Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=C[CH:17]=2)=[CH:5]1)([CH3:3])[CH3:2].[NH2:24]C1C=C2C(C(C3C=CC(C#N)=CC=3)=CN2C(C)C)=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>[Pd].[Pt]=O>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[N:24][CH:17]=3)=[CH:5][N:4]2[CH:1]([CH3:3])[CH3:2])=[CH:8][CH:9]=1
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc(N)cc21
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Product: CC(C)n1cc(-c2ccc(C#N)nc2)c2ccc(N)cc21

Procedure:
Method F This compound can be prepared from 5-(1-isopropyl-6-nitro-1H-indol-3-yl)-pyridine-2-carbonitrile (4, R1=i-Pr, R3=5-(2-cyanopyridine)) in a manner substantially similar to that described immediately above for 4-(6-amino-1-isopropyl-1H-indol-3-yl)-benzonitrile except Degussa type E101 NE/W 10% Palladium on activated carbon can be used instead of platinum (II) oxide in Method E. LRMS (API ES+)=277.0 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[C:23]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]([CH2:16][CH2:17][CH:18]2[C:27]3[C:22](=[C:23]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)COc1cccc2c1CCCC2CCCO
Product: COC(=O)COc1cccc2c1CCCC2CCC(=O)N(c1ccccc1)c1ccccc1

Procedure:
By the same procedure as reference example 1→reference example 2→example 1 (using diphenylamine instead of dibenzylamine), using methyl [1-(3-hydroxypropyl)-1,2,3,4-tetrahydronaphthalen-5-yl]oxyacetate instead of methyl(1-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yl)oxyacetate, was obtained methyl [1-(2-diphenylaminocarbonylethyl)-1,2,3,4-tetrahydronaphthalen-5-yl]oxyacetate. By the same procedure as example 2, using methyl [1-(2-diphenylaminocarbonylethyl)-1,2,3,4-tetrahydronaphtahalen-5-yl]oxyacetate thus obtained, the title compound having the following physical data was given.
Reaction SMILES: C(OCCI)C1C=CC=CC=1.[CH2:12]([O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH:35]([CH2:36][O:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:34][N:33]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:32][CH:31]2[O:64][CH2:65][C:66]2[CH:75]=[CH:74][C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[CH:67]=2)=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH:31]([O:64][CH2:65][C:66]3[CH:75]=[CH:74][C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH:67]=3)[CH2:32][N:33]([C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])[CH2:34][CH:35]2[CH2:36][OH:37])=[CH:28][CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: ICCOCc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22 (d), from tert-butyl (3RS,4RS,5SR)-1-benzyl-4-(4-bromo-phenyl)-5-hydroxymethyl-piperidin-3-ol [Example 68 (e)] by a palladium catalyzed carbonylation with carbon monoxide in methanol there was obtained methyl (3RS,4RS,5SR)-4-(1-benzyl-3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate, hydrogenolysis of which in the presence of 5% palladium-charcoal at atmospheric pressure in methanol analogously to Example 2 (e) gave methyl 4-(3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate. Subsequent introduction of the BOC group analogously to Example 1 (f) yielded tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate, from which by reaction with triphenylchloromethane analogously to Example 68 (i) there was obtained tert-butyl (3RS,4RS,5SR)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-5-trityloxymethyl-piperidine-1-carboxylate. Subsequent alkylation by means of 2-bromomethyl-naphthalene analogously to Example 1 (g) yielded tert-butyl (3RS,4RS,5SR)-4-(4-methoxycarbonyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, reduction of which with lithium borohydride analogously to Example 22 (e) yielded tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 737 (M+NH4)+. Further alkylation with 2-(benzyloxy)-ethyl iodide [Helv.Chim. Acta Vol.71, (1988), 2039] analogously to Example 1 (g) gave tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which after cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 629 (M+NH4)+.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([NH:8][C:9]1[CH:10]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:13][C:14]=1[NH2:15])[CH:5]([CH3:7])[CH3:6]>C(O)(C)C.C(OCC)(=O)C>[CH2:4]([N:8]1[C:9]2[CH:10]=[C:11]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:13][C:14]=2[N:15]=[C:2]1[NH2:1])[CH:5]([CH3:7])[CH3:6]
Reactant: N#CBr
Reactant: CC(C)CNc1cc(-n2ccnc2-c2ccccc2)ccc1N
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)Cn1c(N)nc2ccc(-n3ccnc3-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Add cyanogen bromide (177 mg, 1.67 mmol) to a solution of 1-(3-(isobutylamino)-4-aminophenyl)-2-phenyl-1H-imidazole (410 mg, 1.34 mmol) in 10 mL isopropanol cooled to 0° C. Stir for one hour at this temperature and then stir at room temperature over night. Dilute with ethyl acetate and wash with 1N sodium hydroxide. Dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to radial silica gel chromatography, eluting with methanol containing 4% methanol to provide the title compound as a tan solid (220 mg, 50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example J34) (227 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (290 mg, 60%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21](O)=[O:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[CH3:34][NH2:35]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21]([NH:35][CH3:34])=[O:22])=[O:17])[CH2:14][CH2:15]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Product: CNC(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and methylamine (43%, white solid, MS (m/e): 469.3 (M+H, 100%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>[Pd].COCCOC>[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(Cl)n2)C1
Reactant: OB(O)c1ccccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(-c3ccccc3O)n2)C1
Yield: 49.1 %

Procedure:
A mixture of (S)-tert-butyl 3-(2-chloropyrimidin-4-ylamino)pyrrolidine-1-carboxylate (0.120 g, 0.400 mmol), 2-hydroxyphenyl boronic acid (0.166 g, 1.20 mmol), palladium catalyst (0.013 g, 0.020 mmol), and 1 M aqueous Na2CO3 (0.80 mL, 0.80 mmol) in DME (4 mL) was refluxed for 24 hours. After cooling, water (50 mL) was added and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (66% ethyl acetate/hexanes) to give the title compound as an oil (0.070 g, 49%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=C(C=C)[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:42]C)C=C4)N(CC2)C1.S(=O)(O)[O-].[Na+].[C:84]([OH:88])(C)([CH3:86])[CH3:85]>O>[F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:85]([CH:84]([OH:88])[CH2:86][OH:42])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=Cc1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Oc1ccc2cccc(C(O)CO)c2n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 2-trifluoromethanesulfonyloxy-8-vinylquinoline in 37 ml of tert-butanol and 37 ml of water is added to a suspension, cooled to 0° C. with an ice bath, of AD-mix-α in 300 ml of tert-butanol and 300 ml of water. The reaction mixture is stirred at 0° C. for 16 h and then sodium bisulfite with 300 ml of water is added. The mixture is stirred for 1 h at ambient temperature and extraction is carried out with ethyl acetate (3×200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: cyclohexane/ethyl acetate 1/1) to provide 12.0 g of 2-trifluoromethanesulfonyloxy-8-(1,2-dihydroxyethyl)quinoline in the form of a yellow oil. (Yield: 80%)
Reaction SMILES: S(OC[C@H](CC1C=CC=CC=1)[NH:8][C:9]([O:11]CC1C=CC=CC=1)=O)(=O)(=O)C.[H-].[Na+].S([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(OCC1OC1)(=O)=O.C[N:44](C=O)C>>[CH2:40]([NH:44][C:9]([NH2:8])=[O:11])[C:39]1[CH:38]=[CH:37][CH:36]=[CH:42][CH:41]=1
Reactant: CS(=O)(=O)OC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Product: NC(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Allyl urea 1 (195.2 mg, 0.09 mmol) was dissolved in 6.0 mL of DMF and cooled to 0° C. This was followed by the addition of NaH (54 mg, 1.0 mmol). The glycidyl tosylate (410 mg, mmol) was then added as a solid. The reaction was stirred for 4 hours at 25° C. and then quenched by the addition of 4 mL of saturated aqueous sodium bicarbonate. The reaction was then extracted by 10 mL of Et2O. The organic layer was then washed by 10 mL of saturated aqueous sodium bicarbonate and 2×10 mL of saturated brine. The combined organic portions were then dried over MgSO4, filtered and concentrated in vacuo to provide the desired epoxide 2 (180 mg, 73% yield). The epoxide was then used without further purification. ##STR337##
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH:8](N)[C:9]([OH:11])=O)=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.CC(N(C)C)C[N:17]1[C:26]2[CH:27]=[C:28](S(N(C)C)(=O)=O)[CH:29]=[CH:30][C:25]=2[S:24][C:23]2[CH:22]=[CH:21]C=CC1=2.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=C(C[C:59]([NH:61][CH2:62]C(OC2C=C(OC)C=CC=2)C)=N)C=CC=1>>[CH3:59][N:61]([CH2:21][CH2:22][CH2:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:17][C:9](/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1)=[O:11])[CH3:62]
Reactant: CC(CN1c2ccccc2Sc2ccc(S(=O)(=O)N(C)C)cc21)N(C)C
Reactant: COc1cccc(OC(C)CNC(=N)Cc2cccc(C)c2)c1
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN(C)CCCSc1ccccc1NC(=O)/C=C/c1ccccc1

Procedure:
fenclonine; fonazine mesilate; xylamidine tosylate.
Reaction SMILES: [H-].[Na+].[CH2:3](OC=O)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=O)[CH2:13][CH2:12]2.O.[NH2:20][NH2:21].C(O)(=O)C>C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14]1[NH:20][N:21]=[CH:3][C:13]=1[CH2:12]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: NN
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)Cc1cn[nH]c1-2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of a 60% suspension of sodium hydride in mineral oil (6.83 g, 284.8 mmol) and ethylformate (24.2 mL, 284.8 mmol) in benzene (100 mL) at about 0° C. was added a solution of 5-bromo-1-indanone (30.0 g, 142.4 mmol) in benzene (100 mL) over about 90 minutes. The reaction was then stirred for about 17 hours while being allowed to warm to room temperature. The formed precipitate was collected by filtration and was dissolved in ethanol (600 mL). To this solution was added hydrazine monohydrate (17 mL, 350.5 mmol) and acetic acid (19.2 mL, 335.4 mmol) and the reaction mixture was heated under reflux for about 3 hours. The mixture was cooled, concentrated under vacuum and the precipitate was collected by filtration and was dried under high vacuum to provide the desired product. MS (DCI-NH3): m/z 235, 237 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](SC)[N:3]=1.Cl[C:12]1C=C(C=CC=1)C(OO)=O.[S:22]([O-:26])([O-])(=[O:24])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:22]([CH3:12])(=[O:26])=[O:24])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nc(Cl)cc(Cl)n1

Procedure:
A solution of 4,6-dichloro-2-(methylthio)pyrimidine (48.3 g, 247 mmol) in dichloromethane (1 L) was cooled on an ice bath. 3-Chloroperoxybenzoic acid (152 g, 619 mmol) was added portion-wise keeping the temperature below 10° C. The solution was allowed to warm to room-temperature and stirred over-night. The mixture was diluted with dichloromethane (2 L) and treated with an aqueous solution of sodium thiosulphate and sodium hydrogen carbonate (600 mL). The resulting mixture was stirred over-night. The phases were separated and the organic layer was washed with sodium hydrogencarbonate (500 mL) and brine (1 L), dried over sodium sulphate, filtrated and concentrated in vacuo. The resulting yellow solid was stirred with ether and 4,6-dichloro-2-methanesulfonyl-pyrimidine (32.6 g, 58%) was collected by filtration as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](S(Cl)(=O)=O)=[CH:4][CH:3]=1.C([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](N)[CH:22]=2)[CH2:17][CH2:16]1)(=O)C.N1C=CC=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:26]=[CH:27][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: c1ccncc1
Product: Fc1cccc(C=Cc2c[nH]c3ccccc23)c1
Yield: 82 %

Procedure:
Under ice cooling, 4-fluorobenzenesulfonyl chloride (1.4 g) was added dropwise into a solution (10 ml) of 1-acetyl-6-aminoindoline (1.0 g) in pyridine followed by stirring the resultant mixture for 30 min. After concentrating it under reduced pressure, 5 N hydrochloric acid was added thereto and the resultant mixture was heated under reflux for 5 hr. Then the reaction solution was basified with a conc. aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and purified by NH-silica gel column chromatography (methylene chloride/ethanol system) to give the title compound (1.36 g) as white powdery crystals (yield: 82%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29]C)=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([OH:29])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C(=O)O)ccc3o2)n1
Yield: 99.7 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-methoxycarbonylphenylmethoxy)benzofuran-2-yl]thiazole (0.28 g) and 4N aqueous sodium hydroxide (1.0 ml) in methanol (5 ml) was stirred under reflux 5.5 hours. After being cooled, the resulting solution was concentrated under reduced pressure to give a residue. The residue was dissolved in water and adjusted to pH 4 with diluted aqueous hydrochloric acid to give crystals. The crystals were filtered and washed with water to give 4-tert-butyl-2-[5-(2-carboxyphenylmethoxy)benzofuran-2-yl]thiazole (0.27 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.O=S(Cl)[Cl:16].[CH3:18]O>>[ClH:16].[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([O:13][CH3:18])=[O:12])[NH:2]1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Product: COC(=O)[C@H]1Cc2ccccc2CN1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Aldrich, 500 mg, 2.82 mmol) in MeOH (2.8 mL) was added SOCl2 (824 μL, 11.3 mmol) at 0° C. The resulting reaction mixture was allowed to warm to room temperature over 5 h and then stirred at 50° C. overnight. The reaction mixture was then concentrated in vacuo to give the title compound (457 mg, 71%) as a white solid. 1H NMR (CDCl3) δ 7.30-7.23 (m, 2H), 7.20-7.13 (m, 2H), 4.78-4.69 (m, 1H), 4.56-4.45 (m, 1H), 4.43-4.35 (m, 1H), 3.87 (s, 3H), 3.49-3.43 (m, 2H); MS(ESI+) m/z 192.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][N:16]=2)[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[O:3].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][N:16]=2)[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2)(=[O:29])=[O:3]
Reactant: Cn1ncnc1-c1cc(S(C)=O)c2[nH]c(=O)ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cn1ncnc1-c1cc(S(C)(=O)=O)c2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8-methylsulphinyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolone (0.097 g) and m-chloroperbenzoic acid (0.088 g) in chloroform (10 cm3) was stirred for 18 hours at room temperature. The mixture was then concentrated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with ethyl acetate:methanol, 19:1. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from dichloromethane/hexane to give 8-methylsulphonyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolone, m.p. 226°-232° (0.051 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:17]([O:21][C:22](=[O:53])[N:23]([CH2:36][CH2:37][NH:38][S:39]([C:42]1[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][C:48]=2[CH:49]=[C:50](Br)[CH:51]=1)(=[O:41])=[O:40])[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CO.CCOC(C)=O>[C:17]([O:21][C:22](=[O:53])[N:23]([CH2:36][CH2:37][NH:38][S:39]([C:42]1[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][C:48]=2[CH:49]=[C:50]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:51]=1)(=[O:40])=[O:41])[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(Br)cc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(-c2ccc(O)cc2)cc2cnccc12
Temperature: 85 °C
Yield: 90.2 %

Procedure:
Add Pd(dppb)Cl2 (0.0051 g, 0.0085 mmol), 4-hydroxyphenylboronic acid (0.0258 g, 0.187 mmol) and 2M Na2CO3 (0.21 ml, 0.425 mmol) to [2-(7-bromo-isoquinoline-5-sulfonylamino)-ethyl]-[3-(4-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester, (0.101 g, 0.170 mmol) in 3 ml DMF and 0.75 ml MeOH. Heat the reaction mixture at 85° C. for 1 h, then dilute with EtOAc (20 ml) and wash with H2O (2×20 ml) and brine (10 ml). Concentrate the organic layer and chromatograph on silica gel using a gradient of 0-2% MeOH in CH2Cl2 to give 0.093 g of {2-[7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonylamino]-ethyl}-[3-(4-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester, as a yellow solid in 90% yield. ES Positive Ion MS [M+H]+ ion observed: m/z 607. (Used in Example 98).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][C:11]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>C1COCC1.OS([O-])(=O)=O.[K+]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:34](=[O:36])[CH3:35])[CH2:16]3)=[N:12][C:11]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCCNC3)nc2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a stirring solution of 3-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine dihydrochloride (0.76 mmol, 0.3 g) in THF (5.0 mL) was added triethylamine (3.3 mmol, 0.33 g) and acetyl chloride (2.3 mmol, 0.18 g). The reaction was stirred at room temperature for 1H, diluted with 10% KHSO4 (50 mL) and extracted with ethyl acetate (2×50 mL). The organics were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 3% MeOH:CH2Cl2. The pure fractions were collected and evaporated under reduced pressure. The resulting film was evaporated from CH2Cl2 :hexanes to give 0.2 g of the title compound as a white foam.