Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:14]([O:16][SiH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH3:15]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[CH2:14]([O:16][Si:17]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[CH2:3][CH2:2][CH2:1][N:4]1[CH2:9][CH2:8][N:7]([Si:10]([CH3:11])([CH3:13])[CH3:12])[CH2:6][CH2:5]1)[CH3:15]
Reactant: C=CCN1CCN([Si](C)(C)C)CC1
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN1CCN([Si](C)(C)C)CC1)(OCC)OCC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 99.2 g (0.5 mole) of 1-allyl-4-trimethylsilylpiperazine and 0.65 g of a toluene solution of platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (platinum content 3 wt %) and heated at 70° C. Once the internal temperature became constant, 82.2 g (0.5 mole) of triethoxysilane was added dropwise over 4 hours. Stirring was continued for a further one hour at the temperature. The reaction solution was distilled, collecting 137.5 g of a fraction having a boiling point of 119-122° C./50 Pa.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: O
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Yield: 91.2 %

Procedure:
In a 200 mL three-neck flask, 6.4 g (25 mmol) of 9-bromoanthracene, 3.0 g (25 mmol) of phenylboronic acid, 0.76 g (2.5 mmol) of tri(ortho-tolyl)phosphine, 60 mL of 1,2-dimethoxyethane (DME), and 25 mL of a 2.0 M potassium carbonate aqueous solution were added. The mixture was degassed by being stirred under reduced pressure, and the atmosphere in the flask was replaced with nitrogen. To the mixture, 0.11 g (0.50 mmol) of palladium(II) acetate was added and stirred under a nitrogen stream at 80° C. for 3 hours. After a predetermined time, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with saturated saline, and the organic layer was dried with magnesium sulfate. The obtained mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was concentrated to give a solid. The obtained solid was recrystallized with toluene/methanol to give 5.8 g of white powder, which was the object of the synthesis, in a yield of 92%.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11]([O:13]C)=O)[N:8]=1)([O-:3])=[O:2].[F:17][C:18]([F:24])([CH2:22][NH2:23])[C:19]([NH2:21])=[O:20]>CO>[N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:16])([F:15])[C:11]([NH:23][CH2:22][C:18]([F:24])([F:17])[C:19]([NH2:21])=[O:20])=[O:13])[N:8]=1)([O-:3])=[O:2]
Reactant: NCC(F)(F)C(N)=O
Reactant: COC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Solvent: CO
Product: NC(=O)C(F)(F)CNC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Yield: 35.8 %

Procedure:
To a solution of methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionate (10.0 g, 42.5 mmol) in methanol (60 ml), 2,2-difluoro-3-amino-propionic acid amide (10.4 g, 83.8 mmol) was added and reacted for 20 hours at a room temperature while stirring. Then, insoluble fraction was filtered off from the reaction mixture. The filtrate was concentrated, subjected to silica gel column chromatography and recrystallized from ethanol to obtain 3-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropionylamino]-2,2-difluoropropionic acid amide (4.98 g). m.p. 134.5°-135.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[OH:20][C:21]([C:24]1[O:28][N:27]=[C:26]([C:29](O)=[O:30])[CH:25]=1)([CH3:23])[CH3:22]>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:26]3[CH:25]=[C:24]([C:21]([OH:20])([CH3:22])[CH3:23])[O:28][N:27]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: CC(C)(O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (120 mg, 0.431 mmol) and 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (96 mg, 0.560 mmol). The product was triturated with ethanol. Yield 67 mg (36%). 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 1.47 (s, 6H), 4.31-4.33 (m, 2H), 4.40-4.49 (m, 1H), 6.49 (s, 1H), 7.01 (d, 1H), 7.84 (d, 1H), 7.85-7.88 (m, 1H), 7.99 (s, 1H), 8.74 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6])[CH3:2].[CH3:15][Mg]Br.O>CCOCC>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)([OH:6])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cccc(Br)c1
Reactant: C[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1cccc(Br)c1
Yield: 70 %

Procedure:
To a solution of (3-Bromo-phenyl)-oxo-acetic acid ethyl ester (2.5 g, 9.8 mmol) in ether (20 mL) at 0° C. was added methyl magnesium bromide (10.8 mmol, 3 M in ether, 3.6 mL) with stirring. The reaction was stirred at 0° C. for 15 min. Water was added and the crude partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexane to afford 2-(3-bromo-phenyl)-2-hydroxy-propionic acid ethyl ester as a colorless liquid. (1.87 g, 70% yield). MS: m/z 273 (M+H+).
Reaction SMILES: C([O:14][C:15]([C:17]1[O:18][C@@H:19]([C:35](=[O:41])[N:36]([CH3:40])[CH2:37][CH2:38][CH3:39])[C@H:20]([NH:31][C:32](=[O:34])[CH3:33])[C@@H:21]([NH:23]C(OC(C)(C)C)=O)[CH:22]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:32]([NH:31][C@H:20]1[C@H:19]([C:35](=[O:41])[N:36]([CH3:40])[CH2:37][CH2:38][CH3:39])[O:18][C:17]([C:15]([OH:16])=[O:14])=[CH:22][C@@H:21]1[NH2:23])(=[O:34])[CH3:33]
Reactant: CCCN(C)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](N)[C@H]1NC(C)=O
Reaction time: 3 h

Procedure:
(4S,5R,6R)-5-Acetylamino-4-(tert-butoxycarbonylamino)-6-(methyl-propylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid benzhydryl ester (0.10 g) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and left to stand at 23° C. for 3 hours. The solvent was removed in vacuo and the residue was triturated using diethyl ether (30 ml). The resulting solid was collected by filtration and dried to give the title compound as a white solid. (0.064 g): 1H NMR (250MHz, D2O) 5.99 (1H, m), 5.24 (1H, m), 4.52 (1H, m), 4.25 (1H, m), 3.59-3.18 (2H, m), 3.18+2.97 (3H, s), 2.02 (3H, s), 1.72-1.46 (2H, m), 0.87 (3H, m); Mass Analysis: C15H22F3N3O7. 0.25H2O. Required C, 43.12; H, 5.43; N, 10.06; Found C, 42.99; H, 5.60; N, 10.17; Mass Spec. (Low Resolution) MH+ =300.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:17]2[CH2:21][O:20]C3(CCCCC3)[O:18]2)[NH:10][S@](C(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CC(O)C.O1CCOCC1>O.C(Cl)Cl>[ClH:1].[NH2:10][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C@H:17]([OH:18])[CH2:21][OH:20]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC2(CCCCC2)O1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](O)CO
Reaction time: 1 h
Yield: 187.7 %

Procedure:
To a solution of 250 (1.8 g, 4.3 mmol) and DCM (5 mL) was added a solution of HCl in IPA (7.1 mL, 43 mmol) and the reaction was stirred for 1 h. The reaction concentrated to dryness and 4M HCl in dioxane (5 eq) and H2O (1 mL) was added to cleave the cyclohexyl ketal. The reaction was stirred for 1 h and then concentrated to dryness to afford 1.1 g (94%) of (2S,3S)-3-amino-3-(3,4-dichlorophenyl)propane-1,2-diol hydrochloride (252).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(=O)(O)[O-].[Na+].[CH2:30]([O:32][C:33](Cl)=[O:34])[CH3:31]>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:33]([O:32][CH2:30][CH3:31])=[O:34])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OCC)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added sodium bicarbonate (865 mg, 10.3 mmol), ethylchloroformate (0.147 ml, 1.54 mmol). The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 425 mg (98%) of the product as a solid. MS-ES: m/z 424.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[N:6][CH:7]=1.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[N:9]=[CH:10]2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: Fc1ccc(-c2c[nH]cn2)nc1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(-n2cnc(-c3ccc(F)cn3)c2)c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
In a screw-cap vial, added 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g, 0.30 mmol), 3-Fluorobenzonitrile (0.04 ml, 0.36 mmol), potassium carbonate (0.21 g, 1.5 mmol) and dimethylformamide (1 ml). Stirred the resulting reaction mixture at 110° C. overnight. Cooled the reaction mixture to room temperature, diluted with chloroform (50 ml), sequentially washed with water (50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was triturated with 10% diethyl ether in hexanes to yield the title compound (45 mg) as a dirty yellow colored solid. 1H-NMR (CDCl3), δ (ppm): 8.43 (d, 1H), 8.04 (dd, 1H), 7.93 (dd, 2H), 7.70 (m,4H), 7.48 (dt, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH:38]([C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=2[F:55])[C:39]2[N:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41][CH:40]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH:38]([C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=2[F:55])[C:39]2[CH:40]=[CH:41][C:42]([C:45]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:46])=[CH:43][N:44]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: NCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.9 %

Procedure:
Triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and aminomethylcyclohexane (30 μl, 0.23 mmol) were added to a solution of the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol), which had been obtained in Example 338, in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with hexane:ethyl acetate=3:1 was concentrated under reduced pressure, whereby the title compound (58 mg, 0.11 mmol, 59%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28]>CO.C(NCC)C>[CH2:5]([N:6]([CH2:7][CH3:8])[CH2:25][CH2:24][S:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]3[CH:30]=[C:31]([F:33])[CH:32]=[C:2]([F:1])[CH:3]=3)[CH:12]=2)=[CH:19][CH:18]=1)(=[O:23])=[O:22])[CH3:4]
Reactant: C=CS(=O)(=O)Nc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Solvent: CO
Solvent: CCNCC
Product: CCN(CC)CCS(=O)(=O)Nc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Yield: 29 %

Procedure:
89 mg of 4-[(3,5-difluorobenzyl)amino]-6-({4-[(vinylsulfonyl)amino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 303) was dissolved in 1 mL of methanol, to which 0.28 mL of diethylamine was added, and stirred using a microwave reaction apparatus in an argon atmosphere at 120° C. for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:ammonia methanol=10:1), and solidified in acetone-ether to obtain 41 mg (yield 29%: 2 steps) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([O:11][CH2:15][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Reactant: CCI
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1I

Procedure:
This compound was prepared according to the procedure of Example 13 Step 3, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone and iodoethane as the starting materials. LCMS calculated for C10H10ClFIO2 (M+H)+: m/z=342.9; Found: 342.9.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[NH:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]4[C:3]=3/[C:4](=[CH:15]/[C:16]3[NH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])/[C:5](=[O:14])[NH:6]4)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4[nH]ccc4c3)c21
Temperature: 90 °C

Procedure:
A solution of (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (112 mg, 0.31 mmol) (Starting Material 6), 5-indoleboronic acid (71 mg, 0.44 mmol) (from Example 40, Step A, supra) and sodium carbonate (110 mg, 1.03 mmol) were dissolved in 10 mL DMF and 5 mL water. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time, dichlorobis(triphenylphosphine) palladium(II) (11 mg) (Aldrich) was added, and the reaction was heated, under argon, at 90° C. for 2 days. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH/CHCl3 to give (Z)-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as a red powder. (Yield 38 mg, 76%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:7][C:8]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1OC
Temperature: 60 °C
Yield: 53.6 %

Procedure:
33.71 g (0.32 mol) of sodium carbonate were dissolved in 250 ml of water and heated to 60° C. 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxybenzoic acid were introduced into the solution, and 29.55 g (0.14 mol) of 4-chlorobenzenesulfonyl chloride were added in portions to this solution over the course of 15 min. After the mixture had been cooled, the residue was filtered off with suction and taken up in 1% strength sodium bicarbonate solution and, after filtration, the product was precipitated by adding 1 N hydrochloric acid. 25.90 g (55%) of 2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoic acid of melting point 212-214° C. were obtained. 25.90 g (0.07 mol) of 2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoic acid were suspended in 75 ml of toluene and, after addition of 17.30 g (0.08 mol) of phosphorus pentachloride, the mixture was stirred at 40-45° C. for 2.5 h. It was then concentrated to half the volume in vacuo, and the precipitated product was filtered off with suction and washed with a little toluene. 25.30 g (93%) of 2-(4-chlorophenylsulfonylamino)-4,5-dimethoxybenzoyl chloride, of melting point 175-177° C., were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([O:17]COC)[CH:14]=[C:13]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:12]=1
Reactant: COCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
After adding 60 ml of trifluoroacetic acid to a solution of 30.9 g (84.3 mmol) of the obtained 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester in methylene chloride (100 ml) while cooling on ice, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=1:1) to obtain 15.2 g of 5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid methyl ester (yield: 56%) as a white solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[CH:29]1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[O:40][CH3:41])[CH2:32][CH2:31][CH2:30]1.[NH4+].[Cl-]>O.C1COCC1>[CH:29]1([C:33]2[CH:38]=[CH:37][C:36]([B:16]([OH:21])[OH:17])=[C:35]([F:39])[C:34]=2[O:40][CH3:41])[CH2:30][CH2:31][CH2:32]1
Reactant: COc1c(F)cccc1C1CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C2CCC2)ccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 57.9 %

Procedure:
To a 500 mL round-bottom flask were added a stir bar, dry THF (83 mL) and 2,2,6,6-tetramethylpiperidine (11 mL, 65 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (25 mL, 62.5 mmol) over 2 min. The resultant mixture was stirred for 5 min and then allowed to warm to 0° C. After 35 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (14 mL, 60 mmol) over 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (10.0 g, 55.6 mmol) and dry THF (27 mL) was added over the course of 6 min and stirring continued for 3.5 hours before adding saturated NH4Cl (200 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL×3), the combined extracts dried over MgSO4, filtered and concentrated to dryness to give the crude product as an off-white solid. The crude product was subjected to FCC to give the title compound (7.21 g). 1HNMR (400 MHz, CD3OD): δ 7.11-7.07 (m, 2H), 3.38 (s, 3H), 3.82-3.80 (m, 1H), 2.37-2.33 (m, 2H), 2.19-2.11 (m, 3H), 2.09-1.90 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:15][C:16]1([N:29]2[CH2:34][CH2:33][NH:32][CH:31]([CH3:35])[CH2:30]2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C(Cl)(Cl)(Cl)Cl>[CH3:15][C:16]1([N:29]2[CH2:34][CH2:33][N:32]([CH:7]3[C:6]4[C:10](=[CH:11][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:4][CH:5]=4)[C:9](=[O:12])[CH2:8]3)[CH:31]([CH3:35])[CH2:30]2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]1
Reactant: O=C1C=Cc2ccc(C(F)(F)F)cc21
Reactant: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
A solution of 6-(trifluoromethyl)-1H-inden-1-one (100 mg, 0.505 mmol) and tert-butyl 4-methyl-4-(3-methylpiperazin-1-yl)piperidine-1-carboxylate (420 mg, 1.412 mmol) in carbon tetrachloride (8.00 mL) was heated at 60° C. for 18 h with stirring. After evaporation of solvent, the residue was purified on silica gel to give two diastereomers (3/1 ratio). Yield 180 mg (72%). LC-MS [M+1]=496.4.