Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)O)nc1Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 37.9 %

Procedure:
A mixture of 6-bromo-5-methoxy-pyridine-2-carboxylic acid (0.3 g, 1 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.23 g, 1 mmol), tris(dibenzylidene-acetone)-dipalladium(0) (CAN 52409-22-0, 0.12 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.15 g) and potassium carbonate (0.21 g, 2 mmol) in 1,4-dioxane (10 mL) was stirred for 12 h at 110° C. under a nitrogen atmosphere. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography (silica gel, 10 g, eluting with 10% methanol in methylene chloride) to give the title compound (0.1 g, 29%); MS (EI): m/e=264.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[NH3:18]>O1CCOCC1>[CH:12]1([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:18])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Reactant: N
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2C1CCCC1
Yield: 92 %

Procedure:
To a pressure tube with dioxane (5 mL) was added 4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, then ammonia hydroxide (5 mL). The pressure tube was sealed and heated at 120 C overnight. All solvents were removed via reduced pressure, and the residue were purified through flash column (methylene chloride/methanol:97/3). The product was obtained as a white solid (300 mg, 92%). MS: 329.1 (MH+); HPLC Rf: 5.018 min.; HPLC
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)[C:11](=[O:15])[N:12](C)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[C:43]([CH2:51][CH2:52]Br)[CH:42]=1.CCN(C(C)C)C(C)C>ClC(Cl)C>[Br:40][C:41]1[CH:46]=[CH:45][C:44]2[S:47](=[O:49])(=[O:48])[N:1]([C:2]3[C:3]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[C:4]([C:8]4[CH:9]=[C:10]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([C:23]([N:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[O:24])=[CH:19][N:18]=5)[C:11](=[O:15])[NH:12][CH:13]=4)[CH:5]=[CH:6][CH:7]=3)[CH2:52][CH2:51][C:43]=2[CH:42]=1
Reactant: Cn1cc(-c2cccc(N)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1CCBr
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(-c2c[nH]c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1N1CCc2cc(Br)ccc2S1(=O)=O
Yield: 53.4 %

Procedure:
The mixture of 5-[3-Amino-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (0.2 g, 0.36 mmol), 4-bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride (0.4 g, 1.08 mmol) and DIPEA (1 mL) in dichloroethane (10 mL) was microwaved at 120° C. for 30 min, then added 4-bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride (0.4 g, 1.08 mmol) and DIPEA (1 mL) and microwaved at 120° C. for 30 min. After repeating this process three times, the mixture was concentrated to afford a dark residue. Purification by silica gel chromatography (methylene chloride/acetone) afforded 0.15 g of 5-[3-(6-Bromo-1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[e][1,2]thiazin-2-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one as a pale solid MS (ESI) 796.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][Mg]Cl>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: C[Mg]Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2,4,6-trichloro-1,3,5-triazine (1.0 g, 5.4 mmol) in CH2Cl2 (17 mL) was added MeMgCl (1.8 mL) drop wise and the reaction mixture was stirred at RT for 0.5 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 90%) as a solid. The crude material was taken to the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH2:15][CH2:16][CH3:17])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[Cl:39][C:1]1[N:2]=[C:14]([CH2:15][CH2:16][CH3:17])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCC(=O)NC(C#N)COCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCc1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.25 h

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}butanamide (1.60 g, 6.5 mmol), triphenylphosphine (4.3 g, 16.3 mmol), and carbon tetrachloride (1.6 mL, 16.3 mmol) in acetonitrile (65 mL) was heated at 42° C. for 12 h. The reaction was then concentrated and the residue was stirred in CH2Cl2 (70 mL) and 0.5 N NaOH (60 mL) for 15 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-40% EtOAc:hexanes) to give the title compound as a light yellow solid, in assumed quantitative yield due to inseparable triphenylphosphine oxide. 1H NMR (400 MHz, CDCl3) δ 7.30-7.40 (m, 5H), 4.52 (s, 4H), 2.58-2.68 (m, 2H), 1.68-1.82 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][CH:32]=1.[CH:36]([NH2:38])=[O:37].C(OCCOCCOCCCC)CCC>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[Pd]Cl.C(OCC)C.O>[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:36]([NH2:38])=[O:37]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: NC=O
Agent: Cl[Pd]Cl
Agent: CCCCOCCOCCOCCCC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Product: NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
0.491 g of bis(triphenylphosphine)-palladium(II)chloride, 0.371 g of triphenylphosphine and 2.6 g of imidazole are placed in a 200 ml glass autoclave, and then 8.01 g of 3-(trifluoromethyl)bromobenzene, 25 ml of formamide and 810.3 mg of diethylene glycol dibutylether are added as an internal gas chromatography (GC) standard. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 14 hours. The mixture is then cooled and the content determined by GC (0.8 ml of reaction mixture mixed with 5 ml of water, then 2 ml of diethylether added, and GC determination effected with the organic phase). The yield of title compound is 82% by weight.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(=O)Oc1cccc2c1CCCN2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCc2c(O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of t-butyl 5-(acetyloxy)-3,4-dihydroquinoline-1(2H)-carboxylate (770 mg, 2.64 mmol) in 10 mL of MeOH was added potassium carbonate (365 mg, 2.64 mmol), and the resulting mixture was stirred for 2 hours at room temperature and then filtered and concentrated in vacuo. The crude material was purified on a silica gel column (5% to 35% EtOAc/hexanes) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2)[C:12]([CH2:18][S:19][CH2:20][CH3:21])([C:14]([F:17])([F:16])[F:15])[OH:13].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2)[C:12]([CH2:18][S:19][CH2:20][CH3:21])([C:14]([F:16])([F:15])[F:17])[OH:13]
Reactant: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(O)c(F)c1Cl)C(F)(F)F
Reaction time: 22 h

Procedure:
Analogously to example 10 100 mg (0.20 mmol) 2-Chloro-3-fluoro-α-[(ethylsulfanyl)methyl]-4-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)benzenethanol in 8 ml dichloromethane are treated with 2 ml of a 1 M solution of boron tribromide in dichloromethane at −30° C. The typical work up after 22 hours at room temperature and chromatography on silica gel (acetone in hexane 50%) yields 26 mg of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl.C(OCC)(=O)C>[N:13]1([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Clc1cncc(-c2ccsc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1cc(-c2cncc(N3CCNCC3)n2)cs1
Temperature: 85 °C

Procedure:
A mixture of the product from step 1 above (1.04 g, 5.29 mmol), piperazine (1.32 g, 15.3 mmol), and K2CO3 (0.81 g, 5.82 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 85° C. for 8.5 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The semi-solid residue was purified by column chromatography on silica gel (18×5 cm) using CHCl3/MeOH (9:1) as eluent to furnish an oil. This material was redissolved in ethyl acetate, filtered, and concentrated in vacuo. This gave 0.98 g (75%) of the title compound as a yellow sticky oil. HRMS m/z calcd for C12H14N4S (M)+ 246.0939, found 246.0943. Anal. (C12H14N4S) C, H, N.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([F:12])[F:11].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[CH2:19]([NH:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]([F:12])([F:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(COCCCCCCBr)c1ccccc1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: FC(F)(COCCCCCCNCc1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
A solution of Intermediate 7 (5.0 g, 15.6 mmol) and benzyl amine (3.4 mL, 31.1 mmol) was heated at 120° C. for two hours. The crude reaction was treated with ethyl ether and the resulting solid was filtered. The solvent was concentrated and the result in oil was purified by column chromatography with silica gel and methylene chloride/methanol (from 99:1 to 95:5) as eluent, to yield N-benzyl-6-(2,2-difluoro-2-phenylethoxy)hexan-1-amine (3.2 g, 59%) as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].BrC1C=C2C(=C(C(N)=O)C=1)NN=C2C1CCN(S(CCCN(C)C)(=O)=O)CC1>[CH3:27][N:26]([CH3:28])[CH2:25][CH2:24][CH2:23][S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:35]4[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccc(OC(F)(F)F)cc4)cc23)CC1
Temperature: 100 °C

Procedure:
To a solution 5-bromo-3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 8) (20 mg, 0.04 mmol) in dioxane/water (1:1, 5 mL) was added {4-[(trifluoromethyl)oxy]phenyl}boronic acid (30 mg, 0.12 mmol), potassium carbonate (40 mg), and Pd(dppf)Cl2 (8 mg). The reaction mixture was heated at 100° C. for 1800 seconds. The contents of the vial were partitioned between ethyl acetate and water. The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give 0.62 g of a yellow solid. This was purified via silica gel chromatography using 20% ethyl acetate/pentane as the mobile phase to give the title compound (5 mg, 23%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:9][CH2:10][CH2:11][CH2:12][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=2)=[N:7][CH:6]=1
Reactant: CCCCOc1ccc(B(O)O)cn1
Reactant: Brc1cnc(Br)nc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 75.9 %

Procedure:
A reaction of 115 mmol of 2,5-dibromopyrimidine, 115 mmol of 2-butoxypyrdine-5-boronic acid, 230 mmol of sodium carbonate and 1.2 mmol of tetrakis(triphenylphosphine)palladium(0) in 280 ml of toluene, 140 ml of ethanol and 140 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 15.9 g (38%) of a colorless solid, m.p. 99-101 ° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:30])[C:17]([O:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18]>CN(C)C=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:16]([CH3:30])[C:17]([O:19][CH2:20][CH2:21][S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)OCCSCc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(O)cc1)C(=O)OCCSCc1ccccc1
Temperature: 25 °C

Procedure:
12.1 g of hydroquinone were dissolved in 60 ml of dry dimethylformamide, and while blowing a slow stream of nitrogen into the solution, 31.7 g of potassium carbonate were added thereto at room temperature whilst stirring. Then the mixture was heated to 90° to 95° C. for one hour with stirring. The mixture was cooled to 60° C., and 30.3 g of 2-benzylthioethyl 2-bromopropionate were added dropwise thereto. After the addition was completed, the mixture was further heated to 90° C. for 2 hours. After cooling the reaction mixture to room temperature, it was poured into ice-water and adjusted to pH 7. Then it was extracted with 100 ml of chloroform. The organic phase was dried and the chloroform was distilled off under reduced pressure. The end product of 2-benzylthioethyl 2-(4-hydroxy-phenoxy)-propionate was obtained in a yield of 25.2 g in the form of a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])(F)F)[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[C:16]([CH2:18][F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(CF)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4-(2-nitro-4-trifluoromethylphenoxy)phenol (9.36 mm), ethyl 4-bromo-3-methoxy-2-pentenoate (12 mm.) and K2CO3 (14 mm.) in acetone (20 ml.) is refluxed for 24 hours. After filtration, the filtrate is concentrated and the oily residue chromatographed on silica gel to yield ethyl 4-[4-(2-nitro-4-fluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: [Cl:1][C:2]1C(C)=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1OC(=O)C)(=[O:10])=[O:9].C([SiH]([CH2:47][CH3:48])CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:47]([CH3:48])=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:10])=[O:9]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3ccccc3c2OC(C)=O)sc2ncccc12
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cccc3ccccc23)sc2ncccc12
Yield: 65 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(α-acetoxynaphthylmethyl)thieno [2,3-b]pyridine-3-sulfonamide (97 mg, 0.16 mmoles), CH2Cl2 (3 ml), triethylsilane (0.25 ml, 1.6 mmoles) and boron trifluoride etherate (0.19 ml, 1.6 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 58 mg (66%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](OC2C=CC=CC=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)C2C(=CC=CC=2)[NH:8]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:1][C:2]1[C:3]([C:19]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:20])=[CH:4][C:5]2[C:6]([CH:18]=1)=[C:7]1[C:15](=[CH:16][CH:17]=2)[C:3]2[C:2](=[CH:18][CH:6]=[CH:5][CH:4]=2)[NH:8]1
Reactant: O=C(Oc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cc2ccc3c4ccccc4[nH]c3c2cc1O
Temperature: 25 °C

Procedure:
The aromatic ester is reacted with an aniline in a solvent and heating to form the anilide product. The reaction temperature can be varied to from about 140° C. to about 280° C. or above. Specifically, phenyl 2-hydroxy-11H-benzo(a)carbazole-3-carboxylate can be reacted with aniline in methyl N-pyrrolidinone at about 250° C. The ratio of the phenyl ester to aniline can vary, for example, from about 1:1 equivalent and up to about 20 equivalents. After the reaction is completed, the product mixture is cooled to room temperature, about 25° C., and discharged into an acidic aqueous solution, such as a 5 percent HCl ice cold solution. The precipitated anilide product, such as 2-hydroxy-11H-benzo(a)carbazole-3-carboxanilide, is isolated by filtration and washed with water and methanol. Purification can be accomplished by first dissolving the crude product in a hot solvent, such as DMF, and then precipitating the product by adding water or methanol, or a mixture of methanol and water. The purified product is then characterized by melting point, IR, mass spectrometry, NMR spectroscopy, especially 13C NMR as well as elemental analysis.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].C1COCC1.[H-].[Na+].Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:3][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]3=[N:16][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1ccc(OCc2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A mixture of 3-{[4-(1-methylethyl)phenoxy]methyl}pyridin-2-amine (600 mg) and dehydrated THF (10 mL) was added to a mixture of sodium hydride (60%, 495 mg), 2-chloroethanesulfonyl chloride (1211 mg) and dehydrated THF (10 ml) at room temperature. The reaction mixture was stirred for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (303 mg) as a white solid. The obtained solid was crystallized from THF-diisopropyl ether to give a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:43]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=2)[CH3:44])=[O:42])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH2:27]([N:34]1[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:43]([C:45]2[CH:46]=[CH:47][C:48]([NH:49]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:50][CH:51]=2)[CH3:44])=[O:42])[CH2:38][CH2:39]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.