Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:30])=O>C(Cl)(Cl)Cl.O>[Cl:30][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(CO)cccc2c1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(CCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
53.4 g of Intermediate II and 38.8 ml of anhydrous triethylamine were dissolved in 440 ml of chloroform. Into this solution, maintained at -10° to -2° C., there was dropped a solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous chloroform. The reaction mixture was stirred at room temperature for 4 hours, and then diluted with 400 ml of water. The aqueous phase was extracted with chloroform, and the extracts were added to the chloroform phase. The chloroform solution was washed with brine, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. Yield: 56 g of the title compound, which on recrystallization from ethanol was shown to have a melting point of 112°-113° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:5]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:11]=2)[N:6]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(O)ccc21
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-acetyl-5-hydroxy-1H-indazol-1-yl)acetate (1.80 g, 7.25 mmol) in CH3CN (75 mL) was added 2-(chloromethyl)pyrimidine hydrochloride salt (1.32 g, 7.98 mmol) and Cs2CO3 (5.91 g, 18.13 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was filtered and washed with CH3CN. Solvent was evaporated and the crude mixture was purified by flash column chromatography on silica gel (gradient: c-hexane/EtOAc 1:1 to 1:3). TLC, Rf (c-hexane/EtOAc 1:3)=0.35; MS (LC/MS): 340.9 [M+H]+, 363.0 [M+Na]+; tR (HPLC conditions c): 3.64 min.
Reaction SMILES: C([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](C3N=CC(O)=CN=3)[CH:15]=2)[CH2:10]1)CCCCCCC.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
0.2 g (0.60 mM) of 2-octyl-5-(5-hydroxypyrimidine-2-yl)indan, 0.07 g (0.62 mM) of s-(-)-tetrahydro-2-furancarboxylic acid, 0.13 g (0.62 mM) of DCC, 0.01 g of 4-dimethylaminopyridine and 10 ml of methylene chloride were mixed and stirred for 6 hours at room temperature. The resultant N,N'-dichlorhexylurea was recovered by filtration, washed with dichloromethane, and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/methylene chloride=1/10) and recrystallized from a mixture solvent (toluene/ethanol) to obtain 0.15 g of 2-octyl-5-[5-(tetrahydro-2-furancarbonyloxy))pyrimidine-2-yl]indan (Yield: 82.7%). ##STR149##
Reaction SMILES: C(N)(=[O:8])C1C=CC=CC=1.C(#N)C1C=CC=NC=1.[C:18]([NH2:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C=C(CCC#N)C#N>C(#N)C1C=CC=CC=1.O.N1C=CC=CC=1>[CH2:20]=[C:19]([CH2:24][CH2:23][C:22]([NH2:21])=[O:8])[C:18]([NH2:26])=[O:25]
Reactant: NC(=O)c1ccccc1
Reactant: NC(=O)c1cccnc1
Agent: C=C(C#N)CCC#N
Agent: N#Cc1cccnc1
Solvent: N#Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C=C(CCC(N)=O)C(N)=O
Temperature: 120 °C

Procedure:
Into 10 ml stainless steel tubes were charged 0.1 mmole RhCl3 . 3H2O, 0.4 mmole TLTTP, 4 ml pyridine, 1-2 g of nitrile and a stoichiometric equivalent amount of water. The tubes were pressurized to 150 psig with nitrogen and heated at 120° C. for 17 hours and then the products were determined. In this manner, benzonitrile was converted to benzamide and nicotinonitrile was converted to nicotinamide. These reactions were repeated on a scale up of about 10-times using methyleneglutaronitrile as the nitrile, 115° C. for 27 hours and a nitrogen pressure of 210 psig to produce 2-methyleneglutaramide.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[S:6][CH:7]=[C:8](C=O)C=1)#[N:4].[CH2:12]([OH:14])[CH3:13]>>[C:3]([C:5]1[S:6][CH:7]=[CH:8][C:13]=1[CH2:12][OH:14])#[N:4]
Reactant: CCO
Reactant: N#Cc1cc(C=O)cs1
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1sccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
3.47 g (91.8 mmol) of sodium borohydride were added in portions to a suspension of 12.6 g (91.8 mmol) of 2-cyano-4-formylthiophene in 200 ml of ethanol, and the reaction mixture was stirred at room temperature for 2 h, during which it slowly formed a clear solution. The residue after concentration under reduced pressure was taken up in ethyl acetate and washed successively with saturated brine, 5% strength citric acid and saturated brine, and the organic phase was dried with sodium sulfate and concentrated under reduced pressure to result in 11.7 g of almost pure product (yield 91.5%).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:33]C)[N:19]2[CH2:22][CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][O:28][C:27]([CH3:32])([CH3:31])[CH2:26]2)=[C:15]([NH2:35])[N:14]=1)[CH2:9][CH2:10][CH3:11]>CO.C(Cl)Cl.CO>[NH2:35][C:15]1[N:14]=[C:13]([NH:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[NH:17][C:18](=[O:33])[N:19]2[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][O:28][C:27]([CH3:32])([CH3:31])[CH2:26]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCC3CCOC(C)(C)C3)c2n1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
4M HCl in 1,4-dioxane (3 ml, 12.00 mmol) was added in one portion to a stirred solution of N2-butyl-9-[3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)propyl]-8-(methyloxy)-9H-purine-2,6-diamine (40 mg, 0.102 mmol) in methanol (3 ml) at room temperature and the mixture stirred under nitrogen overnight. The mixture was then concentrated and the residue dissolved in MeOH:DCM (1:15 ml) and loaded onto a 2 g aminopropyl SPE cartridge. The cartridge was washed with MeOH:DCM (1:1, 3 column volumes) and the desired fractions were concentrated in vacuo to give material of ca. 80% purity. This material was dissolved in DCM:MeOH (1:1), applied to a 2 g SCX column and eluted firstly with MeOH:DCM (3 column volumes) and the product then released by 2M ammonia in methanol: DCM (1:1, 3 column volumes). The solvent was removed to yield the title compound as a yellow solid (14 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13]=[C:14]([N:18]=[N+]=[N-])[C:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O[CH2:24]COCCOCCOC(C1C=CC=CC=1)=C(N=[N+]=[N-])C([O-])=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:22]=[C:21]2[C:12]([CH:13]=[C:14]([C:15]([O:17][CH3:24])=[O:16])[NH:18]2)=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NC(C(=O)[O-])=C(OCCOCCOCCO)c1ccccc1
Reactant: COCCOCCOc1ccc(C=C(N=[N+]=[N-])C(=O)[O-])cc1
Product: COCCOCCOc1ccc2cc(C(=O)OC)[nH]c2c1

Procedure:
Following the general procedure of EXAMPLE 3, and making non-critical variations but substituting 4-(2-(2-methoxyethoxy)ethoxy)-α-azidocinnamate (PREPARATION 79) for 4-[(2-(2-hydroxyethoxy)ethoxy)ethoxyl-α-azidocinnamate, the title compound is obtained, NMR (300 MHz, CD3OD) 7.59, 7.20, 7.02, 6.87, 4.25, 4.00, 3.96, 3.80, 3.67 and 3.47.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A 5 liter 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with 5-acetyl-8-hydroxyquinoline (300 gms/1.44 moles) and acetone (3 liters). To this solution was added anhydrous potassium carbonate (443 gms/1.6 moles) in 30 minutes followed by benzyl bromide (229 ml/1.92 moles) slowly in 90 minutes. The resulting slurry was heated to reflux for 12 hours. The reaction mass was filtered through hyflo bed, after completion of reaction and washed with hot ethyl acetate (300 ml). The clear filtrate was distilled out completely at 55-60° C. under high vacuum. The residue was dissolved in acetone (300 ml) and warmed to 50° C. for 5-10 minutes, cooled to 25-30° C., chilled further to 0-5° C. and stirred for 30 minutes. The resulting 5-Acetyl-8-benzyloxyquinoline was isolated by filtration and washed with 1:1 mixture of acetone and diisopropyl ether (150 ml) and dried under vacuum at 60-65° C. for 4-5 hours. Yield-202 gms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3cc(Br)cnc32)cc1
Yield: 111.5 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.147 mmol), 4-fluorophenylboronic acid (25 mg, 0.176 mmol) and dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.015 mmol) were combined in CH3CN (2 ml) and 1 M Na2CO3 (2 ml) and stirred at 60° C. for 3 hrs. EtOAc was added and the mixture was washed with water, dried and evaporated to yield 73 mg (112%) of the title compound. MS ESI (m/z): 445.1/447.2 (M+1)+, calc. 444/446.
Reaction SMILES: C(OC([N:8](CC1C=CC=CN=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.ClCC1N(COCC[Si](C)(C)C)C2C=CC=CC=2N=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:28][C:18]1([NH:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=2)[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Agent: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NCc2ccc(CN)cc2)CCCc2cccnc21

Procedure:
Reaction of N-tert-Butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (120 mg, 0.26 mmol), 2-chloromethyl-1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole (234 mg, 0.79 mmol) and diisopropylethylamine (229 μL, 1.31 mmol) in DMF (2.6 mL) for 18 h at 90° C. followed by purification of the crude material by radial chromatography (2 mm plate, 20:2:1 CHCl3-MeOH-NH4OH) afforded 90 mg (48%) of N-tert-butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-ylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine as a colourless oil.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH3:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Na].[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)#[N:21]>CN(C=O)C.C(Cl)Cl.CC(O)=O>[CH2:1]([C:5]1[N:14]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:20]#[N:21])=[CH:33][CH:32]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1cnccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(=O)c2cc(C)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2ccncc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-butyl-6-methylquinazolin-4(1H)-one (1.0 eq.) from Example 1 in DMF at rt is added NaH (1.0 eq.) to generate the sodium salt. After 20 min, 3-cyano-4-(4-bromomethyl phenyl)pyridine (1 mL of a 2M solution in CH2Cl2, 2 eq.) is added and the mixture is stirred at rt for 3 h. HOAc (100 μL) is added, the excess DMF is removed in vacuo then the crude product is isolated by extraction with EtOAc from brine. Purification by flash chromatography will give the above titled compound.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:28][C:29]([Si:32]([O:35][CH2:36][CH2:37]I)([CH3:34])[CH3:33])([CH3:31])[CH3:30].Cl>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:37][CH2:36][O:35][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -68 °C
Reaction time: 0.75 h

Procedure:
To a −70° C. solution of LiHMDS in THF (1M, 6.97 L, 6.97 mol) was added a solution of the product of Step B (763.5 g, 3.16 mol) in THF (800 mL) over a 2 h period while keeping the temperature at or below −68° C. The resulting solution was stirred for 45 min at −68° C. A solution of the product of Step C (1.267 kg, 4.426 mol) in THF (800 mL) was added over 1 h 50 min period while maintaining a temperature of ˜−66° C. The reaction was stirred at ˜-66° C. for 45 min. The reaction was warmed to −15° C. and worked up by addition to mixture of aqueous HCl and ice. The mixture was extracted with toluene, the organic layer was washed with water, brine and dried over MgSO4. The organic layer was concentrated and purified on silica gel using a mixture of EtOAc in heptanes to provide the product of Step D as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) d=5.69-5.86 (m, 2H), 4.79-4.93 (m, 1H), 4.68-4.80 (m, 1H), 3.67 (s, 3H), 3.53-3.62 (m, 2H), 2.16-2.30 (m, 1H), 2.04-2.16 (m, 2H), 1.70-1.81 (m, 1H), 1.41 (s, 9H), 0.78-0.91 (m, 13H), 0.00 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4]>CO>[NH2:10][C:8]1[CH:9]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[NH:6][CH:7]=1
Reactant: CNC(=O)c1cc([N+](=O)[O-])c[nH]1
Solvent: CO
Product: CNC(=O)c1cc(N)c[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of N-methyl-4-nitro-1H-pyrrole-2-carboxamide (75 mg, 0.44 mmol) in methanol was degassed and flushed with N2 (g). 10% Pd on activated carbon was added and the mixture degassed and flushed with N2 (g). H2 (g) was applied and the reaction mixture stirred at rt for 14 h. The resultant mixture was filtered through celite then concentrated in vacuo to afford 4-amino-N-methyl-1H-pyrrole-2-carboxamide as a green solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2cccc(C#N)c2)n(-c2cccc(C#N)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2cccc(C#N)c2)c1
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 62A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 397 mg of the title compound with 36% purity are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:23]([O:22][C:20]([CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][CH:7]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCC(=O)OCc2ccccc2)cc1

Procedure:
t-Butyl [2-(4-hydroxyphenyl)ethyl]carbamate, benzyl bromoacetate and potassium carbonate were heated in acetone. t-Butyl [p-[[(benzyloxy)carbonyl]methoxy]phenethyl]carbamate, MS: 385 (0.5, M), was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:11]=[C:6]([C:7](OC)=[O:8])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:15]([O:14][C:12]1[CH:11]=[C:6]([CH2:7][OH:8])[CH:5]=[C:4]([CH2:3][OH:2])[CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1cc(CO)cc(CO)c1
Yield: 53.3 %

Procedure:
The product was generated using general protocol E using dimethyl-5-tetradecyloxyisophthalate (D9, 1.171 g, 2.88 mmol), lithium aluminum hydride (0.253 g, 6.34 mmol), Et2O (40 mL) yielded 0.538 g (53.3%) of a white solid. 1H NMR (CDCl3, 300 MHz) δ: 6.9336 (s, 1H, Ar—H), 6.8501 (s, 2H, Ar—H), 4.6821 (s, 4H, Ar—CH2), 3.9708 (t, 2H, O—CH2, 3J=6.58 Hz), 1.7784 (p, 2H, O—CH2—CH2, 3J=7.16 Hz), 1.6328 (t, 2H, O—H), 1.4483 (p, 2H, O—CH2—CH2—CH2, 3J=7.58 Hz), 1.2625 (m, 20H), 0.8810 (t, 3H, CH2—CH3, 3J=6.83 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:50]1[CH2:49][CH2:48][CH:47]([CH2:46][CH2:45][O:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:52][CH2:51]1)(=[O:18])[CH3:16]
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 66% yield. LCMS for C26H30ClN6O2 (M+H)+: m/z=493.1.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][S:8]([NH:11]CC2C=CC(OC)=CC=2OC)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C([Li])CCC.[O:34]1[CH2:37][C:36](=[O:38])[CH2:35]1.FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH:7]([C:36]2([OH:38])[CH2:37][O:34][CH2:35]2)[S:8]([NH2:11])(=[O:9])=[O:10])=[CH:5][CH:6]=1
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(-c3ccccc3)cc2)c(OC)c1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NS(=O)(=O)C(c1ccc(-c2ccccc2)cc1)C1(O)COC1
Reaction time: 0.08 h

Procedure:
Under inert gas, 0.500 g of C-biphenyl-4-yl-N-(2,4-dimethoxybenzyl)methanesulfonamide was initially charged in 5 ml of THF and then, at −78° C., 1.8 ml of a 1.6 N butyllithium solution in hexane were added dropwise. The reaction mixture was stirred for 5 minutes and then admixed dropwise with 0.24 ml of 3-oxetanone. The mixture was stirred at constant temperature for 5 minutes, 0.28 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 2 ml of dichloromethane, and 2 ml of trifluoroacetic acid were added. After stirring at room temperature for 60 minutes, 50 ml of saturated potassium carbonate solution were added and the mixture was extracted with dichloromethane, dried over magnesium sulfate and concentrated. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. This gave the product (170 mg) with a molecular weight of 319.4 g/mol (C16H17NO4S).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[O:30]1[C@H:31]2[O:32][CH2:33][CH2:34][C@H:35]2[C@@H:28]([O:27][C:26]([NH:25][C@H:16]([C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:20][CH:19]=2)=[O:36])[CH2:29]1
Reactant: CCOC(=O)CBr
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a stirred mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (200 mg, 0.34 mmol) and cesium carbonate (330 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL) was added ethyl bromoacetate (75 μL, 0.67 mmol). After stirring at ambient temperature for 2 h, the reaction was diluted with ethyl acetate (50 mL), washed with water (3×40 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by silica gel chromatography (60:40; ethyl acetate:hexane) to afford the title compound (162 mg, 71%) as a white foam. 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.16 (3H, t), 1.17-1.43 (2H, m), 1.92 (1H, m), 2.35 (1H, t), 2.64-2.78 (3H, m), 2.88-3.01 (2H, m), 3.24-3.29 (1H, m), 3.40-3.60 (4H, m), 3.70 (1H, t), 3.78-3.82 (1H, m), 4.10 (2H, q), 4.65 (2H, s), 4.81 (1H, q), 5.00 (1H, d), 5.46 (1H, d), 6.12 (2H, s), 6.73 (2H, d), 7.02-7.07 (3H, m), 7.20-7.28 (3H, m); MS: 679 (MH+)