Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](C2C=CC(CC(C)C)=CC=2)[CH3:14])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5]>>[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:10]2[CH:11]=[CH:12][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1)[CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)Cc1ccc(C(C)c2ccc(CC(C)C)cc2)cc1
Agent: BrBr
Product: CC(C)Cc1ccc(CCc2ccc(CC(C)C)cc2)cc1

Procedure:
The bromine number of 1,2-(4-isobutylphenyl)ethane fraction, corresponding to the recovered unreacted fraction, was 0.20. According to mass spectrometry, the content of component of m/e=292 was 0.3% (m/e of 1,1-di(4-isobutylphenyl)ethane is 294).
Reaction SMILES: C([O:9][CH:10]([CH2:52][O:53][C@H:54]1[O:83][C@H:82]([CH2:84][O:85][CH2:86][C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C@@H:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@H:64]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C@@H:55]1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:11][O:12][C@H:13]1[O:42][C@H:41]([CH2:43][O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1>C[O-].[Na+].CO>[CH2:16]([O:15][C@H:14]1[C@@H:23]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:41]([CH2:43][O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:42][C@@H:13]1[O:12][CH2:11][CH:10]([CH2:52][O:53][C@H:54]1[O:83][C@H:82]([CH2:84][O:85][CH2:86][C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C@@H:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@H:64]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[C@@H:55]1[O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[OH:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OC(CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC(CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
Dimannoside 11 (800 mg, 0.65 mmol) was dissolved in 1M sodium methoxide in methanol (80 mL) and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in dichloromethane, washed with 2M HCl (2×50 mL) and water (50 mL), and dried over magnesium sulfate. Removal of the solvent gave a residue (a to β 4:1, 615 mg) which was purified over silica [hexane/ether 75:25 to 65:35 gradient elution] to afford the title compound 12 (470 mg, 64%), a mixture of 12 and 13 (90 mg, 12%), and 13 (40 mg, 5%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc2cccnc12
Yield: 76.9 %

Procedure:
Prepared according to the procedure described for Example 126 using 8-quinolinesulfonyl chloride (0.68 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (1.0 g); m.p. 187-188° C. after trituration in diethyl ether and recrystallization from ethanol.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](=[CH2:34])[C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:20]2[C:21]3[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[CH:18][CH:19]=1)=[O:12])=O)(C)(C)C.O1CCOCC1>Cl>[NH2:8][CH2:9][C:10](=[CH2:34])[C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:20]2[C:21]3[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: C=C(CNC(=O)OC(C)(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(CN)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1

Procedure:
A solution of ethyl 4-(3-(2-((tert-butoxycarbonylamino)methyl) acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, 0.11 mmol) in 4 M HCl in dioxane solution (537 μL, 2.15 mmol) was stirred for 1 hour. The reaction mixture was quenched with aqueous saturated sodium bicarbonate (500 μL) and extracted with ethyl acetate (×3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-20% MeOH/DCM to give ethyl 4-(3-(2-(aminomethyl)acrylamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C19H20N5O3 [M+H]+: 366, found 366.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[N:27]=[C:26]([CH2:28][CH2:29][CH:30]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32](=O)[NH:31]4)[NH:25][C:22]3=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[N:27]=[C:26]([CH2:28][CH2:29][CH:30]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32](=[S:47])[NH:31]4)[NH:25][C:22]3=[N:23][CH:24]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)c(F)c1
Solvent: C1COCCO1
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)c(F)c1
Yield: 57.1 %

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 180 mg of N-(2-fluoro-4-methyl-phenyl)-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound B8) and 146 mg of Lawesson's reagent at 100° C. for 3 hours in 20 ml of dioxane. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 106 mg of the title compound as a colorless solid of m.p. 271° C. ESI-MS: 538.2 (MH+). TLC: Rf=0.40 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:31]2[O:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][C:27](=[O:37])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OC(=O)C)C>[C:32]([C:29]1[O:30][C:31]2[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[C:27](=[O:37])[CH:28]=1)([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)c1cc(=O)c2cccc(CBr)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 28.2 %

Procedure:
1.8 g of 2-(4-hydroxyphenoxy)methylquinoline, 2.2 g of 8-bromomethyl-2-carboethoxy-4-oxo-4H-1-benzopyran and 1.0 g of potassium carbonate are combined in 100 ml of acetone and refluxed for 18 hours. The mixture is cooled, diluted with ethylacetate and filtered. The filtrate is concentrated and the crude product purified by flash chromatography on silica gel in 5% ethanol in chloroform/hexane (1:1) to give 0.96 g 2-carboethoxy-8-(4- (quinolin-2-yl-methoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran: m.p. 124°-27° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[C:28]([F:31])([F:30])[F:29].O>CN(C=O)C>[O:7]([CH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[C:28]([F:31])([F:29])[F:30])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)c(CBr)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(COc3ccccc3)cnc12
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of phenol (235 mg, 5.0 mmol) in DMF (2.0 mL) is treated with NaH (60% in oil, 100 mg, 2.5 mmol) for 20 min and then treated with 3-(bromomethyl)-4-phenyl-8-(trifluoromethyl)quinoline (183 mg, 0.50 mmol) in DMF (1.0 mL). After 16 h, the reaction is treated with water and extracted with ether. The extract is dried with MgSO4 and concentrated to an oil. Chromatography with 10:90 ethyl acetate:hexane affords the title compound as a white solid (114 mg, 62%). MS (ES) m/z 380.2; HRMS: calcd for C23H16F3NO, 379.1184; found (ESI, [M+H]+), 380.1246;
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:5][O:6][C:16]=1[NH2:17])=[O:18]
Reactant: ON=C(Cl)c1ccccc1F
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2F)noc1N
Yield: 75.5 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylcyanoacetate (5.94 g, 59.92 mmol) and sodium methoxide (4.98 g, 92.18 mmol), a white solid required compound (8.23 g, 34.82 mmol, 76%) was obtained.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:24][OH:25]>N1C=CC=CC=1.C(O)C>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[N:24][OH:25])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(C=O)c2)C(C)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCN1CCC(C)(c2cccc(C=NO)c2)C(C)C1
Yield: 21.1 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-(3-formylphenyl)piperidine (Example 28, 80 mg, 0.27 mmol) in a mixture of pyridine (1 mL) and ethanol (1 mL) was treated with hydroxylamine hydrochloride (22 mg, 0.32 mmol) and the resulting mixture was heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residual orange oil was purified by column chromatography on silica gel (10 g) eluted with a gradient of dichloromethane:methanol:0.880 ammonia (98:1:1 to 94:5:1). This gave the title compound as an oil (18 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Cl.[CH2:22]([C:26]1[N:27]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:28](CCl)=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH2:22]([C:26]1[N:27]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:28]([C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:6]([O:5][CH2:4][CH3:3])=[O:7])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCCCc1ncc(CCl)n1Cc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To dry dimethylformamide (50 mL) under argon was added sodium hydride (0.53 g, 0.022 mol) followed by diethyl benzyl malonate (5.51 g, 0.022 mol) in dimethylformamide (10 mL) at 0° C. The mixture was stirred at ambient temperature for one hour. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-chloromethyl-1H-imidazole hydrochloride (3.5 g, 0.0105 mol) in dimethylformamide (40 mL) was added over 5 minutes. The reaction mixture was stirred at 25° C. for 18 hours, then partitioned between water and methylene chloride. The organic layer was washed with water, dried, and concentrated. The crude product was flash chromatographed over silica gel to give 4.54 g (85%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)(=[O:21])=[O:20])[C:13]=1[OH:34])=[O:10].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:19]([C:14]1[C:13]([OH:34])=[C:12]([NH:11][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[O:10])[CH:17]=[CH:16][C:15]=1[Cl:18])(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Solvent: O=C(O)C(F)(F)F
Product: NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 75 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-(2-bromophenyl)-N′[3-[N″-[3-(t-butoxycarbonylamino)propyl]aminosulfonyl)-4-chloro-2- hydroxyphenyl] urea (21 mg, 0.036 mmol) was stirred in 1 mL of trifluoroacetic acid to from the desired product (16 mg, 75%). 1H NMR (MeOD-d4): δ 8.28 (d, 1H), 7.80 (d, 1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.07 (d, 1H), 7.02 (d, 1H) 3.05 (m, 4H) 1.87 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>CN1CCCC1=O>[F:15][C:16]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Nc1ccc(C(F)(F)F)cc1F
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3F)nccc12
Yield: 46.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-2 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 250 mg, 1.19 mmol), and 2-fluoro-4-(trifluoromethyl)aniline (330 mg, 1.84 mmol) in N-methylpyrrolidinone (2 mL) to afford 195 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.84 (d, J=7.8 Hz, 1H), 8.55 (d, J=7.8 Hz, 1H), 8.15 (d, J=5.7 Hz, 1H), 7.86-7.57 (m, 5H); MS (m/z): 352.18 (M+H)+.
Reaction SMILES: [NH:1](C(C1C=CC=CC=1)=O)[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=C(OC)C=CC=1C[NH-:26].FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:10]([NH2:26])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C[NH-])c(OC)c1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Bz-Phe-2,4-dimethoxybenzylamide (4.2 mg) was dissolved in trifluoroacetic acid (1.0 ml) containing 10% (v/v) trifluoromethane sulfonic acid (TFMSA) and the reaction mixture was kept in the dark for 1 h at 20° C. TFA/TFMSA was removed by blowing with N2 and the residue was suspended in 95% (v/v) CH3CN (1.0 ml). The reaction mixture was analyzed by HPLC system-7 and the generated Bz-Phe-NH2 (>95%) was determined quantitatively using a Bz-Phe-NH2 standard solution (Bz-Phe-NH2 was purchased from Bachem, Switzerland).
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:3].C(N(C(C)C)CC)(C)C.Br[CH2:34][CH:35]=[CH:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]>ClCCl>[O:48]=[C:39]1[C:40]2[C:41](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42](=[O:43])[N:38]1[CH2:37][CH:36]=[CH:35][CH2:34][P:2]([CH2:4][CH:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])([OH:1])=[O:3]
Reactant: O=C(OCc1ccccc1)C(CCc1ccccc1)C[PH](=O)O
Reactant: O=C1c2ccccc2C(=O)N1CC=CCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)C(CCc1ccccc1)CP(=O)(O)CC=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dichloromethane (30 mL) was added to (+)-benzyl 2-((hydroxyphosphinyl)methyl)-4-phenylbutanoate (8.10 g, 24.4 mmol) and 4Å molecular sieves (5.0 g). Diisopropylethylamine (4.70 mL, 3.49 g, 27.0 mmol) was added over 5 min. After cooling the reaction mixture in an ice bath, O,N-bis(trimethylsilyl)acetamide (17.7 mL, 14.6 g, 71.6 mmol) was added in one portion, followed in 10 min by N-(4-bromo-2-butenyl)phthalimide (8.80 g, 31.4 mmol). The mixture was allowed to slowly warm to room temperature and stirred for 20 h before being filtered. The sieve particles were rinsed with ethyl acetate (100 mL) and the filtrate was washed with 2N aqueous hydrochloric acid (2×50 mL) and saturated aqueous sodium chloride (25 mL). The aqueous layers were extracted in succession with ethyl acetate (50 mL). The organic layers were dried (sodium sulfate), decanted, and evaporated to give 15.66 g of almost colorless syrup containing benzyl 2-(((4-(1,3-dihydro-1,3-dioxo-2M-isoindol-2-yl)-2-butenyl)hydroxyphosphinyl)methyl)-4-phenylbutanoate.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[Mg].II.[C:10]([N:14]1[CH:18]=[C:17]([CH:19]=[O:20])/[C:16](=[N:21]/[C:22](=[O:32])[C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])/[S:15]1)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([N:14]1[CH:18]=[C:17]([CH:19]([OH:20])[CH2:2][CH:3]2[CH2:6][CH2:5][CH2:4]2)/[C:16](=[N:21]/[C:22](=[O:32])[C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])/[S:15]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: BrCC1CCC1
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(O)CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To (bromomethyl)cyclobutane (211 mg, 1.42 mmol) in THF (20 mL) was added magnesium (41.3 mg, 1.7 mmol), and initiator iodine (10 mg). The mixture was stirred at rt for 2 hrs, then cooled to −40° C. and added to a solution of Example 21A (100 mg, 0.28 mmol) in THF (20 mL). The mixture was allowed to warm to room temperature, quenched with saturated aqueous NH4Cl, and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 63 mg (53%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.62-1.78 (m, 2 H) 1.65 (s, 9 H) 1.76-1.94 (m, 2 H) 1.97-2.18 (m, 4 H) 2.47-2.59 (m, 1 H) 3.92 (s, 3 H) 4.88 (dd, J=8.29, 6.14 Hz, 1 H) 6.93 (d, J=8.90 Hz, 1 H) 7.37 (dd, J=8.90, 3.07 Hz, 1 H) 7.95 (s, 1 H) 8.05 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 423 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2cccc(Br)c2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3cccc(Br)c3)oc(C)c2C)cc1C(C)C
Yield: 65.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.02 g, 4.32 mmol, RN-117439-59-5), oxalyl chloride (0.415 mL, 4.75 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.556 mL, 4.75 mmol) and 2-(3-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.32 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.36 g (65%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ 1.17 (d, 12H), 1.80 (s, 3H), 2.20 (s, 3H), 3.28 (septet, 2H), 3.74 (s, 3H), 3.87 (s, 2H), 7.06 (d, 1H), 7.19 (d, 1H), 7.24 (s, 1H), 7.38 (dd, 1H), 7.46 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1.O>ClCCl>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44]([O:30][C:27]2[CH:26]=[CH:25][C:24]([N:10]3[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:15])[N:13]=[C:9]3[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:29][CH:28]=2)(=[O:46])=[O:45])[CH:39]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.31 ml, 2.25 mmol) in dichloromethane (5.0 ml) were cooled to −78° C. 3-Pyridinesulfonyl chloride (144 mg, 0.67 mmol) was added in small portions to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (110 mg, 84%) as a solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][O:2]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[I-].[Na+]>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:7][C:4]3([CH2:3][O:2][CH2:1]3)[CH2:5]2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1NCC12COC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CC3(COC3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
A mixture of 2-oxa-6-aza-spiro[3.3]heptane (˜3.72 mmol), 4-bromobenzyl bromide (0.39 g, 1.54 mmol), potassium carbonate (0.64, 4.63 mmol) and sodium iodide (11 mg, 0.08 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solid was removed by filtration, washed with THF and the combined filtrate was evaporated. The resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in pentane then 10% methanol in DCM) to afford the title compound (0.28 g, 68%) as a viscous oil which crystallised on standing to a pale yellow solid. 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.15-7.09 (m, 2H), 4.73 (s, 4H), 3.48 (s, 2H), 3.35 (s, 4H).