Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCCCCc1ccccc1
Yield: 28 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 5-phenyl-1-pentanol (56 mg, 0.34 mmol) as the coupling partner. Chromatography (gradient 5–95% ethyl acetate/hexane) through SiO2 yielded 6 mg (28%) of the titled compound. ESI-MS m/z 438 (MH+), 436 (M−H−).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:15][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C#CCCO
Reactant: O=C(O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(C#CCCO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
Into a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-bromobenzoic acid (10 g, 49.75 mmol, 1.00 equiv) in triethylamine/N,N-dimethylformamide (100/20 mL), but-3-yn-1-ol (6.98 g, 99.57 mmol, 2.00 equiv), copper(I) iodide (1.90 g, 9.97 mmol, 0.20 equiv), Pd(PPh3)2Cl2 (6.98 g, 9.94 mmol, 0.20 equiv). The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 11-12 with sodium hydroxide (1 mol/L). The resulting solution was extracted with 3×300 mL of dichloromethane and the aqueous layers combined. The solution was adjusted to pH 1-2 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 5×300 mL of dichloromethane and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. This resulted in 10 g crude product as brown oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.C1([O:19][C:20](=O)[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[C:24]([CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH:23]=2)C=CC=CC=1>C1COCC1.O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][C:20](=[O:19])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:32])[CH3:33])(=[O:29])=[O:30])=[C:24]([CH2:34][N:35]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH3:36])[CH:23]=2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 3 h

Procedure:
Sodium hydride (60% in oil, 60 mg, 1.5 mmol) was added portionwise to a solution of 4-bromophenethyl alcohol (0.718 g, 3.57) in THF (6 mL) at 0° C. The reaction mixture was cooled to −40° C., and a solution of 16G (0.550 g, 1.19 mmol) in THF (5 mL) was added slowly dropwise. The reaction mixture was slowly warmed to 0° C., and then stirred for 3 h at 0° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 16H (0.503 g, 74%) as a white solid.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[Al+3].[Cl-:29].[Cl-].[Cl-].C1(C)C=CC=CC=1.[Si](O)(O)(O)O>C(Cl)(Cl)Cl>[CH3:26][C:25]([O:24][CH2:23][C@H:21]1[O:22][C@@H:5]([Cl:29])[C@H:6]([O:7][C:8]([CH3:9])=[O:10])[C@@H:11]([O:12][C:13]([CH3:14])=[O:15])[C@@H:16]1[O:17][C:18]([CH3:19])=[O:20])=[O:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [Cl-]
Agent: O[Si](O)(O)O
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of β-D-glucose pentaacetate (20 g) in CHCl3 (100 mL) was added AlCl3 (3.6 g). After stirring at room temperature, toluene (100 mL) was added, followed by silicic acid (2 g). The mixture was stirred for a few minutes and the precipitate was removed by filtration. The solution was partially concentrated under vacuum and extracted with ice cold water (25 mL). The organic phase was concentrated to a syrupy mixture and ether was added to precipitate acetochloro-β-D-glucose as a powder (12 g).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4]1.[H][H]>CO.[Pd]>[NH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: NC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC1(c2ccccc2)CCNCC1
Yield: 102.8 %

Procedure:
3.2 ml of 12N hydrochloric acid solution are added to a solution of 5 g of 4-amino-1-benzyl-4-phenylpiperidine in 25 ml of methanol, followed by addition of 0.5 g of 10% palladium-on-charcoal (50% water) and hydrogen overnight, at atmospheric pressure and at 40° C. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in 15 ml of water, basified by addition of 3.8 ml of 10N sodium hydroxide solution and left stirring. Sodium chloride crystals are added to the aqueous phase and the mixture is extracted twice with 25 ml of dichloromethane. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. 3.4 g of the expected product are obtained. b) A solution of 2.83 g of potassium carbonate in 2.8 ml of water is added to a solution of 4 g of compound of formula (III) obtained in Example 1 in 9.2 ml of toluene and 8 ml of methyl isobutyl ketone, followed by addition of 1.6 g of 4-amino-4-phenylpiperidine, and this mixture is heated at 70° C. for 12 hours. After cooling the reaction mixture to room temperature, 16 ml of water are added and the phases are then separated by settling. The organic phase is washed twice with 16 ml of water and is acidified by adding a solution of 1.5 ml of 12N hydrochloric acid in 16 ml of water, and the phases are then separated by settling. The acidic aqueous phase is washed twice with 10 ml of toluene, the aqueous phase is basified by adding 2 ml of 10N sodium hydroxide solution and is extracted twice with 30 ml of toluene. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. 4 g of the expected product are obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:24]4[CH:25]=[CH:26][C:27]([S:28]([CH3:31])(=[O:29])=[O:30])=[C:22]([F:21])[CH:23]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nn3c(-c4ccc(S(C)(=O)=O)c(F)c4)c(C)nc3s2)cc1OC
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a suspension of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.035 g, 0.087 mmol, 1 eq) in dioxane (1.8 mL), 3-fluoro-4-(methylsulfonyl)phenylboronic acid (0.047 g, 0.217 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.006 g, 0.0087 mmol, 0.1 eq), potassium carbonate (0.06 g, 0.435 mmol, 5 eq) and water (0.8 mL) were added. The reaction mixture was subjected to MW irradiation (120° C., 35 min, 200 W), cooled to RT and concentrated. The residue was purified by silica gel chromatography (0-0.5% MeOH in DCM). Product fractions afforded an oily residue that was further purified by trituration with Et2O providing a pale yellow solid (0.02 g) and by preparative HPLC to give the pure product (0.010 g, 25%). HPLC-MS: (50-100% B in 8 min, 0.6 mL/min): tR=2.41 min, [M+H]+ m/z 448.1. 1H NMR (300 MHz, CDCl3) δ/ppm 8.03 (dd, J=8.3, 7.7, 1H), 7.81-7.70 (m, 2H), 7.39 (dt, J=3.4, 2.0, 2H), 6.94 (d, J=8.2, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.26 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:34][N:33]=2)=[CH:28][CH:27]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:40]3[CH2:39][CH2:38][CH:37]([C:35]4[O:34][N:33]=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=5)[N:36]=4)[CH2:42][CH2:41]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Clc1ccc(-c2noc(C3CCNCC3)n2)cc1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCC(c3nc(-c4ccc(Cl)cc4)no3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.069 g. 0.20 mmol) was dissolved in CH2Cl2 (1 mL), and 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4 mmol) was added, followed by Yb(OTf)3 (0.031 g, 0.22 mmol). The mixture was stirred at room temperature for 16 h. Preparative TLC (silica, 7.5% MeOH/CH2Cl2) afforded 84 mg (69%) of the title compound. MS (electrospray): exact mass calculated for C31H34Cl2N6O3, 608.21; m/z found, 609.2 [M++H]. 1H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers): 8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42 (d, J=8.6 Hz, 2H), 7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB quartet J=15.6 Hz, 1H), 4.62 (br s, 1H), 4.25-4.13 (m, 2H), 4.10-3.98 (m, 2H), 3.90-3.70 (m, 2H), 3.04-2.71 (m, 5H), 2.51-2.40 (m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90 (m, 2H).
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(C(CCCC)CO)C>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:32]([CH:48]([CH2:47][CH2:46][CH2:45][CH3:44])[CH2:43][O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:33]
Reactant: c1ccccc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCCCC(CC)CO
Product: CCCCC(CC)COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of 2-ethylhexanol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 10 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ester was added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine 2-ethylhexyl ester di(p-toluenesulfonate) in 91% yield; mp. 170°-174° C.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:17][N:18]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(C)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[ClH:13].N([O-])=O.[Na+]>[Cu]Cl.O.C(O)(=O)C>[Cl:13][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cl
Reactant: COc1cc(N)ccc1C(C)=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Cl)ccc1C(C)=O
Temperature: 60 °C
Yield: 76 %

Procedure:
A stirred and cooled (0° C.) solution of 30 parts of 1-(4-amino-2-methoxyphenyl)ethanone in 360 parts of a concentrated hydrochloric acid solution, 75 parts of water and 30 parts of acetic acid is diazotated with a solution of 17.25 parts of sodium nitrite in 200 parts of water. After stirring for 30 minutes at 0° C., the whole is poured onto a solution of 30 parts of copper (I) chloride in 240 parts of a concentrated hydrochloric acid solution while stirring. The mixture is heated for 1 hour at 60° C. After cooling to room temperature, the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed successively with water, a diluted sodium hydroxide solution and again twice with water, dried, filtered and evaporated, yielding 28 parts (76%) of 1-(4-chloro-2-methoxyphenyl)ethanone; mp. 55° C.
Reaction SMILES: [Al].[Cl:2][C:3]1[CH:4]=[C:5]([N:11]2[C:15](=[O:16])[C@:14]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)([CH3:17])[N:13]3[CH:27]=[CH:28][N:29]=[C:12]23)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].[I:30]N1C(=O)CCC1=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:11]2[C:15](=[O:16])[C@:14]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)([CH3:17])[N:13]3[C:27]([I:30])=[CH:28][N:29]=[C:12]23)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9]
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2nccn21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Al]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(I)n21
Reaction time: 1 h
Yield: 81.8 %

Procedure:
An aluminum foil covered flask containing a solution of 4-[(R)-1-(3,5-dichloro-4-fluoro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrile (48.8 g, 117.5 mmol) in CH2Cl2 (900 mL) was partially submerged in an ice water bath. To this solution was added a solid mixture of N-iodosuccinimide (29.1 g, 129 mmol) and pyridinium p-toluenesulfonate (2.95 g, 11.7 mmol) in four separate portions over a 30 min period. The reaction was allowed to stir in the thawing ice bath for 1 h and then the bath was removed. Stirring was continued overnight. Saturated aqueous Na2S2O3 (300 mL) was added to the reaction and the mixture was transferred to a separatory funnel using CH2Cl2 (200 mL) and water (1 L). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×500 mL) and EtOAc (500 mL). The combined organic layers were dried over MgSO4 and concentrated in-vacuo to give a yellow oil. This oil was purified by flash chromatography on silica gel (0-2.5% EtOAc/toluene) to give 52 g of the title compound as a white solid, m/z 541.3 [M+H]+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][N:13]([C:24](=[O:46])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:45])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][N:13]([C:24](=[O:46])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:45])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3C(=O)N2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@@H](O)CN3C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of (2R,11aS)-2-(tert-butyldimethylsilyloxy)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (5.53 g) prepared in Reference Example 68 in tetrahydrofuran (20 ml), there was dropwise added, with ice-cooling, a solution of tetrabutylammonium fluoride (4.54 g) in tetrahydrofuran (50 ml) over 5 minutes and the reaction solution was stirred at room temperature for 30 minutes. After the reaction solution was diluted with ethyl acetate, it was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained after concentration of the reaction solution was subjected to silica gel column chromatography and then eluted with chloroform/acetone (1/1) to give 4.1 g (yield 91.0%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])(O)[CH2:5][CH2:6][O:7]2.FC(F)(F)C(O)=O.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][CH:31]=[CH:30]2>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:30]1[C:29]3[C:33](=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=[CH:27][CH:28]=3)[NH:32][CH:31]=1)([CH3:14])[CH2:5][CH2:6][O:7]2
Reactant: CC1(O)CCOc2cc(F)cc(F)c21
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
565 mg (2.82 mmol) of the compound from Example 171A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and subsequent flash chromatography on silica gel (mobile phase: dichloromethane). 632 mg (62% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2
Reactant: FC(F)(F)c1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CC2c3ccccc3CCc3ccccc32)c1
Reaction time: 17 h

Procedure:
Add 5-(3-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.145 g, 0.41 mmol), to a mixture of 10% Pd/C (0.04 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 352 (M+); GC retention time=7.11 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.CCN(C(C)C)C(C)C.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33])([O-:25])=[O:24]>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])(=[O:33])=[O:34])=[N:6][CH:7]=1)([O-:13])=[O:12]
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Temperature: 23 °C
Reaction time: 6 h

Procedure:
To a suspension of resin-bound (2aminoethyl)(5-nitro(2-pyridyl))amine (30 g, 21 mmol), CH2Cl2 (250 mL) and iPr2NEt (18.3 mL, 105 mmol) at 23° C. was added 2-nitrobenzenesulfonyl chloride (23.3 g, 105 mmol). The resulting mixture was shaken at 23° C. for 6 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound {2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:10]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)Cc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
2-hydroxyphenylacetic acid (10 g, 66 mmol) was dissolved in N,N-dimethyl-formamide (100 ml) and cooled on ice-bath. Potassium tert-butoxide (8.85 g, 78 mmol) was added. The mixture was left for 30 min and allowed to reach room temperature. 4-Methoxy-benzylchloride (11.7 g, 72 mmol) in N,N-dimethyl-formamide (30 ml) was then added dropwise, under nitrogen atmosphere and left over-night. The solvent was evaporated under reduced pressure and the crude mixture was dissolved in ether (100 ml) and washed with water (25 ml), brine and dried over sodium sulphate. Chromatography (hexane-ethyl acetate, 2:1) followed by recrystallization hexane-ethyl acetate) gave the title compound (7.6 g, 42%).