Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][CH2:12][CH2:13][NH2:14].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:13][CH2:12][F:11])=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCF)c1cncc(Br)c1

Procedure:
2.03 g (10 mmol) 5-bromonicotinic acid, 1 g (1 eq.) 2-fluoroethylamine, 2.31 g (1.2 eq.) EDC.HCl, 123 mg (0.1 eq.) DMAP and 5.6 mL (4 eq.) triethylamine are stirred in 60 mL dichloromethane for 20 hours at room temperature. The reaction mixture is extracted with dichloromethane and water, the combined organic phases are washed with brine, dried with sodium sulfate and evaporated. The residue is triturated in diethylether and hexane to yield after filtration the desired product as a white powder. MS(ES+): 347 and 349 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.[C:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[C:27]#[CH:28])=[CH:21][CH:20]=1)#[C:17][CH3:18]>[Cu]I>[C:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[C:27]#[C:28][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1)#[C:17][CH3:18]
Reactant: C#CC(=O)Nc1ccc(C#CC)cc1
Reactant: OCc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
40 mL of THF are degassed, combined with 2.62 g (8.03 mmol) of cesium carbonate and 4-iodobenzyl alcohol and again degassed. To this reaction mixture is added successively 138 mg (0.12 mmol) of tetrakistriphenylphosphine palladium, 53 mg (0.28 mmol) of copper (I) iodide, and 0.7 g (3.2 mmol) of propynoic acid-(4-prop-1-ynylphenyl)amide. The mixture is stirred for 24 hours at ambient temperature and the reaction mixture is then evaporated down. The purification of the residues is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (60:1)). Yield: 0.5 g (57.8% of theory); C19H15NO2 (M=289.33); calc.: molecular ion peak (M+H)+: 290; found: molecular ion peak (M+H)+: 290; Rf value: 0.21 (silica gel, dichloromethane/ethanol (50:1)).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), triethylamine (50 mg) and dichloromethane (2.0 ml) was added heptanoyl chloride (0.05 ml) in an ice-water bath. The mixture was stirred at the same temperature for 30 minutes and washed with water. The organic layer was collected and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-(heptanoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (130 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12]C#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CBr.[Mg].Cl.CC[O:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:22](=[O:21])[CH3:23])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CCC1(c2ccc(Cl)cc2)CCC1
Reactant: CCOCC
Agent: CBr
Agent: Cl
Agent: [Mg]
Product: CC(=O)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 2-[1-(4-chlorophenyl)cyclobutyl]acetonitrile (30 g) prepared as described in Example 1 in ether (100 ml) was added to the reaction product of methyl bromide gas and magnesium turnings (5.95 g) in ether (80 ml). The mixture was heated under reflux for four hours. Ice and then concentrated hydrochloric acid (105 ml) were added and the mixture heated under reflux until all solid material had dissolved. The aqueous layer was washed with ether and the ether used for washing was combined with the ether phase of the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to yield a residue which was distilled twice to yield 1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one (b.p. 133°-136°/2.5 mm Hg).
Reaction SMILES: [BH4-].[CH2:2]([C:9]1[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][O:17][C:18](=[O:43])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:22][CH:21]=1>O1CCCC1.C(O)C>[CH3:16][O:17][C:18](=[O:43])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:14][C:11]3[N:10]([CH3:15])[C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][N:12]=3)=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:24][CH:25]=1
Reactant: CCCCCCCOc1cc(I)ccc1COc1ccc(CC(=O)OC)cc1
Reactant: CCCCCCCc1nnc(S)n1C
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCOc1cc(Sc2nnc(CCCCCCC)n2C)ccc1COc1ccc(CC(=O)OC)cc1
Reaction time: 8 h

Procedure:
979 mg (2.45 mmol, 3 eq) of resin-supported borohydride and 11 mg (0.02 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 244 mg (1.22 mmol, 1.5 eq) of 5-heptyl-4-methyl-4H-[1,2,4]-triazole-3-thiol in 4 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 405 mg (0.82 mmol, 1 eq) of [4-(2-heptyloxy-4-iodobenzyloxy)phenyl]acetic acid methyl ester in 4 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered and then concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate: gradient from 70/30 to 50/50). After concentration, 427 mg (92%) of the expected compound are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].FC(F)(F)C([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:13]2[CH2:14][CH2:15][NH:11][C:12]2=[O:16])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CCCN1C(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NCCC1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a suspension of potassium tert-butoxide (2.00 g, 18.0 mmol) in anhydrous tetrahydrofuran (40 mL) was added a mixture of 1-(2,2,2-trifluoroacetyl)-pyrrolidin-2-one (2.12 g, 12.0 mmol) and 4-fluorobenzaldehyde (1.24 mL, 12.0 mmol) in anhydrous tetrahydrofuran (5 mL) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then refluxed for 1 hour and concentrated in vacuo. Water (150 mL) was added to the residue. The white solid precipitated was filtered and re-dissolved in ethyl acetate (50 mL) and then hydrogenated in the presence of catalytic amount of palladium on carbon (20% w/w) at ambient temperature and atmospheric pressure for 3 hours. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate) to afford the title compound as a white solid (0.72 g, 35%): 1H NMR (300 MHz, CDCl3) δ 7.20-7.09 (m, 2H), 7.00-6.90 (m, 2H), 6.42 (s, 1H), 3.31-3.07 (m, 3H), 2.71-2.54 (m, 2H), 2.19-2.03 (m, 1H), 1.89-1.69 (m, 1H); MS (ES+) m/z 194.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]2[C:15]3[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Product: CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)c1
Yield: 45 %

Procedure:
Method G1 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tertbutylbenzoyl chloride to afford the title compound as a white solid (29 mg, 45%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[N:21]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[OH:31][C@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[CH2:29][NH:28][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)n1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(-c4nnn(CC(=O)O)n4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl {5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetate (which was obtained in Example 48) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedures of Example 98 and Example 99 as a white solid; mp>240° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.65 (m, 2 H), 1.90–2.10 (m, 2 H), 2.50–3.10 (m, 5 H), 2.95 (s, 3 H), 3.65–3.85 (m, 2 H), 4.89 (brd, J=8.3 Hz, 1 H), 5.08 (d, J=15.9 Hz, 1 H), 5.15 (d, J=15.9 Hz, 1 H), 6.88 (d, J=8.3 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.09 (dd, J=8.3, 2.0 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.87 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 532.1 (MH+); HRMS Calcd. for C21H30N7O4S (MH+): 532.1973. Found: 532.1965.
Reaction SMILES: [N:1]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C>[N:1]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6]([Cl:14])=[O:7])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(CC(=O)O)N=[N+]=[N-]
Solvent: CN(C)C=O
Product: CCC(CC(=O)Cl)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
3-Azidopentanoic acid (1.72 g, 12.2 mmol) was dissolved in oxalyl chloride (1.49 ml, 2.22 g, 17.5 mmol) and to this stirring solution was added one drop of DMF. The mixture was stirred at room temperature for 30 min and heated at 80° C. for 40 min. The residue was distilled under vacuum, bp 33° C. (0.1 mm), to give a colorless oil (936 mg, 48.2%); ir (neat) νmax : 2100 (N3), and 1795 cm-1 (C=O of acid chloride); 1Hmr (CDCl3) δ: 1.03 (3H, t), 1.60 (2H, m), 3.03 (2H, d) and 3.80 ppm (H, m). Anal. calcd for C5H8N3Cl: C 37.16, H 4.99; found: C 37.40, H 4.92.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CC1NCCc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Yield: 50.2 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 6-methyl-2,4-dichloropyrimidine (6.52 g, 40 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline (6.6 g, 44 mmol), triethylamine(6.8 ml, 48.8 mmol) and N,N-dimethylformamide(30 ml) were used as starting materials, 5.5 g of the titled compound was prepared. (Yield: 50.2%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[C@:17]([CH3:21])([CH2:19][CH3:20])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:19]([C@@:17]1([CH3:21])[NH:18][C:26](=[O:28])[N:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:22])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C)c(OC)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-isovalinamide (Reference Intermediate R8 42 mg) in dry dichloromethane (6 mL), TEA (0.089 mL, 0.638 mmol) was added. The mixture was cooled down to 0° C. and a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (1.500 mL) was added dropwise. The mixture was stirred at that temperature for 1 hour, then a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (DCM) (1.500 mL) was added dropwise again. The reaction was stirred for 30 minutes, it was maintained in the ice-bath and quenched with water (10 mL). The mixture was allowed to reach the room temperature then it was extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was purified by flash chromatography on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 80/20 to 50/50 (Biotage system). This afforded the title compound as a white solid (24 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19][CH2:20][SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:26]([Sn:21]([CH2:20][CH2:19][CH2:18][CH3:17])([CH2:22][CH2:23][CH2:24][CH3:25])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[CH2:16])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(c1ccc(OCc2ccccc2)cc1)[Sn](CCCC)(CCCC)CCCC

Procedure:
1-benzyloxy-4-ethynyl-benzene (70 g, 0.3365 mol), Bu3SnH (59 mL, 0.3365 mol) and Ph(PP3)2Cl2 (120 mg, 0.1718 mmol) were stirred in THF (500 mL) at 25° C. for 16 h and then refluxed for 1 h. The resulting solution was concentrated and then purified on SiO2 (2% ˜5% ethyl acetate/hexane) to yield tributyl-[1-(4-benzyloxy-phenyl)-vinyl]-stannane.
Reaction SMILES: [C:1]([O:20]C(C)C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCCCCCCCC.[CH2:24](O)CCCCCCCCCCCCCCC>>[CH3:24][C@@H:1]([OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Reactant: CCCCCCCCCCCCCCCCO
Product: CCCCCCCC[C@@H](C)O
Temperature: 90 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To the distillation residue, i.e., a mixture of (R)-(-)-2-decanol stearic acid ester and unreacted isopropyl stearate, were added 200 g of palmityl alcohol and 3 g of Lipase PL. After the particle size of the enzyme was regulated by ultrasonication in the same manner as described above, the mixture was stirred at 90° C. and 250 rpm under reduced pressure of 2 mmHg for 24 hours to carry out interesterification while recovering the distillate to obtain free (R)-(-)-2-decanol with high purity (yield: 72%; chemical purity: 99.6%; optical purity: 95% ee).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22]O>S(=O)(=O)(O)O>[CH3:22][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 36 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 97/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g, 99%) as a light yellow oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1052.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:59])[C:56]([F:58])([F:57])[CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C:56]([F:58])([F:57])[C:52]([F:59])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: FC1(F)CNCC1(F)F
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3,4,4-tetrafluoropyrrolidine hydrochloride and isolated as light-yellow gum (12.6 mg, 60%). MS(m/e): 443.4 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:28]2[O:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:29]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: OB(O)c1cc2ccccc2o1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cc3ccccc3o2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-benzofuranboronic acid, the desired product is obtained in the form of an ecru solid (yield=65%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4F)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (40 mg, 46%), MS (ISP) m/z=352.5 [(M+H)+], mp 225° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: C(CC[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:8][CH:7]=1)(O)=O.B(C1C=CC([C:53]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]2)=CC=1)(O)O.B(O)O>>[C:56]([C:53]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]([CH3:43])([CH3:42])[C@H:14]4[C@:27]([CH3:30])([CH2:28][CH:29]=3)[C@@H:26]3[C@:17]([CH3:41])([C@@:18]5([CH3:40])[C@H:23]([CH2:24][CH2:25]3)[C@H:22]3[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]3([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]5)[CH2:16][CH2:15]4)=[CH:10][CH:11]=2)[CH2:55][CH2:54]1)([OH:58])=[O:57]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C7(C(=O)O)CC7)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the methods described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 1-(4-boronophenyl)cyclopropanecarboxylic acid as the reactant boronic acid. The product was isolated as a white solid (1.76 mg, 5%). LCMS: m/e 597.64 (M−H)−, 4.43 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.92 (s, 3H), 0.94 (s, 3H), 0.99 (d, J=3.52 Hz, 6H), 1.02 (s, 3H), 1.03-1.71 (m, 21H), 1.71 (s, 3H), 1.82-1.95 (m, 2H), 2.10 (dd, J=17.28, 6.15 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.30-2.39 (m, 1H), 2.97-3.09 (m, 1H), 4.61 (br. s, 1H), 4.74 (s, 1H), 5.25 (d, J=4.69 Hz, 1H), 7.04 (d, J=7.62 Hz, 2H), 7.25 (d, J=7.62 Hz, 2H).
Reaction SMILES: C(NC(C)C)(C)C.CS(O[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=O)=O.[NH2:33][C@@H:34]([CH3:44])[C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[OH:36]>CN(C)C=O>[OH:36][C@H:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[C@@H:34]([NH:33][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[CH3:44]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCOS(C)(=O)=O)cc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 57.5 %

Procedure:
Diisopropylamine (0.40 mL) was added to a mixture of ethyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.32 g) and 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.32 g) in N,N-dimethylformamide (6 mL), and the mixture was stirred for 14 hrs at 80° C. After being cooled to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=15/1) to afford ethyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl-amino]ethoxy}biphenyl-4-carboxylate (0.22 g).