Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7].[Cl:19]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:19][CH2:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCN(c2nc(C)c(C)s2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2nc(CCl)c(C)s2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a mixture of ethyl 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine-4-carboxylate (6.51 g), acetonitrile (100 mL) was added N-chlorosuccinimide (3.24 g) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give ethyl 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine-4-carboxylate as colorless crystals (1.93 g, yield 26%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 76-77° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1>>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: CS(=O)(=O)Nc1ccc(N/C=C2\C(=O)Nc3ccccc32)cc1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one (0.164 g, 1.02 mmol) and N-(4-aminophenyl)-methanesulfonamide [53250-82-1, 0.186 g, 1.0 mmol] to provide a yellow solid (0.249 g). 1H NMR (DMSO) 10.67 (d, 1H); 10.45 (s, 1H); 9.56 (s, 1H); 8.50 (d, 1H); 7.52 (d, 1H); 7.35 (d, 2H); 7.18 (d, 2H); 6.95 (m, 1H); 6.89 (m, 1H); 6.80 (m, 1H); 2.92 (s, 3H). MP>250. APCI (−ve) 328. Analytical Calculated for C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76; S, 9.73. Found: C, 58.40; H, 4.63; N, 12.75; S, 9.63.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].FC(F)(F)C(O)=O.C(ON=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[F:8][C:9]([F:13])([F:12])[CH2:10][O:11][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cccnc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A reactor vessel is charged with 3-aminopyridine (2.0 g, 21 mmol), 2,2,2-trifluoroethanol (15 g, 150 mmol), and trifluoroacetic acid (3.63 g, 31.8 mmol). The solution is cooled to 15° C. and then t-Butylnitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel so that the temperature rises to the range 25° C.-30° C. Potassium carbonate (4.4 g) is added to the vessel and the reaction mass is stirred overnight followed by dilution with water and extraction with ethyl acetate. The solvent is evaporated to obtain 3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (3.94 g, crude yield 59.5%) with an actual yield of 56.8%.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:23]([C:21]2[N:22]=[C:18]([CH3:17])[O:19][C:20]=2[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[O:24])=[N:12]1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)c2nc(C)oc2-c2cccc(C)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([OH:11])=[O:10].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]=[CH:7][Cl:8])[C@H:3]1[C:9]([O:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:21]=1)=[O:10]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)O
Product: CC1(C)[C@H](C=C=CCl)[C@H]1C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Example 1, 1.2 g of the acid of Example 27 and 1 g of 3-phenoxy-benzyl alcohol were reacted to obtain 3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3-(3-chloro-1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.Cl.[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1>C1COCC1>[OH:38][CH:36]1[CH2:37][N:34]([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:35]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.5 g, 2.76 mmol), CDI (0.671 g, 4.14 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (1.2154 ml, 8.28 mmol) and azetidin-3-ol hydrochloride (0.756 g, 6.90 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.51 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.53 g (10 mmol) of 3-methyl-4-nitrophenol, 1.95 g (10 mmol) of t-butyl bromoacetate and 2.76 g (20 mmol) of potassium carbonate in 10 mL of DMF are stirred at RT for 2 h. Water is added and the mixture is extracted with EtOAc and the organic phase is washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residual oil is filtered through a pad of silica gel using CH2Cl2 as the eluant to give (3-methyl-4-nitrophenoxy)-acetic acid t-butyl ester as an oil: 1H-NMR (CDCl3) δ 8.08 (d, J=9.56, 1H), 6.82-6.75 (m, 2H), 4.58 (s, 2H), 2.63 (s, 3H), 1.49 (s, 9H); Anal. Calcd for C13H17NO5 C, 58.42; H, 6.41; N, 5.24; Found C, 58.04; H, 6.51; N, 5.09.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2)#[CH:9]>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:8]#[C:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: Brc1ccccn1
Reactant: C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccccn3)c21

Procedure:
Using Method J above, 2-bromopyridine (44.9 mg, 0.28 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 5) (50 mg, 0.19 mmol) using DPPFPdCl2 (7.7 mg) (Aldrich) and CuI (2 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent and heating at reflux for 2 days, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(2-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 30 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:13]Br>C(O)(=O)C.O>[Br:13][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: BrBr
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(Cl)c(O)c(Br)c1

Procedure:
To a solution of 3-chloro-4-hydroxyphenylacetic acid (2.5 g) in glacial acetic acid (35 mL) was added 0.8 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 51 h. The resulting mixture was diluted with water, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-chloro-4-hydrox-yphenylacetic acid. This crude product was dissolved in methanol (15 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 18 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with water carefully, extracted with dichloromethane. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-chloro-4-hydroxyphenylacetic acid methyl ester (2.5 g, 68%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[O:17]C)(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:1])=[C:11]([OH:17])[CH:12]=1
Reactant: COc1cc(Br)ccc1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)cc1O
Yield: 98.3 %

Procedure:
A mixture of 4-bromo-2-methoxyphenyl benzoate (5 g), sodium hydroxide (3 g), water (5 mL) and ethanol (50 mL) is heated at reflux for 1.5 hours. It is then evaporated to low bulk and the resulting residue is treated with water (20 mL) and concentrated hydrochloric acid (10 mL), and extracted with dichloromethane (150 mL). The organic solution is extracted with saturated aqueous sodium bicarbonate solution (3×25 mL), dried over magnesium sulphate and evaporated, to give 5-bromo-2-methoxyphenol (3.25 g), in the form a colorless solid, m.p. 67°-68° C. [Elemental analysis: C,41.5; H,3.5; Br, 37.8%; calculated: C,41.6; H,3.5; Br, 39.5%].
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([O:19]C)=O)=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1.Cl.[CH3:31][NH2:32]>>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]([NH:32][CH3:31])=[O:19])=[CH:14][C:13]=3[CH:21]=2)=[N:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with methylamine hydrochloride gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.71 (d, 1H, J=4.8 Hz), 8.00–7.92 (m, 2H), 7.56–7.52 (m, 1H), 7.44–7.39 (m, 2H), 7.12 (m, 2H), 6.69 (bdd, 1H), 2.96 and 2.94 (2s, 3H).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:14](O)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=NC=2C=1.[NH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40]>CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=1)[C:14]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[O:15])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(N)CO
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)C(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 10 ml of DMF, and the mixture was stirred at RT for 20 min. The resulting solution was added dropwise to a solution of 168 mg (1.88 mmol) of 2-amino-2-methyl-1-propanol in 2 ml of DMF. The reaction mixture was stirred at RT for 20 min. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 364 mg (74% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].CN(C)CCN>CS(C)=O>[CH3:29][S:30]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: CS(=O)[O-]
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2n1
Temperature: 125 °C
Reaction time: 5 h
Yield: 37.2 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (89 mg, 0.194 mmol) from Example 78, sodium methane sulfinate (80 mg, 0.777 mmol), and N,N-dimethylethylenediamine (7 mg, 0.078 mmol) in anhydrous DMSO (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added copper (I) trifluoromethane-sulfonate benzene complex (20 mg, 0.038 mmol). The reaction vessel was sealed and the mixture was stirred at 125° C. for 5 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (33 mg, 37%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.90-8.02 (m, 2H), 7.78 (s, 1H), 7.25-7.36 (m, 2H), 5.54 (s, 2H), 4.74 (br s, 1H), 3.50 (br s, 1H), 3.33-3.34 (m, 4H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.15-1.30 (m, 4H); LCMS (ESI) m/z 458 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].OO.S(S([O-])=O)([O-])(=O)=[O:18].[Na+].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
4-methylthio-3-nitrobenzoic acid (4.36 g, 20 mM) was dissolved in acetic acid (200 ml), and treated at ambient temperature with H2O2 (2.5 ml, 30%, 22 mM). After stirring at ambient temperature for 4 days, excess peroxide was decomposed with sodium metabisulfite, and solvent evaporated. The residue was purified by chromatography on silica, eluting with methanol, to give 4-methanesulphinyl-3-nitrobenzoic acid (4.1 g, 89%), mp 238-239°. Nmr (DMSO-d6): δ 2.90 (s, 3H); 8.29 (d, 1H); 8.56 (dd, 1H); 8.68 (d, 1H).
Reaction SMILES: [N+:1](=[C:3]([C:10](=[O:13])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2].C(N(CC)CC)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[Br:33]Br>C(Cl)Cl>[N+:1](=[C:3]([C:10](=[O:13])[CH:11]([Br:33])[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2]
Reactant: BrBr
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)C(C)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-cooled solution of allyl 2-diazo-3-ketopentanoate (9.1 g, 0.05 mole) in 100 mL of CH2CL2, was added 8.35 mL of triethylamine, followed by dropwise addition of 11.6 mL trimethylsilyl triflate (13.34 g, 0.06 mole) over twenty minutes. The resulting solution (orange) was stirred at 0° C. for one hour. A solution of bromine (8.0 g, 0.05 mole) in 30 mL CH2Cl2 was added over twenty minutes at 0° C. The mixture was stirred at 0° C. for one hour. The reaction mixture was then washed with water three times, dried over magnesium sulphate and concentrated to give the title compound as an oil (12.74 G, 97% yield).
Reaction SMILES: O[NH-].C1[CH2:7][O:6][CH2:5][CH2:4]1.C(#[N:10])C.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:24]1([P:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[O:6]1[CH2:5][CH2:4][N:10]=[CH:7]1
Reactant: CC#N
Reactant: C1CCOC1
Agent: [NH-]O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C1=NCCO1

Procedure:
Hydroxyamide IX is then subjected to cyclodehydration in an inert organic solvent (e.g., THF, acetonitrile or methylene chloride) under an inert atmosphere (e.g., argon) with triphenylphosphine (employing a molar ratio of IX:triphenylphosphine of about 0.5:1 to about 1:1) and carbon tetrachloride in the presence of an amine base (e.g., triethylamine or diisopropylethylamine) to form an oxazoline ##STR26##
Reaction SMILES: ClCCl.[CH:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([CH2:27][OH:28])[O:25][CH3:26])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([O:28][CH2:27][CH:24]([O:25][CH3:26])[CH2:23][O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(CO)COCCCCCCCCCCCCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COS(C)(=O)=O
Yield: 79.1 %

Procedure:
To 100 ml of dichloromethane are added 10.8 g of 1-(12-cyclohexyldodecyl)-2-methylglycerine and 4.42 ml of triethylamine, to which 3.64 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. Then, the mixture is stirred at room temperature for 2 hours to complete the reaction. The reaction mixture is washed with water, an aqueous sodium bicarbonate solution and water, and dried. The solvent is removed by distillation to leave 10.42 g of the captioned compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[OH:29])=[O:18].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3c(C(C)=O)ccc4ccccc34)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 1-hydroxy-2-acetonaphthone (250 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (5 mg, yield 30%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[C:5]([N:12]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:20]=[CH:21][CH:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:9][C:6]1[C:5]([N:12]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][CH:20]=[CH:21][CH:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[OH:8]
Reactant: O=C1C2C=CCCC2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.6 %

Procedure:
Iron powder (2.48 g) was added into a solution of 6-chloro-4-fluoro-2-nitro-3-(tetrahydrophthalimido)phenol (3.67 g) in acetic acid (60 ml) and stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, evaporated to give 3.6 g of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:11].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[CH2:17]1[C:18]2[C:14](=[CH:13][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:35]3[CH2:36][CH2:37][CH:32]([C:28]4[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=4)[CH2:33][CH2:34]3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: O=C(CCCl)c1ccc2c(c1)CCC2
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[C:26]([F:29])([F:28])[F:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[C:20]=3[C:26]([F:27])([F:29])[F:28])[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1C(F)(F)F
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1cccc(-n2cnc3ccc(OCc4ccccc4)nc32)c1C(F)(F)F
Temperature: 80 °C

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.10 g, 0.44 mmol) and 1,3-difluoro-2-(trifluoromethyl)benzene (0.12 g, 0.67 mmol) were dissolved in DMF (1.0 mL) and Cs2CO3 (0.29 g, 0.89 mmol) was added. The reaction mixture was heated to 80° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether. The combined organic portions were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound.