Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.044 g, 0.11 mmol) and EtOH (3.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80° C. for 19 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 2:3) and then a gradient of methanol (2 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 20%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.67 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [N:1]1[C:9]2[CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[N:1]1[C:9]2[CH2:8][CH:7]([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@@H]1Cc2cccnc2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC1Cc2cccnc2C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 102.7 %

Procedure:
To a solution of 895 mg (6 mmol) of (+)-(6R)-(6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol in 50 ml of anhydrous dichloromethane was added at −15° C. 0.918 ml (6.6 mmol) of triethylamine and 0.465 ml (6 mmol) of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 45 min. The mixture was then diluted with water and dichloromethane and extracted with dichloromethane. Organic layer was dried and evaporated to give 1.4 g (100%) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(C(C)=O)C.[CH3:35][O:36][CH2:37][CH2:38]Br>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:21][CH2:22][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:38][CH2:37][O:36][CH3:35])[CH:11]=3)=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(O)ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a suspension of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (519.2 mg, 1.71 mmol), K2CO3, 10 mL of methyl ethyl ketone, and 2 mL of DMF is added 2-bromoethyl methyl ether. The resulting mixture is stirred at 85° C. for 8 h. The mixture is concentrated and the residue is partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase is extracted with additional ethyl acetate (20 mL). The combined organic phases are washed with saturated NaCl, dried over MgSO4, and then the solution is concentrated and the product is washed with diethyl ether to afford 505.0 mg (81.7% yield) of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1>O1CCOCC1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:48]1[CH:49]=[CH:50][C:45]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][C:2]=2[C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:46][CH:47]=1
Reactant: O=Cc1ccc(-c2cn3ccccc3n2)cc1
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ccccn3c2-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
0.2 g (0.9 mM) 4-imidazo[1,2-a]pyridin-2-ylbenzaldehyde (prepared as described by Sundberg et al.; J. Heterocyclic Chem., 25, 129, 1988) is dissolved in 5 mL of Dioxane. To this is added CsCO3 (1.1 eq), palladium acetate (8 mol %), triphenyl phosphine (16 mol %), triethylamine (2 eq) and 4-bromo-pyridine (1.4 eq). The reaction mixture is heated (microwave) for 45 min at 100° C. The reaction mixture is cooled to RT, diluted with DCM. The organic layer is washed with water, dried and concentrated. The crude product purified by column chromatography to obtain the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:24]=[C:23]([C:25]([OH:27])=O)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:28])[CH:21]=2)[N:16]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[N:47]1([CH2:52][CH2:53][NH2:54])[CH2:51][CH2:50][CH2:49][CH2:48]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:24]=[C:23]([C:25]([NH:54][CH2:53][CH2:52][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:27])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:28])[CH:21]=2)[N:16]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cc(-c2ccc(CN3CCOCC3)cc2Cl)nc2ccc(F)cc12
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCN1CCCC1)c1cc(-c2ccc(CN3CCOCC3)cc2Cl)nc2ccc(F)cc12
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A mixture of 2-(2-chloro-4-(morpholinomethyl)phenyl)-6-fluoroquinoline-4-carboxylic acid (303 mg, 0.76 mmol) (preparation 18) in DCM (6 ml) was prepared at room temperature and N-methylmorpholine (0.166 ml, 1.51 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (159 mg, 0.91 mmol) added and the mixture stirred for 1 h in a sealed vial. 2-(Pyrrolidin-1-yl)ethanamine (0.143 ml, 1.13 mmol) was then added and the mixture stirred in a sealed vial for 17 h. The mixture was then diluted with DCM (5 ml) and the organic layers washed with water (2×3 ml) and filtered through a phase separator and the organic layers concentrated under reduced pressure and purified by column chromatography (0-10% 7M NH3 in MeOH/DCM) to afford an off white solid. Analysis by 1HNMR showed impurities and the mixture was further purified by mass directed autopreparative HPLC to afford the desired product as an off-white solid (228 mg, 0.46 mmol, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
4-Bromoaniline (56.0 g., 0.33 Mol.), 2,5-hexanedione (37.6 g., 0.33 Mol), and acetic acid (5 ml) were placed into Toluene (500 ml) and heated under reflux for 8 hours employing a dean stark trap to remove the water from the reaction. The reaction was cooled to room temperature and concentrated under reduced vacuum. The resulting oil was taken into ethyl acetate, washed one time each with 2N hydrochloric acid, 2N NaOH, and H2O, dried over NA4SO4, and concentrated under reduced vacuum to yield a brown solid. Material was purified by silica gel flash chromatography eluting with hexane. Concentration of the appropriate fractions yielded 55.0 gm. of a light yellow solid. (68%) NMR was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+249 m.p. 71°-73° C.
Reaction SMILES: Cl.[NH2:2][OH:3].CC(O)=O.[Cl:8][C:9]1[C:14]([CH:15]=O)=[C:13]([Cl:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=1>CCO>[Cl:8][C:9]1[C:14]([CH:15]=[N:2][OH:3])=[C:13]([Cl:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1nc(Cl)c(C=NO)c(Cl)n1
Temperature: 70 °C
Yield: 39.9 %

Procedure:
To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50° C. for about 1 hour, 60° C. for about 30 minutes and 70° C. for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M+H) 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) δ 2.62, 2.65 (3H), 7.53, 8.30 (1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([N:8]=[N+]=[N-])[CH3:7])=[CH:4][CH:3]=1.Cl>[Pd]>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: C[C@H](N=[N+]=[N-])c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Product: C[C@H](N)c1ccc(F)cc1
Reaction time: 4 h
Yield: 108.3 %

Procedure:
A mixture of the crude product of Step 2 (1.2 g, 7.3 mmol), conc. HCl (1 ml in 50 ml CH3OH) and Pd/C (10% w/w) (140 mg) was hydrogenated at 60 psi for 4 hr. After removal of the solvent, the residue was redissolved in 20 ml water and washed with ether. The aqueous layer was then basified to pH 11 and extracted with ether. The ether solution was dried and solvent evaporated to give 1.1 gram of (S)-p-fluoro-α-methylbenzylamine.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:47]=[CH:46][C:12]([O:13][C:14]2[CH:45]=[CH:44][C:17]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:43])([CH3:42])[C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=5)=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)([CH3:20])[CH3:19])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O.P(=O)(O)(O)O>[C:1]1(=[O:7])[N:41]([C:38]2[CH:39]=[CH:40][C:35]([O:34][C:31]3[CH:32]=[CH:33][C:28]([C:27]([C:24]4[CH:25]=[CH:26][C:21]([C:18]([CH3:20])([CH3:19])[C:17]5[CH:16]=[CH:15][C:14]([O:13][C:12]6[CH:11]=[CH:10][C:9]([N:8]7[C:1](=[O:7])[CH:2]=[CH:3][C:4]7=[O:5])=[CH:47][CH:46]=6)=[CH:45][CH:44]=5)=[CH:22][CH:23]=4)([CH3:42])[CH3:43])=[CH:29][CH:30]=3)=[CH:36][CH:37]=2)[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: CC(C)(c1ccc(Oc2ccc(N)cc2)cc1)c1ccc(C(C)(C)c2ccc(Oc3ccc(N)cc3)cc2)cc1
Reactant: O=C1C=CC(=O)O1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Oc2ccc(N3C(=O)C=CC3=O)cc2)cc1)c1ccc(C(C)(C)c2ccc(Oc3ccc(N4C(=O)C=CC4=O)cc3)cc2)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
In the same reactor used in Example 2A, there were placed 26.5 g (0.27 mole) of maleic anhydride, 0.7 g of phosphoric acid and 150 ml of mixed xylene. A solution was then added dropwise thereto under reflux of xylene, the solution having been prepared by thermally dissolving 52.8 g (0.1 mole) of 1,4-bis[4(4-aminophenoxy),α,α-dimethylbenzyl)benzene obtained in Example 1A in a mixture of 100 ml of mixed xylene and 50 ml of N,N-dimethylformamide. A dropping time of 5 hours and an aging time of 2 hours were used in order to carry out the reaction. The reaction solution was concentrated to about 1/2 the original amount and then cooled. When a temperature of 80° C. had been reached; 50 g of water was added thereto. Afterward, the solution was slowly cooled with stirring, so that crystals were precipitated. The crystals were then cooled to room temperature, filtered, and washed with cold methanol. 66.5 g of desired crude 1,4-bis[4-(4-maleimidophenoxy)-α, α-dimethylbenzyl]benzene was obtained. Its yield was 96.7%, and its purity according to HLC was 97.5%.
Reaction SMILES: Cl[C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[C-:49]#[N:50].[Na+].C1OCCOCCOCCOCCOC1.O>C1(C)C=CC=CC=1.[Ni]>[C:49]([C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])#[N:50]
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Reactant: [C-]#N
Agent: [Ni]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C#N

Procedure:
The mixture, prepared under argon, of 0.280 g of tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a), 0.080 g of sodium cyanide and 0.005 ml of 15-crown-5 in 2 ml of toluene is initially charged at room temperature with stirring and admixed with 0.75 ml of Ni-catalyst solution (preparation described below). The reaction mixture is stirred at 80° C. for 24 hours and then admixed with a further 0.75 ml of Ni catalyst solution. The reaction mixture is stirred at 80° C. over a further 24 hours and then admixed once more with 0.75 ml of Ni catalyst solution. After stirring for a further 24 hours, the mixture is cooled, admixed with water (30 ml) and extracted with ethyl acetate (2×30 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=6.10.
Reaction SMILES: Cl[CH2:2][Cl:3].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:16])=[C:12](CO)[N:13]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O>[Cl:3][CH2:2][C:12]1[N:13]=[C:9]([C:5]2[O:4][CH:8]=[CH:7][CH:6]=2)[O:10][C:11]=1[CH3:16]
Reactant: Cc1oc(-c2ccco2)nc1CO
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1CCl
Yield: 31 %

Procedure:
The dichloromethane (1 mL) solution of {2-(furan-2-yl)-5-methyloxazol-4-yl}methanol (36 mg, 0.2 mmol), N,N-dimethylaminopyridine (37 mg, 0.3 mmol) and p-toluene sulfonyl chloride (57 mg, 0.3 mmol) was stirred at 60° C. for 2 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 4-(chloromethyl)-2-(furan-2-yl)-5-methyloxazole (13 mg, 31%) as a transparent oil.
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:22]([N:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Product: CC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1 -aza-4,7,10,13,16,19-hexaoxacycloheneicosane and pivalyl chloride.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].I[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>>[CH3:16][C:12]1[CH:11]=[C:10]([N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(I)c1
Reactant: Nc1ccccc1N
Product: Cc1cccc(N(c2cccc(C)c2)c2ccccc2N(c2cccc(C)c2)c2cccc(C)c2)c1

Procedure:
The procedure of Example 1 was repeated except the use of 5.4 g of o-phenylenediamine of the formula (12) and 42.6 g of m-iodotoluene of the formula (14): ##STR11## as a starting material to obtain the expected compound of the formula (4) (12.6 g, yield: 55.1%).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:27]=2)=[N:7][N:6]=1)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>CS(C)=O.O>[N:38]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:27]=2)=[N:7][N:6]=1)=[N+:39]=[N-:40]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N=[N+]=[N-])s3)ccc21
Temperature: 60 °C
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (300 mg, 0.554 mmol) in DMSO (3 mL) was added sodium azide (215.8 mg, 3.32 mmol). The reaction was heated at 55-65° C. for 4 h, then diluted with H2O and extracted with EtOAc (80 mL×3). The combined organic layers were washed with water (50 mL×4), dried, filtered and concentrated to give the crude material (240 mg). MS (ESI, pos. ion) m/z: 505 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[O:9][C:8]([CH:10]=O)=[CH:7][CH:6]=1.[NH3:17].CO>[Ni]>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[O:9][C:8]([CH2:10][NH2:17])=[CH:7][CH:6]=1
Reactant: N
Reactant: O=Cc1ccc(Oc2ccc(F)cc2F)o1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Oc2ccc(F)cc2F)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
To a solution of 5-(2,4-difluoro-phenoxy)-furan-2-carbaldehyde (2060 mg, 9.19 mmol) in 7N ammonia/methanol solution (100 mL) was added Raney nickel (5.9 g), and the mixture was stirred for 24 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite pad, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (1814 mg, 88.06 mmol, 87.7%) was obtained as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([C:25]2[N:24]=[CH:23][C:22]([O:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:13][CH:12]=3)[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:27][CH:26]=2)=[CH:33][CH:32]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(C)(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CCC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-benzoylamino)-propionic acid methyl ester (isomer 1, 80 mg, 0.15 mmol) is dissolved in the tetrahydrofuran (1 mL) and sodium hydroxide solution (5 M, 1.0 mL, 5 mmol) is added. The reaction is monitored by HPLC, and upon complete conversion, the reaction is neutralized with 5N HCl, diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated. The title compound is used without further purification. MS (ES): 515.2 [M−H]−, the structure was also confirmed by proton NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:41])[CH2:39][CH3:40])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using propanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:29])([CH3:28])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[S:17]([NH:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[CH3:27])(=[O:19])=[O:18].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:6][Si:7]([CH3:28])([CH3:29])[CH2:8][CH2:9][O:10][CH2:11][C:12]1([CH:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]([S:17]([NH:20][C:21]2[O:25][N:24]=[C:23]([CH3:26])[C:22]=2[CH3:27])(=[O:18])=[O:19])[CH:15]=[CH:14][S:13]1
Reactant: O=Cc1ccccc1
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)C2C=CSC2(COCC[Si](C)(C)C)C(O)c2ccccc2)c1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
n-BuLi (2.39 M, 177 μl) was slowly added to a solution of (2-trimethylsilylethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (156 mg, 0.38 mmol) in THF at −78° C. under nitrogen. The reaction was stirred at −78° C. for 45 min., then benzaldehyde (45 μl, 0.42 mmol) was added in one lot at −78° C. and the solution was allowed to come to room temperature. Stirring was continued for 1 hr. Purification was achieved by column chromatography using 10% ethyl acetate/hexanes to give 179 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide as a yellow viscous oil (90% yield).