Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][CH:29]=1)[CH2:8][C:9]1[N:10]=[C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[O:12][CH:13]=1)(C)(C)C.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.FC(F)(F)C(O)=O>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([NH:7][CH2:8][C:9]3[N:10]=[C:11]([CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][C:19]([S:22]([F:27])([F:26])([F:23])([F:24])[F:25])=[CH:20][CH:21]=4)[O:12][CH:13]=3)=[CH:33][CH:32]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(CCCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CNc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Yield: 26.4 %

Procedure:
A solution of 450 mg (0.72 mmol) [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-{2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-carbamic acid tert-butyl ester in 4 ml dichloromethane and 4 ml trifluoroacetic acid was stirred at r.t. for 1 h. Water was added and the mixture neutralized with solid sodium carbonate. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The residue was stirred with a little isopropanol, the crystallized material isolated by filtration, washed with ether and dried to give 100 mg (27%) of product.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]([C:12]1[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[C:9]([CH3:11])=[O:10].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:16][C:15]1[CH:14]=[CH:13][C:12]([NH:8][C:9](=[O:10])[CH3:11])=[CH:18][CH:17]=1)[CH3:7]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1
Yield: 80.1 %

Procedure:
Ethyl bromoacetate (452 g, 2.7 mol.) was added to a mixture of paracetamol (300 g, 1.984 mol) and anhydrous K2CO3 (1.80 kg, 7.814 mmol) in anhydrous acetone (3 L) and refluxed for 16 hours. Acetone was distilled and water (5 L) was added. Crude 1 was filtered, dried and recrystallised from a mixture of toluene:hexane (1:5) to give pure 1 (377 grams, 80%) as a white shining powder. The melting point was found to be 104.2-106.2° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Product: Cc1c(Cl)nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 17) and tert-butyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate [JP 63183560 A2], to afford the product as a colourless oil, (100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:32][C:31]=2[C:39](O)=[O:40])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[O:34][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:32][C:31]=2[C:39]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]([CH3:20])[C:13]4=[O:21])[CH:8]=2)=[O:40])=[CH:28][CH:29]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: CS(=O)(=O)c1nc(C(=O)O)c(-c2ccc(F)cc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2nc(S(C)(=O)=O)oc2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 20 h
Yield: 53.5 %

Procedure:
6-(5-amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (110 mg, 0.28 mmol) was dissolved in DMF (5 mL) with 5-(4-fluoro-phenyl)-2-methanesulfonyl-oxazole-4-carboxylic acid (142 mg, 0.5 mmol) at RT. HATU (150 mg, 0.39 mmol) was added, followed by DIEA (0.5 mL, 2.87 mmol). The mixture was stirred for 20 h. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 82 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 548.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[N:13]1C=CC=CC=1.N[C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[O:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([C:20]2[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=2)=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:13])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2ccc(-c3cc(Cl)cc(S(N)(=O)=O)c3Cl)cc2o1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (174 mg, 0.709 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (100 mg, 0.675 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (154 mg, 64%), single spot at Rf 10.50 (60:40 hexane:ethyl acetate). mp 167.0-167.3° C., HPLC purity 97% (tR 1.97 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.93 (1H, d, J=2.3 Hz), 7.47 (1H, d, J=8.6 Hz), 7.46-7.40 (4H, m), 7.00 (1H, dd, J=8.6, 2.0 Hz), 2.61 (3H, s). LCMS: 355.07 (M−). FAB-MS (MH+, C14H10Cl2N2O3S): calcd 356.9867, found 356.9875.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].Br[CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[C:17]([O:19][CH3:20])=[O:18]>>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:16]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCCC2
Reactant: COC(=O)C(Br)CCCCBr
Product: COC(=O)C(CCCCBr)Oc1cc2c(cc1[N+](=O)[O-])CCCC2

Procedure:
In a manner similar to that of Reference Example 5, 5,6,7,8-tetrahydro-3-nitro-2-naphthol was allowed to react with methyl 2,6-dibromohexanoate to give methyl 6-bromo-2-(5,6,7,8-tetrahydro-3-nitro-2-naphthyloxy)hexanoate as an oily product, which was then allowed to react, in a manner similar to that of Reference Example 8, with 1-(4-fluorophenyl)piperadine to obtain methyl 6-[4-(4-fluorophenyl)-1-piperazinyl]-2-(5,6,7,8-tetrahydro-3-nitro-2-naphthyloxy) hexanoate as an oily product. The overall yield was 79.4%.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[C:37]([C:39]3[N:47]=[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][N:41]4[N:40]=3)[CH:36]=[N:35]2)=[CH:30][CH:29]=1.[C:48]([O:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([C:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[C:37]([C:39]3[N:47]=[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][N:41]4[N:40]=3)[CH:36]=[N:35]2)=[CH:30][CH:29]=1.[C:48]([O:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([C:61]2[CH:66]=[CH:65][C:64]([NH:67][C:9]3[N:10]=[C:3]4[C:2]([C:22]5[CH:21]=[N:20][N:19]([C:16]6[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=6)[CH:23]=5)=[CH:7][CH:6]=[CH:5][N:4]4[N:8]=3)=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)=[O:54])([CH3:51])([CH3:49])[CH3:50]
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: Fc1ccc(-n2cc(-c3nc4ccccn4n3)cn2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3nc4c(-c5cnn(-c6ccc(F)cc6)c5)cccn4n3)cc2)CC1

Procedure:
2-Chloro-8-([1-(4-fluoro-phenyl)1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-(4-fluorophenyl)pyrazole-4-boronic acid in a manner analogous to Example 2c (0.45 g, 67%). 280b) 4-{4-[8-(1-(4-Fluoro-phenyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-([1-(4-fluoro-phenyl)1H-pyrazol-4-yl]-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.077 g, 23%). MP=176-178° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 9.26 (s, 1H), 8.76 (m, 2H), 7.95 (m, 3H), 7.65 (m, 2H), 7.45 (m, 2H), 7.15 (m, 2H), 7.09 (m, 1H), 4.08 (m, 2H), 2.80 (m, 2H), 2.63 (m, 1H), 1.73 (m, 2H), 1.48 (m, 2H), 1.42 (s, 9H). MS=554 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16]([O:18]CC)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].[OH-].[K+]>CCO.C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[C:5]([C:16]([OH:18])=[O:17])=[N:6][N:7]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Yield: 93.4 %

Procedure:
D2 (38 mmol, 1.0 eq.) and aq. KOH-solution (3M, 190 mmol, 5.0 eq.) in EtOH (152 mL) were heated for 45 min at 50° C. The mixture was cooled to RT and diluted with DCM and water. The aq. phase was washed a second time with DCM. The aq. phase was acidified with aq. HCl-solution (1N) to pH=1 and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na2SO4. Removal of the solvent yielded the product D3 as a brown solid (8.88 g, 93% over 2 steps). 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.34 (t, J=7.0 Hz, 3H), 4.02 (q, J=7.0 Hz, 2H), 7.37 (dd, J=J=9.0 Hz, 2H), 7.87 (dd, J=9.0 Hz, J=4.6 Hz, 2H), 8.38 (s, 1H), 12.68 (br s, 1H). MS (ES) C12H11FN2O3 requires: 250. Found: 251 (M+H)+ and 273 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C/C=C/C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid (2.8 g) and 4-nitrophenol (1.71 g) in 20 mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (2.1 g). The mixture was stirred at room temperature for 18 hours and the usual work up furnished 4.0 g of (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([CH3:27])=[C:21]3[NH:20][C:19]2=[O:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([CH3:27])=[C:21]3[N:20]([CH2:2][CH3:3])[C:19]2=[O:28])=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Iodoethane (0.289 mL) was added to a mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (998 mg) and cesium carbonate (1.96 g) in DMF (10 mL) at room temperature. The mixture was stirred at 50° C. for 4 h. The mixture was diluted with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15%-30% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (801 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: Cc1cccc(-c2cc(N3CCC[C@H]3CO)nc3c(I)c(C)nn23)c1
Reactant: COc1ccc(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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(C)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
(S)-(1-(7-(3-Methylphenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (22 mg), 4-methoxyphenylboronic acid (17 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (12 mg).
Reaction SMILES: [S:1](Cl)Cl.[CH2:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH3:5].N1C=CC=CC=1.[Cl:17][C:18]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:19]=1[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(OCC)C>[Cl:17][C:18]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][S:1][N:6]([CH2:4][CH3:5])[S:7]([CH3:10])(=[O:9])=[O:8])=[CH:26][CH:27]=1
Reactant: ClSCl
Reactant: CCNS(C)(=O)=O
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCN(SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 g of sulphur dichloride in 15 ml of dry diethyl ether was added over 10 minutes to a stirred solution of 3.1 g of N-ethylmethanesulphonamide in 15 ml of the same solvent, keeping the temperature between 10°-15° by means of external cooling. A solution of 2.0 g of dry pyridine in 15 ml of dry diethyl ether was then added over 15 minutes at the same temperature and the reaction mixture was allowed to warm to room temperature over 1 hour. The resulting suspension was added over 5 minutes to a solution of 7.2 g of 4-[2-chloro-4-(trifluoromethyl)phenoxy]aniline (1A) in 75 ml of dry diethyl ether containing 2.0 g of pyridine, keeping the temperature of the mixture between 5°-10° C. After stirring at 10°-15° for 1 hour, the reaction mixture was washed three times with water, the ether layer was separated, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using diethyl ether as eluent, to give 2, as a buff solid m.p.: 98°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:20].[K+].CO.C[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:20])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ncsc2CBr)c1
Reactant: CC(=O)[O-]
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ncsc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-Bromomethyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (10 mL) together with KOAc (1.52 g) at 20° C. for 30 min. MeOH (20 mL) and NaOMe (0.84 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:2) as eluent to give 3-(5-hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.43 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: COc1cc2cc[nH]c2cc1O
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc2[nH]ccc2cc1OC
Temperature: 80 °C
Yield: 35 %

Procedure:
6-Hydroxy-5-methoxyindole (2 g; 0.0123 mole) dissolved in 10 ml of dimethylformamide (DMF) is introduced dropwise in the course of 20 minutes into a mixture of 1-bromohexadecane (4.5 g; 0.0148 mole) and potassium carbonate (1.87 g; 0.0135 mole) in 45 ml of DMF at 70° C. and under nitrogen. The reaction mixture is stirred under nitrogen at 80° C. for 3 and a half hours. The blackish mixture is poured into ice-cold water with stirring and the brownish solid formed is immediately filtered off and washed with water. It is taken up in dichloromethane and dried over sodium sulphate. After chromatography on silica 60 (eluent: toluene/CH2Cl2, 50:50), and recrystallization in hexane, the derivative 26 is obtained (1.66 g; 35% yield).
Reaction SMILES: CS[C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.Cl[C:29]1C=CC=C(C(OO)=O)C=1.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(#N)C>[CH3:29][S:39]([C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:26])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1)(=[O:43])=[O:41]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-(methylthio)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (2.38 g, 6.07 mmol) in acetonitrile (25 mL) was added m-chloroperbenzoic acid (70%, 3.20 g, 13.3 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (0.87 g, yield 34%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:17][CH2:16][N:15]([CH2:32][C:33]([OH:35])=[O:34])[CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1N(CCO)CCN(C[CH2:46][S:47](O)(=O)=O)C1.C(Cl)(Cl)=S.C(Cl)(Cl)Cl>Cl>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:13][CH2:14][N:15]([CH2:32][C:33]([OH:35])=[O:34])[CH2:16][CH2:17][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)=[C:46]=[S:47]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: Nc1ccc(C(C(=O)O)N2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Agent: Cl
Agent: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1CCN(CC(=O)O)CCN(C(C(=O)O)c2ccc(N=C=S)cc2)CCN(CC(=O)O)CC1

Procedure:
To a solution of α-(4-aminophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, samarium-153 complex prepared from 220 μl of 153Sm solution in 0.1N HCl were added 2 μl of HEPES buffer (0.5M, pH 8.9), 2 μl of thiophosgen and 200 μl of chloroform. It was vortexed vigorously 2 or 3 times for a few seconds each time. The chloroform layer was discarded and the aqueous layer which contained mainly the desired product was saved and further purified. The yield of α-(4-isothiocyanatophenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, samarium-153 complex, as analyzed by HPLC on GF-250 column based on the 153Sm activity using the HPLC System I was usually over 90%. To purify, the aqueous layer was passed through a Sep-Pak™ C-18 cartridge and eluted with 90 percent acetonitrile in water. The first 300 μl of effluent was discarded, and the desired product came off in the next 1200 μl, with 86-93% recovery. The bulk of the solvent was then evaporated off in a Speed Vac™ concentrator over a period of about 2 hours.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C>[C:6]1([CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:3][CH2:2][CH2:1][NH2:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: NCCNC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 90.15 g of ethylenediamine, 50.7 g of benzhydryl chloride and 300 ml of acetonitrile is heated under reflux for 24 hours. It is partitioned between 400 ml of diethyl ether and 175 ml of 10% sodium hydroxide solution, the ether phase is separated off, dried over magnesium sulphate, evaporated to dryness and distilled under reduced pressure. N-diphenylmethylethylenediamine is obtained, b.p.0.13 =116°-124° C., m.p. 23°-24° C.