Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[O:22][C@@H:21]([C:23]([OH:25])=[O:24])[C@H:20]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:19]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:18]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O[C:53]1[C:58]([F:59])=[C:57]([F:60])[C:56]([F:61])=[C:55]([F:62])[C:54]=1[F:63])=O.C(OCC)(=O)C>CN(C)C=O.N1C=CC=CC=1>[F:59][C:58]1[C:57]([F:60])=[C:56]([F:61])[C:55]([F:62])=[C:54]([F:63])[C:53]=1[O:24][C:23]([C@H:21]1[C@H:20]([NH:26][C:27](=[O:29])[CH3:28])[C@@H:19]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH:18]=[C:17]([C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[O:22]1)=[O:25]
Reactant: CC(=O)N[C@@H]1[C@@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1[C@@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,3R,4S)-3-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid 6-benzhydryl ester (4.4 g) in dry dimethylformamide (10 ml) and pyridine (0.70 ml) was added pentafluorophenyl trifuoroacetate (1.27 ml) and the reaction was stirred at 23° C. for 1 hour. More pyridine (0.70 ml) and pentafluorophenyl trifluoroacetate (1.27 ml) was added and the reaction was stirred for a further 2 hours. The reaction mixture was diluted using ethyl acetate and washed consecutively using 1N hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dired over anhydrous magnesium sulphate and the solvent was removed in vacuo to give the crude title compound as a tan foam, (8.11 g); 1H NMR (250MHz, D6 -DMSO) 9.97 (1H, broad s), 7.49--7.27 (11H, m), 6.91 (1H, s), 6.52 (1H, m), 4.93 (1H, m), 4.58 (1H, m), 4.47 (1H, m), 1.88 (3H,s), 1.42 (18H, s).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:20]1[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[NH:2][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][N:24]=2)=[O:21])[N:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)Oc1ccc(Br)nc1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(OC(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 110 °C

Procedure:
A mixture of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 75 mg, 0.24 mmol), 2-bromo-5-(trifluoromethoxy)pyridine (CAS number 888327-36-4; 59 mg, 0.24 mmol), BINAP (15 mg, 0.024 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol) and sodium tert-butoxide (33 mg, 0.34 mmol) in dry toluene (2.4 ml) was sealed, evacuated and purged with nitrogen and heated at 110° C. for 17 hours. The reaction was partitioned between ethyl acetate and water, washing with water, brine, filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:6])=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: BrBr
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 96.2 %

Procedure:
A stirred suspension of 2,6-dinitroaniline (5 g, 27.3 mmol) in glacial acetic acid (50 mL) was added bromine (1.5 mL, 30 mmol) dropwise and heated at 120° C. for 2 h. After cooling to ambient temperature, the resultant mixture was poured into water (50 mL). The precipitate solid was collected by filtration and washed with water then dried in-vacuo. The solid was re-dissolved in EtOAC, washed with water and saturated brine. The organic layer was collected and concentrated in-vacuo to give the desired product (6.88 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (br s, 2H), 8.58 (s, 2H).
Reaction SMILES: O=[C:2]1[CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][C:16](=O)[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:2][NH:3][CH2:4][CH2:5]1
Reactant: O=C1COCCOCC(=O)NCCOCCOCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCOCCNCCOCCOCCOCCN1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 6.7 g. of the diamide obtained in Example 19 in 100 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 50 ml. anhydrous tetrahydrofurane and 3.8 g. LiAlH4 while stirring. After the addition is complete, the mixture is stirred under reflux and under a nitrogen atmosphere for 11 hours. After cooling to room temperature, the reagent is destroyed by adding 10 ml. water in 25 ml. THF, followed by 10 ml. NaOH (15% in water) and then 30 ml. water. The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 with benzene as eluant. The solution is evaporated to dryness and the desired product is obtained as a colourless oil which crystallizes at low temperature.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:24][CH:25]=1>>[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[N:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2nccn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 393.05 g/mol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:24]4[CH:27]=[CH:28][C:21]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:22][CH:23]=4)[CH2:10][CH2:9]3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2ccc(CNCCCN3CCN(CCCNCc4ccc(-c5ccccc5)cc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 4-phenylbenzaldehyde (955 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26](I)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: c1cocn1
Reactant: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (167 mg, 2.4 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 7.3 mL, 7.3 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[butyl(methyl)amino]carbonyl)-5-iodobenzoate (864 mg, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0) tetrakis(triphenylphosphine) (112 mg, 0.10 mmol). The reaction mixture is heated at reflux for 1.5 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O>C1(C)C=CC=CC=1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12

Procedure:
A solution of tryptamine (3.04 g, 19.0 mmol) and phthalic anhydride (3.0 g, 20.0 mmol) in toluene (300 ml) was boiled under reflux for 12 h using a water separator. The solvent was removed i. vac. and the residue was recrystallized from methylene chloride/cyclohexane. Yield: 4.46 g (81%)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2c(cn1)NCCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCOc3ccncc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In a 25 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (370 mg, 2.72 mmol) and 4-methoxy-benzenesulfonyl chloride (618 mg, 2.99 mmol) were dissolved in dichloromethane (10 ml). Triethylamine (0.45 ml, 3.23 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain pale-green solid (700 mg, 84.1%).
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][C:20]4([C:27](=[O:29])[NH2:28])[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=O)(C)(C)C.ClC1[S:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=1>>[C:36]([C:33]1[S:32][C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]3[CH:24]4[CH2:25][C:20]5([C:27](=[O:29])[NH2:28])[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[O:15])[CH2:10]2)=[N:35][CH:34]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OC2C3CC4CC2CC(C(N)=O)(C4)C3)C1
Reactant: N#Cc1cnc(Cl)s1
Product: N#Cc1cnc(NC2CCN(C(=O)OC3C4CC5CC3CC(C(N)=O)(C5)C4)C2)s1

Procedure:
The title compound was prepared from (3R) (1-carbamoyl-4-adamantyl) 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate isomer 2 following procedures analogous to those described in Example 33 using 2-chloro-5-cyanothiazole in Step 2. LC-MS Method 1 tR=1.32 min, m/z=415; 1H NMR (CD3OD) 1.55 (2H), 1.85-2.15 (12H), 2.25 (m, 1H), 3.35-3.80 (4H), 4.40 (br s, 1H), 4.78 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[Li]CCCC.[CH2:18]1[O:20][CH2:19]1.O>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:18][CH2:19][OH:20]
Reactant: Cn1cnc(-c2ccccc2)c1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1CCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
A solution of 674 mg (4.26 mmol) of 1-methyl-4-phenylimidazole (Kashima, C.; Harada, Y.; Hosomi, A. Heterocycles 1993, 35, 433) in 8.5 mL of THF at −78° C. was treated with 1.9 mL (4.69 mmol) of a 2.5 M nBuLi in hexanes solution. After stirring for 10 min, 1.1 mL (21.3 mmol) of ethylene oxide was added. The reaction was stirred for min then warmed to 25° C. and stirred for 1 h. Upon cooling to 0° C., 1.1 mL (21.3 mmol) of ethylene oxide was added, and the reaction was warmed to 25° C. and stirred overnight. The reaction was poured into H2O and extracted with Et2O. The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using EtOAc/MeOH (95:5), and the collected product was recrystallized from CH2Cl2/EtOAc to give 178 mg (21%) of title compound as a white solid: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CCCCCC.[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:29][C:27]1([C:58]1[CH:63]=[C:62]([CH:64]=[O:65])[C:61]([CH3:66])=[CH:60][C:59]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[S:29][C@:27]1([C:58]1[CH:63]=[C:62]([CH:64]([OH:65])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=2)[C:61]([CH3:66])=[CH:60][C:59]=1[O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C(O)c2cc([C@]3(O)S[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 1-bromo-4-(methoxymethoxy)benzene (1.55 g, 7.13 mmol) in tetrahydrofuran (7.5 mL), 2.67 M n-butyllithium in hexane (2.58 mL, 6.9 mmol) was added dropwise at −60° C. under a nitrogen atmosphere. Then, a solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-formyl-4-methylphenyl]-5-thio-D-glucopyranose (1.80 g, 2.30 mmol) in tetrahydrofuran (10 mL) was added dropwise and stirred at −78° C. for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give the titled compound (1.2 g, 57%) as a yellow amorphous substance.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].C(N(CC)CC)C>>[O:25]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:24])[N:15]1[CH2:14][CH2:13][CH:12]=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The reaction was carried out with oven dried glassware. DMSO (85 μl, 1.1 mmol) was added to oxalyl chloride solution (0.35 mL 2 M DCM solution with 5 mL dry DCM) at −78° C. The reaction mixture was stirred at −78° C. for 10 min. 2-(3-Hydroxy-propyl)-isoindole-1,3-dione solution (102 mg, 0.5 mmol, in 2 mL DCM) was added drop wise in 2 min. Then triethylamine (0.35 mL, 2.5 mmol) was added drop wise in 2 min. The mixture was stirred for additional 30 minutes at −78° C. and was warmed up to room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude product was purified by flash chromatography to give 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:28])[C:16]3[CH:21]=[CH:20][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:28])[C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(C#C[Si](C)(C)C)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N(C)[C@@H]2CCN(c3ncnc4[nH]ccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-5-((trimethylsilyl)ethynyl)pyridin-2-amine (26 mg, 0.06 mmol) and K2CO3 (20.0 mg) in MeOH (4.0 mL) was stirred at the ambient temperature for 16 hours. The volatiles were removed and the residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 319 (M+H)+.
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5]([C:9]1[S:13][C:12]([S:14]([NH:17]C(C)(C)C)(=[O:16])=[O:15])=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:24][CH:23]=2)[CH:10]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[CH2:5]([C:9]1[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:24][CH:23]=2)[CH:10]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cnnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2ccc(Cn3cnnn3)cc2)c(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
BCl3 (1.0 mL, 1M, 1.0 mmol) was added to a solution of 5-iso-butyl-N-tert-butyl-3-(4-tetrazol-1-ylmethylphenyl)thiophene-2-sulfonamide (177.0 mg, 0.408 mmol, see step (b) above) in CH2Cl2 (10 mL) under N2 (g), and the reaction mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step used without further purification.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][C:14]([OH:16])=[O:15].[CH3:17][C:18]([OH:20])=[O:19].[CH3:21][C:22]([OH:24])=[O:23].[CH3:25][C:26]([OH:28])=[O:27]>>[CH2:3]1[N:4]([CH2:13][C:14]([OH:16])=[O:15])[CH2:5][CH2:6][N:7]([CH2:17][C:18]([OH:20])=[O:19])[CH2:8][CH2:9][N:10]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:12][N:1]([CH2:25][C:26]([OH:28])=[O:27])[CH2:2]1
Reactant: CC(=O)O
Reactant: C1CNCCNCCNCCN1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
1,4,7,10 tetraazacyclododecane 1,4,7,10 N, N′, N″, N′″ tetraacetic acid
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])[CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:28](=[O:30])[CH3:29])[CH:36]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C(C)=O)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208. mg, 0.5 mmol), 3-acetylphenylboronic acid (90 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-acetyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a colorless oil.