Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1)#[N:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:13][S:14]([OH:16])(=[O:12])=[O:15].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1ccc(C#N)cc1
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A mixture of 3-(4-cyanophenyl)propanol (3.77 g, 23.4 mmol), methanesulfonylchloride (2.96 g, 25.8 mmol), triethylamine (2.60 g, 25.7 mmol) and ethyl acetate (100 ml) was stirred at room temperature for 30 minutes. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (60 g) with hexane-ethyl acetate (1:1) to give 3-(4-cyanophenyl)propane methanesulfonate as a colorless oil (4.79 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[N+]([O-])(O)=O.[N:18]#[C:19][NH2:20].C(OCC)C>C(O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:19]([NH2:20])=[NH:18])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: N#CN
Solvent: CCO
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Product: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reaction time: 2 h
Yield: 75.6 %

Procedure:
4-(2-Methylimidazol-1-yl)phenylamine (10 g, 57.73 mmol) was dissolved in ethanol (100 mL). Nitric acid (3.96 mL, 57.73 mmol) was carefully added followed by cyanamide (2.427 g, 57.73 mmol). The reaction mixture was heated to reflux overnight. Extra cyanamide (1.942 g, 46.19 mmol) and nitric acid (2.98 mL, 46.19 mmol) were added and then the reaction mixture was refluxed for 16 hours. The reaction mixture was allowed to reach room temperature and ethyl ether (100 mL) was added. The mixture was refrigerated for 2 h and the solid obtained was filtered off and washed with ethyl ether yielding 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (9.40 g, 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CO>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)[CH2:9][NH2:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CN)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution in methanol (15 ml) of the mixture containing [1-[(3-tert-butyl-4-hydroxyphenyl)methyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]carbamic acid tert-butyl ester, hydrazine monohydrate (2 ml) was added and the resulting mixture was stirred at room temperature for 4 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to give [2-amino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in the amount of 1.55 g (69%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]#[C:18][C:19]#[C:20][C:21]#[C:22][C@@H:23]2[O:25][C@H:24]2[CH:26]=[CH:27][CH:28]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.O1CCCC1>[C:11]1([C:17]#[C:18][C:19]#[C:20][C:21]#[C:22][C@@H:23]2[O:25][C@H:24]2[CH:26]=[CH:27][CH2:28][OH:29])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Diisobutylaluminum hydride (0.35 ml of a 1.76M solution in toluene, 0.61 mmole) was added dropwise to a stirred -78° C. solution of (trans)-3-[3-(6-phenyl-1,3,5-hexatriynyl)oxiranyl]-2-propenal (50 mg, 0.20 mmole; see example 5) in 6 ml of dry tetrahydrofuran. The mixture was stirred for 2 hours at -78° C. and was then quenched at that temperature by the dropwise addition of ca. 0.5 ml of a solution of methanol-acetic acid 4:1. The mixture was warmed to room temperature, water was added and the mixture was extracted with ether. The combined ether extracts were washed with water and saturated aqueous sodium chloride and were dried over anhydrous magnesium sulfate. Removal of solvent gave an oil which was purified by preparative thin layer chromatography (ethyl acetate-hexane 1:1) to afford 34 mg pure title compound, melting point 65°-66° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=3)=[C:4]([CH3:14])[S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH3:16]
Reactant: Cc1sc(N)nc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)c1cc(=O)nc2sc(C)c(-c3ccc(Br)cc3)n12

Procedure:
The procedure is as in Example 1, except that 9.4 g of 2-amino-4-(p-bromophenyl)-5-methyl thiazole and 5.95 g of acetylene dicarboxylic acid diethyl ester are used. 2-methyl-3-(p-Bromophenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 217° to 220° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][CH:2]([NH2:14])[CH2:3][O:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[CH:7][C:6]=1[Br:13].[F:15][CH:16]([F:26])[C:17]1[C:21]([C:22](O)=[O:23])=[CH:20][N:19]([CH3:25])[N:18]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][CH:2]([NH:14][C:22]([C:21]1[C:17]([CH:16]([F:26])[F:15])=[N:18][N:19]([CH3:25])[CH:20]=1)=[O:23])[CH2:3][O:4][C:5]1[C:6]([Br:13])=[CH:7][C:8]([Br:12])=[CH:9][C:10]=1[Br:11]
Reactant: CC(N)COc1c(Br)cc(Br)cc1Br
Reactant: Cn1cc(C(=O)O)c(C(F)F)n1
Solvent: c1ccncc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(COc1c(Br)cc(Br)cc1Br)NC(=O)c1cn(C)nc1C(F)F
Temperature: 0 °C
Reaction time: 12 h
Yield: 27.5 %

Procedure:
A mixture of 0.3 g (0.8 mmol) 1-methyl-2-(2,4,6-tribromo-phenoxy)-ethylamine (compound Z1.193, prepared as described in example P7) and 0.15 g (0.9 mmol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid in 2 ml pyridine under a nitrogen atmosphere is cooled to 0° C. Phosphorus oxychloride (0.08 ml, 0.9 mmol) is added dropwise and the reaction mixture is stirred at 80° C. for 12 h. The reaction mixture is diluted with water and 3-times extracted with ethyl acetate. The combined ethyl acetate layers are washed with 1.5 N HCl, saturated NaHCO3, water and brine, dried over sodium sulphate and evaporated to dryness. The residue is purified by column chromatography (using 60-120 mesh-silica gel in hexane; eluent: ethyl acetate) to yield 0.12 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-methyl-2-(2,4,6-tribromo-phenoxy)-ethyl]-amide (27% of theory) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:4]1[CH:3]=[C:2]([B:29]([OH:34])[OH:30])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(-c2ccc3ccccc3c2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1cccc(-c2ccc3ccccc3c2)c1
Temperature: -10 °C
Yield: 67.9 %

Procedure:
Under an argon gas atmosphere, a mixture of 212 g (748 mmol) of 2-(3-bromophenyl) naphthalene and 3 L of dehydrated THF was cooled down to −10 degrees C., and added with 600 mL (948 mmol) of hexane solution of 1.6M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for one hour at 0 degrees C. The reaction solution was further cooled down to −78 degrees C. and added with 450 g (2.39 mol) of triisopropyl borate in drops. Subsequently, the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. The reaction mixture was further added with 3 L of toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by toluene, 126 g of 3-(2-naphthyl)phenylboronic acid was obtained at an yield of 67%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:11][C:12]1[CH:13]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31](Cl)[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:23][C:16]1[CH:15]=[C:14]([CH:24]([NH:26][C:27]([C:29]2[N:30]=[C:31]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:32][CH:33]=2)=[O:28])[CH3:25])[CH:13]=[C:12]([F:11])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccccc2Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 30.4 %

Procedure:
2-Chlorophenylboronic acid (40.7 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (18 mg, 30%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:17][CH:18]([CH2:20]O)O>>[CH2:9]([C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:20][CH:18]=[CH:17]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Reactant: OCC(O)CO
Product: Brc1cc(Cc2ccccc2)cc2cccnc12

Procedure:
2-bromo-4-benzylaniline and glycerol can be combined to form 6-benzyl-8-bromoquinoline,
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:13]=O.O.[CH3:16][NH:17][CH3:18]>>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][C:8]=1[CH2:16][N:17]([CH3:13])[CH3:18]
Reactant: CNC
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: C=O
Solvent: O
Product: CN(C)Cc1cc(OC(F)(F)F)ccc1O
Temperature: 3 °C
Reaction time: 2 h

Procedure:
130 g of 4-trifluoromethoxyphenol are initially charged in 97 ml of 40% aqueous dimethylamine solution and cooled to 3° C. At 0-5° C., 66 ml of 37% aqueous formaldehyde solution are added dropwise within 45 min. The mixture is kept at 5-10° C. for a further 2 hours and is subsequently stirred at room temperature for 19 hours. It is cooled again to 0° C., 4.9 ml of 40% aqueous dimethylamine solution are added and 3.3 ml of 37% aqueous formaldehyde solution are subsequently added dropwise. The mixture is stirred at room temperature for a further 3 hours. The mixture is admixed with 100 ml of water. The organic phase is removed, the aqueous phase is extracted twice with dichloromethane, the combined organic phases are dried and the solvent is distilled off under reduced pressure. The crude product is subsequently fractionally distilled under reduced pressure. 118 g (69% of theory) of a light yellow liquid having a boiling point of 110-112° C. at 18 mbar were obtained.
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[O-]S(C(F)(F)F)(=O)=O.[O:50]=[S:51]1(=[O:65])[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=2)[CH2:53][CH2:52]1>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:64][C:61]3[CH:62]=[CH:63][C:58]([CH2:57][N:54]4[CH2:55][CH2:56][S:51](=[O:65])(=[O:50])[CH2:52][CH2:53]4)=[CH:59][CH:60]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ncc2ccc(Br)n2n1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (100 mg, 0.467 mmol) was dissolved in N,N-dimethylformamide (9.00 mL) at 0° C. and N,N-diisopropylethylamine (244 μL, 1.40 mmol) was added and the reaction was let stir for 30 minutes. N-Phenylbis(trifluoromethanesulphonimide) (184 mg, 0.514 mmol) was added and the reaction was let warm to room temperature. After 100% conversion to the triflate, 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine (140 mg, 0.584 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was taken up in EtOAc (30 mL) and washed three times with water (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-amine as a yellow foam (134 mg, 66%). LCMS (m/e) 301 (M—N(CH2)4SO2); 1H-NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 7.73 (d, 2H, J=8.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 6.92 (s, 1H), 6.81 (d, 1H, J=4.8 Hz), 6.76 (d, 1H, J=4.8 Hz), 3.63 (s, 2H), 3.10-3.03 (m, 4H), 3.03-2.97 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=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.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: OCc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CO)cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
A suspension of N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 50 (14.0 g, 37 mmol) in toluene (120 mL) was treated with 4-(hydroxymethyl) phenylboronic acid (7.87 g, 51.8 mmol, 1.4 equiv), potassium carbonate (K2CO3, 15.32 g, 111 mmol, 3.0 equiv), ethanol (EtOH, 40 mL), and H2O (40 mL) at 25° C., and the resulting mixture was degassed three times under a steady stream of argon at 25° C. Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 2.14 g, 1.85 mmol, 0.05 equiv) was subsequently added to the reaction mixture, and the resulting reaction mixture was degassed three times again before being warmed to gentle reflux for 6 h. When thin layer chromatography (TLC) and HPLC showed the coupling reaction was complete, the reaction mixture was cooled to room temperature before being treated with H2O (240 mL). The resulting mixture was then stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% ethyl acetate (EtOAc)/hexane (2 X 50 mL), and dried in vacuo. The crude desired N-[3-(2-Fluoro4′ -hydroxymethyl-biphenyl4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 51 (12.50 g, 94% yield) was obtained as off-white solids. This material was found to be essentially pure by HPLC and 1H NMR and was directly used in the subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ1.76 (s, 3H, COCH3), 3.35 (t, 2H, J=5.4 Hz), 3.69 (dd, 1 H, J=6.4, 9.2 Hz), 4.08 (t, 1H, J =9.1 Hz), 4.46 (d, 2 H, J=5.7 Hz, CH2OH), 4.68 (m, 1 H), 5.16 (t, 1 H, J=5.7 Hz, OH), 7.25-7.52 (m, 7 H, aromatic-H), 8.18 (t, 1 H, J=5.8 Hz, NHCOCH3). LCMS (ESI) m/e 359 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(I)cc1

Procedure:
To a suspension of 10 g (40.32 mmol)of 4 -iodobenzoic acid in 100 ml absolute ethanol was added 2 ml thionyl chloride and the mixture was then heated at reflux for 3 hours. Solvent was removed in vacuo and the residue was dissolved in 100 ml ether. The ether solution was washed with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was then removed in vacuo and the residue kugelrohr distilled (100 degrees C.; 0.55 mm) to give the title compound as a colorless oil, PMR (CDCl3): δ1.42 (3H, t, J~ 7 Hz), 4,4 (2H, q, J~ 7 Hz), 7.8 (4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH:10]2C(=O)O[C:13](C)([CH3:17])[O:12][C:11]2=[O:19])=[C:4]([F:32])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:10][C:11]([O:12][CH2:13][CH3:17])=[O:19])=[C:6]([F:8])[CH:7]=1
Reactant: CSCc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1c(F)cc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12

Procedure:
11 mg (166 μmol) of copper powder were added to a solution of 1.60 g (3.33 mmol) of the compound from Example 96A in 6 ml of pyridine and 1.3 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the crude product was purified firstly by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5/1) and then by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.15 g (81% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH3:12][C:3]1[C:2]([NH:1][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[CH:7][N:6]=[CH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cncc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cncc(NC2CCOCC2)c1C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a stirred solution of methyl 5-amino-4-methylpyridine-3-carboxylate (805 mg, 4.84 mmol) in DCE (20 ml) under a nitrogen atmosphere was added oxan-4-one (537 μl, 5.80 mmol) followed by trifluoroacetic acid (742 μl, 9.69 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (1.54 g, 7.27 mmol). The reaction was stirred for 16 h at room temperature after which time more oxan-4-one (100 μl) and sodium triacetoxyborohydride (300 mg) were added and the reaction stirred for a further 6 h. Distilled water (20 ml) was added and solid NaHCO3 was added until pH8. The phases were separated and then the aqueous phase was washed with EtOAc (2×50 ml), the combined organics were washed with brine (50 ml), dried using Na2SO4, filtered and evaporated to afford the title compound as a pale yellow solid (1.11 g, 88%) which was used in the next stage without any further purification. LC-MS 96%, m/z=251.0, 1H NMR (500 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.10 (s, 1H), 4.03 (dt, J=11.9, 3.5 Hz, 2H), 3.92 (s, 3H), 3.68-3.58 (m, 1H), 3.54 (tt, J=8.1, 4.1 Hz, 3H), 2.35 (s, 3H), 2.12-2.05 (m, 2H), 1.53 (ddd, J=23.8, 11.0, 4.3 Hz, 2H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=CC=CC=1[N+:51]([O-:53])=[O:52].C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[N+:51]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3ccccc3[N+](=O)[O-])cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) was coupled with 1-bromo-2-nitrobenzene (150 mg, 0.74 mmol) (Aldrich) using CuI (13 mg, 0.068 mmol) (Aldrich) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) as catalyst in 2 mL DMF and 4 mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-(2-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 115 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:22][CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC(F)(F)F)cc1Br

Procedure:
To a solution of 2-bromo-4-trifluoromethoxyphenol (Description 11; 8 g, 0.03 mol) and K2CO3 (8.6 g, 0.06 mol) in dimethylformamide (100 ml) was added allyl bromide (4 ml, 0.045 mol). The solution was stirred for 4 h. at room temperature undre nitrogen whereupon water (400 ml) and ethyl acetate (3×100 ml) were added and the combined organic phase was washed with water (200 ml), saturated brine (200 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (eluting with 5% ethyl acetate in hexane) to give the title compound as a yellow oil 1H NMR (250 MHz, CDCl3) δ4.60 (2H, dt, J 5, 1.6 Hz), 5.33 (1H, dq, J 10.5, 1.4 Hz), 5.48 (1H, dq, J 17.3, 1.6 Hz), 6.04 (1H, m), 6.86 (1H, d, J 9 Hz, 7.13 (1H, dd, J 8.4, 2.7 Hz), and 7.45 (1H, d, J 2.8 Hz).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10]C(=O)[C:8]2=[O:13].[OH:16]O.Cl>[OH-].[Na+].O>[F:14][C:2]([F:1])([F:15])[C:3]1[C:11]([NH2:10])=[C:7]([CH:6]=[CH:5][CH:4]=1)[C:8]([OH:13])=[O:16]
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
7-Trifluoromethylisatin (10 g, 46 mmol) was dissolved in 5% sodium hydroxide solution (83 ml). To this was added dropwise over 30 minutes a solution of 50% hydrogen peroxide (7.4 ml) in water (4.6 ml); the temperature rose to 50°. The solution was stirred an additional 30 minutes, acidified (conc. HCl) to pH 1-2, and the tan product was filtered.