Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([S:42]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[C:10]5[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=5[N:12]=[CH:13][N:14]=4)[CH:17]=[N:18]3)[CH2:24]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C5CC5)C4)c3)ncnc21
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a oven dried 2 L round bottom flask equipped with the overhead stirring, a nitrogen inlet, a septa and a thermocouple was charged anhydrous tetrahydrofuran (THF, 800 mL), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (16, 38.6 g, 94.2 mmol) and N,N-diisopropylethylamine (DIEA, 22.0 mL, 126 mmol, 1.34 equiv) at room temperature. The resulting solution was then cooled to 0-5° C. before being charged with cyclopropanesulfonyl chloride (14.3 mL, 134 mmol, 1.42 equiv) portion wise over eight minutes via syringe at 0-5° C. After 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm gradually to room temperature. When HPLC showed that the reaction was complete after 22 h, the reaction mixture was concentrated under reduced pressure to remove about 400 mL of solvent. The residue was treated with ethyl acetate (EtOAc, 500 mL) and the resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL). The aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to yield the crude product (25) as an amber oil. The crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution) to afford {1-(cyclopropylsulfonyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25, 39.4 g, 48.4 g theoretical, 81.4% yield) as a light yellow oil, which solidified upon standing at room temperature in vacuum. For 25: 1H NMR (DMSO-d6, 300 MHz) δ 8.98 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 4.66 (d, 2H, J=9.5 Hz), 4.28 (d, 2H, J=9.3 Hz), 3.69 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 2.84 (m, 1H), 1.01 (m, 4H), 0.82 (t, 2H, J=8.4 Hz), −0.12 (s, 9H) ppm; C23H31N7O3SSi (MW, 513.69), LCMS (EI) m/e 514 (M++H) and 536 (M++Na).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2s1
Reactant: C1CNCCN1
Product: c1ccc2sc(N3CCNCC3)nc2c1

Procedure:
2-Chlorobenzothiazole (5.00 g), is heated in alcohol (75 ml) with 3.05 g piperazine (3.05 g) for 20 hr. 1% mixture is partitioned between methylene chloride/ether and aqueous sodium bicarbonate, the phases are separated, the organic phase is dried with sodium sulfate and concentrated to give 2-piperazinobenzothiazole which is reacted at 70° in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (7.45 g) and potassium carbonate (2.44 g) for 6 hr and at 20°-25° for 3 days. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated, the organic phase is dried with sodium sulfate and concentrated. The concentrate is chromatographed on silica gel eluting with methanol/methylene chloride (6/94) to give the title compound which is recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:35][C:36]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=O>C1COCC1>[F:22][C:18]([F:23])([O:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH2:1][C:36]([CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:35])(=[O:3])=[O:4])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)[CH:19]([F:21])[F:20]
Reactant: CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Reactant: COC(=O)C1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1)C1CCOCC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The 1-(methylsulfonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (2.85 g, 0.008 mol) was dissolved in anhydrous THF (200 ml) and cooled to −10° C. under an argon atmosphere. 1.0M solution of lithium bis(trimethylsilyl)amide in THF (17.6 ml, 0.0176 mol) was added with cooling to −30° C. and the mixture added a solution of methyl-tetrahydro-2H-pyran-4-carboxylate (CAS Number 110238-91-0) in THF (2 ml). This was allowed to reach room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl solution and diluted with H2O and ethyl acetate. The organic phase was collected, dried over MgSO4, filtered and evaporated to dryness to yield crude 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanone. (3.64 g, 97%)
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:26][C:27]([NH2:29])=O)[CH2:22][C:23]([NH2:25])=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CN(C=O)C.ClC(Cl)(Cl)C(Cl)=O.CCCCCC>C(Cl)Cl>[CH3:31][Si:2]([CH3:1])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:26][C:27]#[N:29])[CH2:22][C:23]#[N:25])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC(N)=O)CC(N)=O)c3)ncnc21
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC#N)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanediamide (29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM (200 mL, 3 mol) and TEA (36 mL, 0.26 mol) and cooled in an ice bath under nitrogen atmosphere. The trichloroacetyl chloride (15 mL, 0.14 mol) was added dropwise turning the reaction to a dark solution. This was stirred at 0° C. for ½ h. The reaction was then concentrated to remove the DCM and the resulting DMF solution was diluted with water to precipitate the product. The solid precipitate was collected and washed with water to give a dark solid. The solid was then dissolved in DCM and washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue. The residue was taken up in DCM, and hexane was added until the solution became slightly cloudy. This was stirred at rt to precipitate 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedinitrile as white needle-like crystals (22.7 gm, 85%), LC/MS (M+H)+: 408, 1H NMR (DMSO-d6) δ 9.07 (s, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.88 (d, 1H), 7.19 (d, 1H), 5.75 (s, 2H), 5.30 (m, 1H), 3.62 (t, 2H), 3.40 (m, 4H), 0.91 (t, 2H), 0.10 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:23]=[CH:22][C:21]([OH:24])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)[NH2:6].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:41][PH:42][CH:43](C)C(O)=O.C(N1[CH2:55][CH2:54][O:53]CC1)C>CN(C)C=O>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:23]=[CH:22][C:21]([OH:24])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)[NH:6][C:54](=[O:53])[CH2:55][CH2:41][PH:42][CH3:43]
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1
Reactant: CPC(C)C(=O)O
Reactant: CCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)NC(=O)CCPC
Temperature: 25 °C
Reaction time: 28 h

Procedure:
360 mg (0.52 millimole) of triiodothyronine methyl ester hydrochloride and 220 mg (1.07 millimoles) of dicyclohexylcarbodiimide, dissolved in 0.5 ml of dimethylformamide, are added successively to the solution of 110 mg of methylphosphinopropionic acid (0.72 millimole) and 0.3 ml (2.35 millimoles) of N-ethylmorpholine in 2 ml of dimethylformamide with stirring, ice cooling and exclusion of moisture. The mixture is allowed to warm to room temperature with stirring, and the precipitated dicyclohexylurea is then filtered off under suction after standing for 28 hours under the exclusion of light at room temperature. The residue which remains after distilling off the solvent is precipitated repeatedly from ethanol/ether.
Reaction SMILES: [CH3:1][Mg]I.[CH2:4]([N:11]1[C:19]2[C:14](=C(C#N)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+].C([O:26][CH2:27][CH3:28])C>O1CCCC1>[C:27]([C:28]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]2[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:26])[CH3:1]
Reactant: C[Mg]I
Reactant: N#Cc1cccc2c1ccn2Cc1ccccc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1ccn2Cc1ccccc1
Reaction time: 1 h

Procedure:
3.3 ml of a 2M solution of methylmagnesium iodide in diethyl ether was added to a mixture of 1.00 g of 1-benzyl-4-cyanoindole (prepared as described in Example 88) in 50 ml of tetrahydrofuran, with ice-cooling, and the reaction mixture was stirred for 1 hour. After this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The aqueous layer was extracted with diethyl ether, and the resulting organic fraction was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using 50 g of silica gel and a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 1.00 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([I:10])[C:3]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OCc1cc(I)c(OCC(F)(F)F)c(Cl)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
6-Chloro-5-hydroxy-4-iodo-2-pyridinemethanol (CAS Registry No. 208519-37-3) (21.5 g, 75 mmol) was dissolved in hexamethylphosphoramide (210 mL). Over a period of 30 min sodium hydride (3.0 g of 60% dispersion in oil, ˜75 mmol) was added with stirring at room temperature. The mixture was stirred for another 45 min at room temperature and 2,2,2-trifluoroethyl trifluoromethane sulfonate (12.5 mL, 90 mmol) was added drop wise with stirring and temperature control (<40° C.). The mixture was stirred for 18 h at 120° C., cooled to room temperature and poured into water (800 mL). The mixture was acidified with 2N—HCl (50 mL) and extracted with ethyl acetate (2×350 mL). Organic phases were washed with water (2×400 mL), pooled and dried with Na2SO4. Solvents were evaporated and the brown, solid residue (27.9 g) was purified by chromatography on silica with ethyl acetate/n-heptane (1:1) to give the title compound as a white solid (24.8 g, 90%), LC-MS (UV peak area/ESI) 100%, 367.916 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 100 °C
Yield: 80.2 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.518), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1(2H)-carboxylate (160.1 mg, 0.518 mmol), tetrakis(triphenylphosphine)palladium (119.7 mg, 0.104 mmol), Na2CO3 (1.30 ml, 2.59 mmol) and DME (50 mL). The reaction mixture was stirred under nitrogen at 100° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (183.4 mg, 80%). LRMS (APCI pos): m/e 442 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H), 7.36 (s, 1H), 7.03 (t, 1H), 6.54 (dd, 1H), 6.47 (m, 2H), 6.30 (m, 1H), 4.13 (m, 2H), 3.83 (br s, 2H), 3.68 (m, 2H), 2.64 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C:5]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH:37]S(O)(=O)=O.[CH3:42][C:43]#[N:44]>>[CH3:36][C:2]([CH3:1])([CH3:35])[CH2:3][CH2:4][C:5]1([NH:44][C:43](=[O:37])[CH3:42])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)CCC1(O)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC#N
Product: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of the product from Example 8F (20 mg, 38 μmol) in CH3CN (0.2 mL) at 0° C. was added conc. H2SO4 (0.2 mL) dropwise. The resulting mixture was stirred at room temperature for 3 h and was poured onto ice (˜5 mL). The mixture was allowed to warm to room temperature, and the product was collected by filtration to give the title compound as an off-white solid (19 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 13.65 (br s, 1H), 10.26 (s, 1H), 9.15 (s, 1H), 8.12 (d, J=7.0 Hz, 1H), 7.69-7.79 (m, 2H), 7.47-7.65 (m, 4H), 3.06 (s, 3H), 2.50 (s, 3H), 1.74-2.06 (m, 2H), 0.84-1.00 (m, 1H), 0.66 (s, 9H), 0.39-0.58 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A stirred solution of 21.0 mL of (2-methylphenyl)magnesium bromide (42.0 mmol, 2.0M in diethyl ether) was evaporated in situ at room temperature. The syrupy residue was redissolved in 50 mL of THF and cooled to -20° C. under argon. To this solution was added a solution of 6.84 g (50.0 mmol) of thricefused zinc chloride. The resulting thick white slurry was warmed to room temperature and stirred for 1 hour. After cooling to -78° C., a solution of 11.32 g (40.0 mmol) of 1-bromo-4-iodobenzene and 500 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium in 50 mL of THF was added over the course of thirty minutes. After an additional 20 minutes, the cooling bath was removed, the reaction stirred at room temperature for 2 hours and then quenched with 100 mL of 1M hydrochloric acid. The mixture was extracted twice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSO4) and evaporated. The crude product (11.3 g) was purified by distillation (bp 93°-95° C. at 0.5 Torr) to give 8.06 g (82%) of title compound as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (48.4 mg, 0.7 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]1[CH2:11][NH:10][C:9](=O)[CH2:8][O:7]1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:13]1([C@H:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[C@H:6]2[O:7][CH2:8][CH2:9][NH:10][CH2:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COC(C(Oc2ccccc2Br)c2ccccc2)CN1
Reactant: OB(O)c1ccncc1
Product: c1ccc([C@H](Oc2ccccc2-c2ccncc2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-Phenyl-(2-pyridin-4-yl-phenoxy)-methyl]-morpholine was synthesized from 6-[(2-Bromo-phenoxy)-phenyl-methyl]-morpholin-3-one and 4-pyridineboronic acid according to general procedures A and B and was isolated as a thick viscous gum. 1H NMR (CDCl3) δ: 8.65 (d, 2H), 7.60 (d, 2H), 7.32-7.18 (m, 7H), 6.96 (m, 1H), 6.90 (d, 1H), 5.10 (d, 1H), 3.93 (d, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 2.75 (m, 2H), 2.48 (m, 2H), 1.80 (br s, 1H). MS (ES) m/z 347.08 [C22H22N2O2+H]+. Analysis: Calcd for C22H22N2O2:0.5H2O: C, 74.34; H, 6.52; N, 7.88. Found: C, 74.15; H, 6.84; N, 7.37.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]4[N:15]=[CH:16][S:17][C:13]=4[CH:12]=3)[S:8][C:7]=2[CH:20]=1.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[S:17]1[C:13]2[CH:12]=[C:11]([C:9]3[S:8][C:7]4[CH:20]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=4[C:10]=3[C:34]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:38][CH:37]=3)=[O:35])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(-c3ccc4ncsc4c3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc3ncsc3c2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Example 18, Step 2 (63 mg, 0.21 mmol) and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (1.38 mL, 0.25 mmol) in 1 mL of methylene chloride was added AlCl3 (212 mg, 1.6 mmol) and the reaction was stirred at room temperature for 3 hrs. When acylation was complete, to demethylate, ethanethiol (0.069 mL, 0.93 mmol) was added dropwise and the reaction stirred for a further 1.5 hrs. The reaction was cooled to 0° C. and quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with 10% MeOH/methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 2% MeOH/methylene chloride to 4% MeOH/methylene chloride as the gradient eluant to obtain the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH3:18][O-:19].[Na+]>>[Cl:1][C:2]1[C:3]([O:19][CH3:18])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[N:9][C:8](=[O:12])[C:7](=[O:13])[N:6]=2
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Reactant: C[O-]
Agent: [Na+]
Product: COc1c(Cl)cc2c(c1[N+](=O)[O-])=NC(=O)C(=O)N=2

Procedure:
Similarly, the reaction of 7-chloro-6-fluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione with sodium methoxide gave 7-chloro-6-methoxy-5-nitroquinoxaline-2,3-dione, and with ethanethiol gave 7-chloro-6-ethylthio-5-nitroquinoxaline-2,3-dione.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[C:8]=1[CH:9]=[CH:10][CH:11]([S:21]([CH:24]([CH:34]=[CH:35][C:36]1[C:41]([O:42][CH3:43])=[CH:40][C:39]([O:44][CH3:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([NH2:33])[CH:26]=1)(=[O:23])=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([NH2:20])[CH:13]=1.[O:56]1CC[CH2:58][CH2:57]1>>[CH3:55][O:54][C:48]1[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=[C:7]([O:6][CH3:5])[C:8]=1/[CH:9]=[CH:10]/[CH:11]([S:21]([CH:24](/[CH:34]=[CH:35]/[C:36]1[C:37]([O:46][CH3:47])=[CH:38][C:39]([O:44][CH3:45])=[CH:40][C:41]=1[O:42][CH3:43])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([NH:33][C:57](=[O:56])[CH3:58])[CH:26]=1)(=[O:23])=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([NH:20][C:1](=[O:3])[CH3:2])[CH:13]=1
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(C)=O)c2)c(OC)c1
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of acetyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzyl-sulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-(acetamido)-4-methoxybenzylsulfone in 68% yield. M.p. 220-223° C. NMR (DMSO-d6) δ 2.02 (s, 2H), 3.84 (s, 3H), 3.86 (s, 6H), 3.88 (s, 3H), 4.22 (s, 2H), 6.08 (s, 2H), 7.09-7.12 (d, 1H vinylic), 6.88-7.86 (m, aromatic), 8.35 (s, 1H).