Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][CH2:21]1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])=[O:6].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41]1>C(Cl)Cl>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)=[C:2]([NH:1][C:45]([C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)=[O:46])[CH:3]=1)=[O:6]
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1ccsc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccsc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 272.1 %

Procedure:
To a suspension of 3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.1 g, 0.229 mmol) in methylene dichloride (5 ml), triethylamine (0.069 g, 0.489 mmol), thiophene-3-carboxylic acid (0.044 g, 0.344 mmol) and 1-propane phosphonic cyclic anhydride (0.21 g, 0.489 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulphate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.34 g, 34%) of the titled compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:20]2=[CH:21][CH:22]=[N:23][CH:24]=[C:19]2[C:5]2[C:6]([OH:18])=[CH:7][C:8]([CH:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:26].[N:27]1([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:26].[CH3:25][C:2]1([CH3:1])[C:20]2=[CH:21][CH:22]=[N:23][CH:24]=[C:19]2[C:5]2[C:6]([O:18][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:7][C:8]([CH:10]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CC(c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2)C1CCCCC1

Procedure:
5,5-Dimethyl-8-(1-cyclohexylethyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(1-cyclohexylethyl)-5H[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5](=[O:22])[CH2:6][C:7]1[N:8]([CH3:21])[C:9](=[O:20])[C:10]([F:19])=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:12]=1>C1COCC1>[F:19][C:10]1[C:9](=[O:20])[N:8]([CH3:21])[C:7]([CH2:6][C:5]([O-:22])=[O:4])=[N:12][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+:2]
Reactant: COC(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 ml of 2N sodium hydroxide are added to a solution of 759 mg of (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid methyl ester in 8 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 695 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate in the form of a white solid which is used as it is in the next step.
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2].[H][H]>Cl.CCO.[Pd]>[CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:24])[CH3:25])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Yield: 37 %

Procedure:
To a suspension of (E)-ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)acrylate (0.8 g, 2.3 mmol) in 2% HCl in EtOH (80 ml) was added palladium on carbon (10%, 0.5 g). The mixture was stirred under an atmoshphere of hydrogen (1 am) at room temperature for 24 hr. The catalyst filtered through celite. The filtrate was evaporated at reduced pressure. The residue was neutralized with sat. NaHCO3, extracted with EtOAc, and dried over MgSO4. The solvent was concentrated under reduced pressure and purified by silica gel flash column chromatography hexane/EtOAc (6:4) to give the product (0.33 g, 38%). 1H NMR (300 MHz, CDCl3) δ 7.72 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.15 (qrt, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 3.17 (m, 1H), 3.04 (t, 2H), 2.83 (m, 1H), 2.68 (m, 3H), 2.18 (m, 1H), 2.05 (m, 1H), 1.96 (m, 2H), 1.36 (d, 6H), 1.26 (t, 3H), 0.94 (t, 3H); ESI (+) MS m/e=388 (MH+), ESI (−) MS m/e=386 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:53]6[CH2:54][CH2:55][N:50]([CH2:56][CH2:57][OH:58])[CH2:51][CH2:52]6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: OCCN1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)cc3)cn2)cc1
Yield: 83.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (70.0 mg, 0.106 mmol) obtained in Step A in Example 1-D-19 and 1-piperazineethanol (26.0 μl, 0.212 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a yellow solid (68.1 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-111) as a yellow powder (24.7 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH3:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(Br)c1OC
Reactant: NC(=O)c1ccccc1
Product: COc1cc(C(C)=O)cc(Br)c1OC

Procedure:
3-Bromo-4,5-dimethoxybenzoic acid (2.0 g) was converted to the benzamide derivative analogously to O3.043, and the latter was converted to the title compound analogously to O2.059. 1.22 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][NH:40][CH3:41].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][N:40]([CH3:41])[C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N(C)CCN(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (8.84 g) obtained in Reference Example 1(2) is dissolved in chloroform (100 ml), and thereto are added 1-hydroxybenzotriazole (7.14 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.00 g) and N,N,N′-trimethylethylenediamine (5.33 g) under ice-cooling. The mixture is then stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol/28% ammonia water=200/10/1) to give methyl trans-4-{[[2-(dimethylamino) ethyl](methyl)amino]carbonyl}-cyclohexanecarboxylate (11.98 g).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.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>[CH:2]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:1][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: C1=CCCC=C1
Reactant: Nc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C1=CC(Nc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
Hydroamination of 1,3-Dienes with Arylamines: Sixteen examples of hydroamination of 1,3-dienes with arylamines are shown in Table 3 below (Entries 1-16). Typical reaction conditions are 0.5 mmol amine, 2 mmol cyclohexadiene, 2 mol % Pd(PPh3)4, 10 mol % TFA, toluene, 25° C., mixed for 24 hours. A typical procedure is given for Entry 1, Table 1: Pd(PPh3)4 (5.8 mg, 0.0050 mmol) was suspended in 0.1 mL of toluene in a screw-capped vial. 1,3-Cyclohexadiene (160 mg, 190 μL, 2.00 mmol) and aniline (46.6 mg, 45.6 μL, 0.500 mmol) were added to the reaction mixture. The vial was sealed with a cap containing a PTFE septum and removed from the drybox. Trifluoroacetic acid (5.7 mg, 3.9 μL, 0.050 mmol) was added to the reaction mixture by syringe. The reaction mixture was then stirred at room temperature for 24 h. All volatile compounds were evaporated under reduced pressure, and the residue was adsorbed onto silica gel. The product was eluted using 0.5% ethyl acetate/hexanes to give 85.5 mg (99%) of N-cyclohex-2-en-1-ylaniline as a colorless oil. Additional compounds were made in a similar fashion and analyzed as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13](O)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]1=[O:22].[CH3:23][C:24]1[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:26][C:27]([CH3:30])=[CH:28][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[C:24]([CH3:23])=[N:29][CH:28]=[C:27]([CH3:30])[N:26]=3)[CH2:32][CH2:33]2)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])[C:9]1=[O:22]
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccccc3Cl)CC2)n1

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 85, step 2) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl to give the title compound as a colorless solid. MS: 521.3 ([M+H]+)
Reaction SMILES: [O-]CC.[Na+].Cl.[CH:6]([NH2:8])=[NH:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](=O)[C:23]([F:26])([F:25])[F:24])[C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[C:22]([C:23]([F:26])([F:24])[F:25])=[N:8][CH:6]=[N:7][C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: N=CN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
0.52 mL of sodium ethoxide (21% wt. ethanol solution) was added at room temperature to a solution in which 95 mg (1.18 mmol) of formamidine hydrochloric acid salt was dissolved in 2 mL of anhydrous ethanol at room temperature. After stirring at room temperature for 10 minutes, to the resulting solution, was added a solution in which 232 mg (0.786 mmol) of tert-butyl-3-oxo-4-(trifluoroacetyl)-piperidine-1-carboxylate (product of PREPARATION 47) was diluted with 2 mL of anhydrous ethanol. Thereafter, the temperature of the solution was raised to 80° C., followed by stirring for about 18 hours. After cooling to room temperature, ethanol was removed under reduced pressure, and the reaction solution was diluted with ethylacetate, then washed in sequence aqueous NaCl. An organic layer was dried over anhydrous magnesium sulfate and filtered off. The filtrated solution was distilled off under reduced pressure and then, the residue was isolated and purified by prep-TLC (ethylacetate 20% normal hexane in solvent) to give 30 mg of the title compound in a yield of 13%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2O.S(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl

Procedure:
A mixture of 45.2 g. of 6-chloro-4-hydroxyquinoline-3-carboxylic acid, ethyl ester (0.18 mol.) and 250 ml. of thionyl chloride is refluxed for 20 hours. The excess thionyl chloride is then removed in vacuo, the residue treated with 200 ml. of water and the ester is extracted with ether. After washing the ethereal extract twice with water, it is dried with Na2SO4 and the solvent distilled off. The residual 4,6-dichloroquinoline-3-carboxylic acid, ethyl ester is triturated with petroleum ether (40°-60°), filtered and dried. Yield: 45.3 g. (93%); m.p. 87°-88°.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[OH:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:41]2[CH:42]=[C:37]([OH:36])[CH:38]=[CH:39][CH:40]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(O)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (6.8 mg, yield 15%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:37][CH2:36][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[C:23]5[C:28]=4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO>[N:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:37][CH2:36][C:11]3([CH2:12][CH2:13][N:14]([C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[C:23]5[C:28]=4[CH2:27][NH:26][CH2:25][CH2:24]5)=[O:18])[CH2:15][CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c2C1
Agent: Cl
Solvent: CO
Product: O=C(c1cccc2c1CNCC2)N1CCC2(CC1)CCN(c1ccncc1)CC2

Procedure:
1.25 M hydrogen chloride in methanol (9.4 ml, 11.7 mmol) was added at RT to a solution of tert-butyl 8-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.77 g, 1.57 mmol) in methanol (2 ml), and the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo, the residue was taken up in a small amount of ethanol (2 ml), and diethyl ether (50 ml) was added. The mixture was then cooled for 30 min in an ice bath, and the resulting solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 0.56 g (83%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Cl>C1COCC1>[I:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=2)=[CH:14][CH:13]=1
Reactant: COc1cccc(CCl)c1
Reactant: COc1ccc(CC(=O)c2ccc(I)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2cccc(OC)c2)C(=O)c2ccc(I)cc2)cc1
Reaction time: 3.5 h
Yield: 82.9 %

Procedure:
Potassium bis(trimethylsilyl)amide (2.5 g, 12.5 mmol) was added to a solution of 1-(4-iodophenyl)-2-(4-methoxyphenyl)ethanone (4.225 g, 12.00 mmol) and THF (60 mL) at rt under N2. After 3.5 h, 3-methoxybenzyl chloride (2.2 mL, 15 mmol) was added. After 2.5 days, the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (150 mL). The ethyl acetate extract was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (99:1→4:1; hexanes:ethyl acetate) to give 4.7 g of 1-(4-iodophenyl)-3-(3-methoxyphenyl)-2-(4-methoxyphenyl)propan-1-one as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.76 (d, 2H), 7.20 (d, 2H), 7.09 (t, 1H), 6.81 (d, 2H), 6.76-6.65 (m, 3H), 5.13 (t, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.35 (dd, 1H), 2.93 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][OH:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CO)cc1
Product: O=S(=O)(c1ccc(CO)cc1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 107° C., and MS: m/e=336.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-hydroxymethyl-benzenesulfonyl chloride.
Reaction SMILES: [Mg].[CH3:2][CH:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:5](=[O:6])[CH2:4]1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].II.Cl>CCOCC.C1C=CC=CC=1>[OH:6][C:5]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH:3]([CH3:2])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7]1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CC(C)CC(C)(C)C1
Temperature: 0 °C

Procedure:
300 ml of absolute ether, 150 ml of dry benzene and 170 g of magnesium shavings are added to a 6 liter flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Now, there is introduced dropwise a mixture of 1.100 kg of dihydroisophorone and 960 g of ethyl chloroacetate dissolved in 1.200 l of ether and 600 ml of benzene. (If the reaction does not begin during the addition of the first 200 ml and warming at slight reflux does not begin spontaneously, then a few small crystals of iodine are added). The beginning of the reaction is recognizable by turbidity and heat-evolution. The addition of the reagents is continued in such a manner that the mixture boils only moderately, the addition being completed within 11/4 hours. Thereafter, the mixture is held at reflux temperature for a further 31/2 hours and, after cooling, added to 2.5 kg of ice and 1.2 l of concentrated hydrochloric acid. The organic phase is separated and washed with water (containing 1% concentrated hydrochloric acid), with water and several times more with 10% sodium carbonate solution. After evaporating the solvent in vacuo, there remain behind 1.69 kg of crude product which are distilled. The main fraction (1.250 kg) is washed with 10% sodium carbonate solution and again distilled (100° C./3 mm Hg). There are thus obtained 1.046 kg of ethyl 1-hydroxy-3,3,5-trimethyl-cyclohexylacetate.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH2:13][NH2:14]>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([NH:13][NH2:14])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: NN
Solvent: CO
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 55 °C
Yield: 86 %

Procedure:
To a solution of (4-Hydroxy-phenyl)-acetic acid methyl ester (5 g, 30.08 mmol) in MeOH (20 mL, anhydrous) was added hydrazine (3.77 mL, 120.35 mmol) and then heated to 55° C. for 1 hour. A white precipitate formed during heating. The reaction was then cooled to rt and stirred for an additional hour to facilitate precipitation of solid. The reaction was filtered and the solid was washed with MeOH and dried resulting in the desired product (4.3 g, 86%) as a white solid. 1H-NMR (DMSO): δ 9.20 (1H, s), 9.10 (1H, s), 7.04-7.02 (2H, d, J=8.6 Hz), 6.67-6.65 (2H, d, J=8.6 Hz), 4.17-4.16 (2H, s), 4.11-4.09 (1H, q, J=5.0, 5.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[CH3:30])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1ccc(N)c(C)c1
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c(C)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-methoxy-2-methylaniline (53 mg, 0.39 mmol). The title compound was obtained as a solid (75 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.12(1H, s), 9.00 (2H, s), 8.63 (1H, m), 7.12 (1H, dd), 6.83 (1H, m), 6.76 (1H, m), 3.73 (3H, s), 2.14 (3H, s). MS m/z: 468.15, 470.12 [M+H]+.