Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH2:24])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH:24][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=2)(=[O:35])=[O:34])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5 b) and 3-trifluoromethylphenylsulfonyl chloride, according to the general working procedure 131 mg of 21-(3-trifluoromethylphenyl-sulfonylaminomethyl)biphenyl-2-carboxylic acid benzylamide were obtained; m.p. 126° C. MS (ES+): m/e=525 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:36][CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=O)[O:19][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[N:37]1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:60]>ClCCl>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:60][CH2:5][CH:6]1[CH2:36][CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:19])[NH:37][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: N
Reactant: CC(=O)OCC1CCCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: Cc1cccc(C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCCC(CN)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 3 h

Procedure:
A solution of 150 mg of the product of Example 49 and 146 mg of 2,6-lutidine in 15 ml of dichloromethane was added to a solution of 290 mg of trifluoromethanesulfonic anhydride at 0° C. After 3 hours, 25 ml of 33% aqueous ammonia were added and the mixture was stirred for 16 hours. The mixture was extracted with dichloromethane and the combined extracts were dried and concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol/acetic acid/water (90:18:3:2) gave 50 mg of 3-[9-(aminomethyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-11-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione acetate of melting point 215° C. (decomposition).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:62])([F:61])[O:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56]>ClCCl.CN(C=O)C>[CH3:15][C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:55](=[O:56])[C:54]3[CH:58]=[CH:59][CH:60]=[C:52]([O:51][C:50]([F:49])([F:61])[F:62])[CH:53]=3)=[C:5]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH:6]=2)[N:14]=1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(CNC(=O)c3cccc(OC(F)(F)F)c3)c(NCC(=O)OCc3ccccc3)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of compound 58d (50 mg, 0.13 mmol), TEA (0.027 mL), HOAt (1.8 mg) and EDCI (37 mg, 0.19 mmol) in a mixture of dichloromethane (0.8 mL) and DMF (0.3 mL) was added 3-trifluoromethoxybenzoic acid (27 mg, 0.13 mmol). The resulting solution was stirred overnight at rt, and then concentrated. The residue was triturated with water, and then purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 58e (30 mg, 43%). ESI-MS m/e 541.4 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12](Cl)=[N:13][C:14]2[N:15]([N:36]=[CH:37][CH:38]=2)[C:16]=1[N:17]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>C(#N)C>[C:20]([O:19][C:18]([N:17]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:26]=1)[C:16]1[N:15]2[N:36]=[CH:37][CH:38]=[C:14]2[N:13]=[C:12]([NH:40][C@H:41]2[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]2)[C:11]=1[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CC#N
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO[Si](C)(C)C(C)(C)C)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 22.9 %

Procedure:
To an acetonitrile (5 mL) solution containing tert-butyl {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]carbamate (570 mg, 1.20 mmol), (S)-3-amino-1-tert-butoxycarbonylpiperidine (1.51 g) was added, and this mixture was stirred at 85° C. for 48 hr. The reaction solution was concentrated, and the residue was purified with column chromatography (35% ethyl acetate-hexane) to obtain the title compound (204 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:16]2([OH:19])[CH2:17][CH2:18][O:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: O=C1CCOC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ncc(Br)cn2)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
5-Bromo-2-iodopyrimidine (10 g, 35.1 mmol) was dissolved in dry toluene (100 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 14.7 mL) was added dropwise and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxolan-3-one (2.97 mL, 38.6 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed successively with water and brine, then dried over magnesium sulphate. The solvent was removed under reduced pressure to afford a dark yellow oil. The crude material was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0-100% ethyl acetate in heptanes, to afford the title compound (2.15 g, 25% at 86% purity) as a yellow oil. δH (500 MHz, DMSO-d6) 9.01 (s, 2H), 5.66 (s, 1H), 3.99-3.93 (m, 2H), 3.88-3.77 (m, 2H), 2.46 (dt, J 12.6, 8.9 Hz, 1H), 2.16 (ddd, J 12.6, 6.4, 3.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[C:12]([O:13]COC)=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:17])=[O:6].S(=O)(=O)(O)O.CC(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:17])=[O:6]
Reactant: COCOc1ccc[n+]([O-])c1C(=O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]
Yield: 80.8 %

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-methoxymethoxy pyridine 1-oxide (4.00 g), 3.6N-sulfuric acid (11 mL) and acetone (50 mL) was refluxed for 5 hours. The reaction mixture was poured into water, neutralized with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromobenzoyl)-3-hydroxypyridine 1-oxide (2.81 g). Physical properties and spectrum data of the product are shown below.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.Cl.[N:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:53]>CO.C(Cl)(Cl)Cl>[ClH:53].[CH2:19]([C:4]1[CH:3]=[C:2]([O:1][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)CCCN1CCCCC1
Reactant: ClCCl
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21

Procedure:
0.46 g. (1.47 mmoles) of 1-Hydroxy-3-n-pentyl-6,6,9-trimethyl-10a,6a,7,8 -tetrahydrodibenzo[b,d]pyran, 0.31 g. (1.47 mmoles) of γ-piperidinobutyric acid hydrochloride and 0.32 g. (1.55 mmoles) of dicyclohexylcarbodiimide were combined in 25 ml. of methylene chloride and stirred at room temperature for 4 hours. The insoluble by-product of dicyclohexylurea was removed by filtration and the methylene chloride was evaporated to give a gummy yellowish residue. The gummy material was triturated several times with petroleum ether and dried in vacuo to give 350 mg. of product as a colorless foam-like solid. The sample was pure by thin-layer chromatography (10% MeOH/CHCl3) and the infrared spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si](C(C)(C)C)(C)C)[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]12([NH:38][C:39](=[O:51])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][C@H:48]([NH2:50])[CH3:49])[CH:42]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>>[NH3:38].[C:28]12([NH:38][C:39](=[O:51])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][C@H:48]([NH:50][CH2:16][C@@H:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[C:10]([CH2:26][OH:27])[CH:11]=4)[OH:18])[CH3:49])[CH:42]=3)[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: C[C@@H](N)Cc1cccc(CC(=O)NC23CC4CC(CC(C4)C2)C3)c1
Product: C[C@H](Cc1cccc(CC(=O)NC23CC4CC(CC(C4)C2)C3)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(CO)c1
Product: N
Temperature: 90 °C

Procedure:
A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl) phenyl]methanol (preparation 23), (900 mg, 2 mmol) and N-1-adamantyl-2-{3-[(2R)-2-aminopropyl]pheny}acetamide (preparation 163), (1.3 g, 4 mmol) were heated at 90° C. for 24 hours. The reaction mixture was then cooled to room temperature and the crude product was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, to afford the title compound as a pale foam in 83% yield, 1.16 g. 1H NMR (400 MHz, CD3OD) δ: 7.48-7.28 (6H, m), 7.17-6.72 (6H, m), 5.14 (2H, s), 4.78-4.74 (1H, m), 4.73-4.64 (m, 2H), 3.36 (2H, s), 2.95-2.84 (2H, m), 2.70-2.63 (2H, m), 2.59-2.50 (1H, m), 2.03 (3H, m), 2.00 (6H, m), 1.70-1.64 (6H, m), 1.05 (3H, d), 0.84 (9H, s), 0.00 (3H, s), −0.18 (3H, s) ppm.
Reaction SMILES: Br[CH2:2][C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][C:4]([S:6][C:7]([F:10])([F:9])[F:8])([CH3:11])[C:3](=[O:12])[CH2:2][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: CC(C)(SC(F)(F)F)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(SC(F)(F)F)C(=O)Cn1cncn1
Yield: 61.2 %

Procedure:
26.5 g (0.1 mol) of 1-bromo-3-methyl-3-trifluoromethylthio-butan-2-one were added dropwise to a mixture of 8.3 g (0.12 mol) of 1,2,4-triazole and 28 g (0.2 mol) of potassium carbonate in 150 ml of acetone at room temperature. The mixture was subsequently stirred under reflux for 1 hour, the inorganic salts were filtered off and the filtrate was concentrated. The residue was taken up in methylene chloride, washed with water, dried over sodium sulphate and distilled. 15.5 g (62% of theory) of 3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylmercaptobutan-2-one of boiling point 91° C./0.5 mm Hg and of melting point ~45° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.N>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: Nc1cccnc1N
Agent: N
Product: c1ccc(COCCCc2nc3cccnc3[nH]2)cc1
Yield: 86 %

Procedure:
4-(Benzyloxy)butanoic acid (5.0 g) and 2,3-diaminopyridine (1.12 g) were stirred at 150° C. for 10 hr. Under ice-cooling, to the reaction mixture was added concentrated aqueous ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.36 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.[CH:36](=O)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)[CH2:37][CH2:38][CH3:39]
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CCCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCNc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(OC)cc3)[nH]2)cc1

Procedure:
2-(4-Aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.0 g) obtained in Example 48, sodium borohydride (0.13 g), 4N sulfuric acid (0.2 ml) and butyraldehyde (0.3 ml) were treated in the same manner as in Example 72 to give 2-(4-butylaminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.1 g). This was converted to hydrochloride to give 2-(4-butylaminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride (0.20 g), melting point 250° C. or above.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCCC1>[CH2:47]([N:46]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COc1ccc(C=O)cc1

Procedure:
To a 100 mL solution of freshly distilled tetrahydrofuran (THF) was added p-formylphenoxyacetic acid (K & K Labs) (MW 180, 0.540 g, 3.0 mmol), triethyl amine (MW 101.19, 0.333 g, 3.3 mmol) and trimethylacetyl chloride (MW 120.57, 0.398 g, 3.3 mmol). After 20 minutes of heating at reflux, dioctadecylamine (Fluke) (MW 522.01, 1.723 g, 3.3 mmol) was added. The reaction was refluxed overnight.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In a nitrogen atmosphere, 20.00 g of 4-propylbromobenzene, 0.58 g of tetrakis-triphenylphosphine palladium, and 55 mL of an aqueous potassium carbonate solution (2 mol/L) were dissolved in 100 mL of ethanol, and the resultant solution was heated to 60° C. Then, a solution prepared by suspending 15.27 g of 4-methoxyphenylboronic acid in 60 mL of ethanol was added dropwise to the solution. After stirring at 60° C. for 2 hours, the mixture was allowed to cool to room temperature, and toluene was added to separate the mixture into layers. An aqueous layer was subjected to extraction with toluene, and the toluene extract was combined with an organic layer. The resultant mixture was washed with saturated brine and dried by adding sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethanol to yield 21.60 g of 4-(4-propylphenyl)anisole.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[N:26]=[C:25](S(C)(=O)=O)[C:24]3[N:31]([CH3:34])[CH:32]=[N:33][C:23]=3[CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].[OH2:35].CCO[C:39]([CH3:41])=[O:40]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[N:26]=[C:25]([O:35][C@H:23]([C@H:24]3[CH2:25][NH:26][C:39](=[O:40])[CH2:41]3)[CH3:22])[C:24]3[N:31]([CH3:34])[CH:32]=[N:33][C:23]=3[CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: O
Reactant: COc1ccc(-c2cc3ncn(C)c3c(S(C)(=O)=O)n2)cc1OC
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ncn(C)c3c(O[C@@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of alcohol (1.0-1.2 eq) in DMF was added NaHMDS (1.0M in THF, 1.3 eq), and the reaction was stirred for 15 min. 2.41 or 2.65 (1.0 eq) was added and the reaction was stirred at RT for 2 hours. Water and EtOAc were added, the layers separated, and the aqueous layer was extracted with EtOAc, and the combined organics were dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The isolated material was transferred to sealable vial, TFA was added and the reaction was heated to 60° C. for 12-18 hours. The reaction was concentrated and the residue was purified by RP-HPLC to yield Examples 3D.01-3D.09.
Reaction SMILES: C(O[CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:24]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:26]=[N:25]2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(OC(=O)C)(=O)C.[BrH:40]>ClCCl.CC(O)=O>[C:8]([O:7][C@@H:6]1[C@@H:11]([N:24]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:26]=[N:25]2)[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]1[Br:40])(=[O:10])[CH3:9]
Reactant: COC(=O)c1cn([C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)nn1
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cn([C@@H]2[C@@H](OC(C)=O)[C@@H](Br)O[C@H](COC(C)=O)[C@@H]2OC(C)=O)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
1,2,4,6-Tetra-O-acetyl-3-deoxy-3-[4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl]-D-galactopyranose 23 (33 mg, 0.072 mmol) was dissolved in dichloromethane (1 ml) which had been dried over 4 Å molecular sieves. Acetic anhydride (14 l, 0.20 mmol) and HBr (0.2 ml of a 33% solution in AcOH) were added, and the mixture was stirred under N2 at room temperature. After 3 h 15 min, the reaction mixture was diluted with dichloromethane (30 ml) and poured into ice-water (30 ml). The organic phase was washed with NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give 24 (16 mg, 46%), which was used immediately in the synthesis of 25.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CON(C)[C:30](=[O:46])[CH:31]([O:44][CH3:45])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([C:30](=[O:46])[CH:31]([O:44][CH3:45])[C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[S:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2cscn2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2csc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)n2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a −78° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0.096 g, 0.32 mmol) in anhydrous THF (2 mL) under argon was added a solution of LiHMDS (1.0 M in THF, 0.35 mmol) dropwise. After stirring for 30 min, a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.121 g, 0.41 mmol) in anhydrous THF (1.5 mL, 1.0 mL) was added dropwise. After stirring for 35 min, the cold bath was removed and the reaction was allowed to warm to room temp. The mixture was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (25-45% EtOAc-hexanes) gave 1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow solid (0.050 g, 29% yield). MS: m/z 533.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]#[N:13])=[N:9][C:10]=1[CH3:11])=[O:5])C.Br[CH2:15][C:16]1[CH:20]=[C:19]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[O:18][N:17]=1.C([O-])([O-])=[O:28].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[C:12]([C:8]1[N:7]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[S:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[O:18][N:17]=2)[C:6]([C:4]([OH:3])=[O:5])=[C:10]([CH3:11])[N:9]=1)(=[O:28])[NH2:13]
Reactant: CCOC(=O)c1[nH]c(C#N)nc1C
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(N)=O)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 194 mg 2-Cyano-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester, 301 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and 150 mg K2CO3 in 2 ml DMF was stirred for 5 h at RT. After addition of 2 ml brine the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was then dissolved in 5 ml THF/MeOH/water 3:1:1 and treated with 30 mg LiOH monohydrate at RT. Then the solvent was removed under reduced pressure and the residue was taken-up in 5 ml 5 M HCl. The acid precipitated as a brown solid and was dried under reduced pressure. Yield: 280 mg