.7, 126.0, 127.7, 127.9, 128.2 (2C), 128.8, 130.5 (2C), 137.1, 138.2, 142.0, 143.5, 148.0, 153.9, 156.8, 169.9; IR (KBr, cm−1) 517, 669, 712, 741, 781, 806, 839, 914, 1007, 1082, 1105, 1169, 1261, 1341, 1362, 1441, 1472, 1508, 1605, 1665, 2857, 2886, 2930, 2955, 3057, 3227; HRMS (ESI+) m/z 654.2618 ([M+Na]+, C34H45N3NaO3Si2+ requires 654.2612).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH:25]=O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:25][C:17]1[NH:16][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:5])=[O:4]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[CH3:19]
Reactant: CCI
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)CCC2=O
Reaction time: 144 h
Yield: 99.3 %

Procedure:
5-Hydroxy-1-indanone (2.5 g, 16.0 mmol) was dissolved in acetone (60 ml) and potassium carbonate (waterfree, 5.15 g, 36.9 mmol) and ethyl iodide (2.88 ml, 35.3 mmol) were added. The reaction was stirred at it under an atmosphere of nitrogene for 6 days. The mixture was filtered, the filtrate collected and the solvent evaporated at reduced pressure. Chromatography on silica (flashmaster, hex to hex/EtOAc 2/3 in 20 min, 15 min hex/EtOAc 2/3) gave the product as off-white solid (2.8 g, 99%). [1H-NMR (DMSO-d6, 600 MHz) δ 7.54 (d, 1H), 7.07 (s, 1H), 6.94 (d, 1H), 4.13 (q, 2H), 3.05-3.03 (m, 2H), 2.58-2.56 (m, 2H), 1.35 (t, 3H); LCMS RtJ=0.88 min; [M+H]+=177.2]
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[O:19]1[CH2:23][CH2:22][NH:21][C:20]1=[O:24]>>[O:17]=[S:13]1(=[O:18])[CH2:14][CH2:15][CH2:16][N:12]1[C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][O:19][C:20]2=[O:24])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: O=C1NCCO1
Product: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Yield: 37.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoate (2 g) described in Preparation Example 116 and oxazolidin-2-one (515 mg), the title compound (758 mg) was obtained.