Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:16]#[C:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:21][CH2:20]2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].CO>C(OCC)(=O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]\[CH2:18][N:19]2[CH2:20][CH2:21][C:22]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:23][CH2:24]2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cc(C#CCN2CCC3(CCCCC3)CC2)ccc1C1CCCCC1
Agent: [Pd]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1cc(/C=C\CN2CCC3(CCCCC3)CC2)ccc1C1CCCCC1

Procedure:
3 g of the hydrochloride of the acetylenic compound obtained in Example 1 above are liberated by aqueous 10% sodium hydroxide solution. The oil obtained after extraction with diethyl ether is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under vacuum. The residue thus obtained is taken up in 100 ml of ethyl acetate, 5 ml of methanol are added, followed by 0.2 g of Pd/BaSO4 and the reaction mixture is hydrogenated at room temperature and at atmospheric pressure. The catalyst is separated out by filtration through silica, the filtrate is concentrated under vacuum and the residual oil is then chromatographed on a column of silica gel, eluent: 98/2 (v/v) dichloromethane/methanol. Concentration of the pure fractions gives the hydrochloride, which is recrystallized from ethyl acetate; Y=44%; m.p.=238° C.
Reaction SMILES: C(N(C(C)[C:25]([O:27][CH2:28][CH3:29])=[O:26])CCOC1C=CC(I)=CC=1)CCCCCCCCCCC.FC(F)(F)C(O)C=C.[CH2:39]([N:51]([CH2:69][CH2:70]CC(OCC)=O)[CH2:52][CH2:53][O:54][C:55]1[CH:60]=[CH:59][C:58](/[CH:61]=[CH:62]/[CH:63]([OH:68])[C:64]([F:67])([F:66])[F:65])=[CH:57][CH:56]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>>[CH2:39]([N:51]([CH2:69][CH2:70][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:52][CH2:53][O:54][C:55]1[CH:60]=[CH:59][C:58](/[CH:61]=[CH:62]/[CH:63]([OH:68])[C:64]([F:66])([F:67])[F:65])=[CH:57][CH:56]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCN(CCOc1ccc(I)cc1)C(C)C(=O)OCC
Agent: C=CC(O)C(F)(F)F
Product: CCCCCCCCCCCCN(CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1)CCC(=O)OCC
Yield: 76 %

Procedure:
[N-Dodecyl-N-[2-[4-iodophenoxy]ethyl]amino]propanoic acid, ethyl ester (0.95 g, 1.79 mmol) and 4,4,4-trifluorobut-1-en-3-ol (complex with 0.7 THF, 0.95 g, 5.4 mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48) and afforded the title compound (0.633 g, 76%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][C:22]2=[O:31])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:25][C:24]3([CH2:26][CH2:27][N:28]([C:2]4[N:3]=[N:4][C:5]([C:8]5[O:12][N:11]=[C:10]([CH3:13])[N:9]=5)=[CH:6][CH:7]=4)[CH2:29][CH2:30]3)[O:23][C:22]2=[O:31])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1OC2(CCNCC2)CN1c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)CN(c3cccc(F)c3)C(=O)O4)nn2)n1

Procedure:
The object product (82 mg, 57%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (70 mg) obtained in Example 43(2), 3-(3-fluorophenyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (80 mg) obtained in Example 29(3) and potassium carbonate (50 mg).
Reaction SMILES: O1CCOCC1.[ClH:7].[Br:8][C:9]1[S:13][C:12]([CH2:14][NH:15]C(OC(C)(C)C)=O)=[N:11][CH:10]=1>C(O)C>[ClH:7].[NH2:15][CH2:14][C:12]1[S:13][C:9]([Br:8])=[CH:10][N:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ncc(Br)s1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: NCc1ncc(Br)s1

Procedure:
4 N hydrochloric acid dioxane solution (2.3 L) was added dropwise to a solution (1.6 L) of 542 g of 5-bromo-2-t-butoxycarbonylaminomethylthiazole in ethanol at an internal temperature of 40° C. over a period of 1.1 hr. The mixture was stirred until the internal temperature reached 23° C. The precipitated crystal was collected by filtration, was washed twice with ethanol, and was then dried under the reduced pressure to give 394 g of 2-aminomethyl-5-bromothiazole hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: OCCCc1cccc2nc(Cc3ccccc3Cl)oc12
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc2nc(Cc3ccccc3Cl)oc12
Reaction time: 1 h

Procedure:
A solution of 2-(2-chlorobenzyl)-7-(3-hydroxy-1-propyl)benzoxazole (10 g, 0.033 mole) in ether (50 ml) was treated with methanesulfonyl chloride (4.4 g, 0.037 mol) and triethylamine 3.7 g, 0.037 mol). After stirring for 1 hour, the triethylamine hydrochloride was filtered and the ether was evaporated to give the title compound which was pure by TLC.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([NH2:17])=[C:6]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([NH2:9])=[NH:8].[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)#N.C(O)C>C(N(CC)CC)C>[CH3:16][O:15][C:11]1[CH:10]=[C:6]2[C:5](=[C:4]([O:3][CH3:2])[C:12]=1[O:13][CH3:14])[N:17]=[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[N:8]=[C:7]2[NH2:9]
Reactant: CCOC(=O)N1CCN(C#N)CC1
Reactant: COc1cc(C(=N)N)c(N)c(OC)c1OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)c(OC)c3n2)CC1

Procedure:
A solution containing 2.62 g. (0.01 mole) of 3,4,5-trimethoxy-2-aminobenzamidine hydrochloride and 1.83 g. (0.01 mole) of 1-cyano-4-ethoxycarbonylpiperazine in 50 ml. of anhydrous ethanol is stirred at ambient temperature overnight. A 5-ml. aliquot of triethylamine is then added and the reaction mixture is heated under reflux for 12 hours. It is then worked up as described in Example XI, giving 6,7,8-trimethoxy-4-amino-2-[4-ethoxycarbonylpiperazin-1-yl]quinazoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:47].O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:47])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Reactant: [F-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC(Cc1ccc(CCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[3-(tosyloxy)propyl]benzyl}-L-glutamate (see Example 10) (100 mg, 0.15 mmol) was dissolved in 1 ml acetonitrile, and tetra-n-butylammonium tetra-(tert-butyl alcohol)-coordinated fluoride (Angew. Chem. 2008, 120, 8532-8534) (169 mg, 0.30 mmol) were added. The mixture was stirred at 70° C. for 2 h. Another 169 mg of the fluoride source was added and the reaction stirred for further 1.5 h at 70° C. After cooling to room temperature, the mixture was poured into water (10 ml) and extracted with tert-butyl methyl ether (3×10 ml). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a reversed phase (RP-18) column with an acetonitrile/water gradient. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([C:14]1([OH:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1>>[C:1]([CH2:2][CH2:3][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)([OH:24])[C:15]1=[O:23])#[N:4]
Reactant: C=CC#N
Reactant: COc1cccc(CC2(O)C(=O)Nc3ccccc32)c1
Product: COc1cccc(CC2(O)C(=O)N(CCC#N)c3ccccc32)c1

Procedure:
Reaction of acrylonitrile with -3-(m-anisyl)-3-hydroxyindolin-2-one by a process analogous to that of Example 1 gives 1-(2-cyanoethyl)-3-(m-anisyl)-3-hydroxy-indolin- 2-one. Hydrogenation of the 1-(2-cyanoethyl)- 3-(m-anisyl) 3-hydroxy-indolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)- 3-(m-anisyl)-3-hydroxy-indolin-2-one. Cyclodehydration of the 1-(3-aminopropyl)-3-(m-anisyl)-3-hydroxy-indolin- 2-one by a procedure analogous to that of Example 3 gives 10-(m-anisyl)-2,3,4,10-tetrahydro-pyrimido[1,2-a] indol 10-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>ClCCl>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:18](=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of 2-amino-4-nitrophenol (10 g, 64.9 mmol) in dichloromethane (250 mL) under nitrogen at 0° C. was added pyridine (10.5 mL, 129.9 mmol) followed by butyryl chloride (7.05 mL, 68.2 mmol) over a period of 5 min. After 30 min at 0° C., the solution was left warming up to room temperature for 2 days. The organic layer was washed with aqueous copper sulfate solution and brine. Insoluble material from the aqueous layer was filtered off and washed with water to afford 4.95 g (34%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>O.CO.O1CCCC1>[NH2:8][C:5]1[N:4]=[CH:3][C:2]([B:24]([OH:29])[OH:25])=[CH:7][N:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Nc1ncc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(B(O)O)cn1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
By the alternative synthetic route in Scheme 8, to a 3-L flask under nitrogen was charged tetrahydrofuran (1055 mL), followed by 5-bromopyrimidine-2-amine 9 (70.0 g, 0.40 mol). The mixture was cooled to a temperature between −60° C. and −70° C. and lithium bis(trimethylsilyl)amide (LiHMDS) (1M in tetrahydrofuran, 483 mL, 0.483 mol) was charged over 30 min while maintaining the temperature between −60° C. and −70° C. The mixture was stirred at −60° C. to −70° C. for 1 h. n-Butyllithium (2.5 M in hexanes, 515 mL, 1.29 mol) was charged over 1 h while maintaining the temperature between −60° C. and −70° C., and the reaction mixture was then aged for 2 h. Additional n-butyllithium (2.5 M in hexanes, 48 mL, 0.12 mol) was charged over 15 min while maintaining the temperature between −60° C. and −70° C., and the reaction mixture was stirred for 1 h. To the mixture was added triisopropyl borate (91.0 g, 0.48 mol) over 1 h while maintaining the temperature between −60° C. and −70° C., and the reaction mixture was stirred for 1 h. The mixture was then allowed to warm to 0-5° C. and water (700 mL) was added over 1 h. After being aged at 0-5° C. for 30 min, the resulting layers were separated. To the aqueous layer was added water (420 mL) over 30 min, followed by addition of tert-butyl methyl ether (822 mL). The mixture was allowed to warm to 20-25° C. and was stirred for 30 min. The layers were separated and the aqueous layer was washed with tert-butyl methyl ether (5×700 mL). The aqueous layer was cooled to 0-5° C., and 35% aqueous hydrochloric acid solution (137 mL) was added over 1 h while maintaining the temperature between 0-5° C. The mixture was stirred at 0-5° C. for 1.5 h, filtered, washed with water (14 mL) and the cake was dried under vacuum at 45-50° C. to afford the crude product (26.7 g). The crude product was charged to a 5-L flask, followed by addition of methanol (908 mL), and the mixture was stirred at room temperature (rt) for 20 min. The mixture was warmed to 65° C. and stirred for 1.5 h. To the mixture was added water (2136 mL) over 2 h and the suspension was stirred for 1.5 h. The mixture was cooled to 20° C. and stirred for 14 h. The solid was collected by filtration and the filter cake was washed with water (13 mL), dried under vacuum at 45-50° C. for 12 h to afford 2-aminopyrimidin-5-ylboronic acid III (23.6 g, 42% yield)
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:16]=2[CH:15]=[CH:14]1.[CH3:23][O:24][C:25](C#N)=[O:26]>C1COCC1.O.CN(P(N(C)C)(N(C)C)=O)C>[O:22]=[C:21]1[C:16]2[CH:15]=[CH:14][S:13][C:17]=2[CH2:18][CH2:19][CH:20]1[C:25]([O:24][CH3:23])=[O:26]
Reactant: O=C1CCCc2sccc21
Reactant: COC(=O)C#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1CCc2sccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
n-Butyl lithium (2.5 M, 15.8 mL) is added dropwise via syringe to a solution of diisopropyl amine (55 mL) in anhydrous THF (20 mL) at −10° C. under an atmosphere of nitrogen. After stirring for 30 min at this temperature, the solution is cooled to −78° C. and a solution of containing 6,7-dihydro-1-benzthiophen-4(5H)one (BI.1, 5.00 g) in anhydrous THF (20 mL) is added dropwise over 15 minutes. The solution is warmed to 0° C. and stirred for one hour at that temperature. After re-cooling to −78° C., HMPA (5.7 mL) and methyl-cyanoformate (3.1 mL) are sequentially added. The solution is stirred for 10 minutes at −78° C. The reaction mixture is quickly poured into cold water (100 mL) and extracted with ether (250 mL). The organic phase is washed with brine, dried over Na2SO4, filtered, and concentrated to give a red oil. This oil is chromatographed on a Biotage column eluting with 0-30% ethyl acetate in heptane (500 mL each 10%) to give 3.87 g (56%) of the title compound as a white solid. Physical characteristics. Mp. 85-86° C.; MS (ESI+) m/z 211.0 (M+H)+; HRMS (FAB) m/z 211.0425 (C10H10O3S+H). Anal. Found: C, 57.15; H, 4.84.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C@H:11]([OH:14])[CH2:12][OH:13].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:13][CH2:12][C@@H:11]([OH:14])[CH2:10][C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: OC[C@@H](O)Cc1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)Cc2cc3ccccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a solution of (S)-3-indol-2-yl-propane-1,2-diol (S)-1 (15 g, 78.5 mmol) in dry pyridine (120 mL) was added p-toluenesulfonyl chloride (15.5 g, 81.3 mmol) at 0° C. After stirring for 5 hours at 0° C., the solution was poured into cold hydrochloric acid (100 mL, 6N) and extracted with ether (3×60 mL). The combined extracts were washed with hydrochloric acid (6N, 2×30 mL) followed by brine (2×80 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography to give 24.5 g (90.4%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:28]1[CH2:29][CH2:30][N:25]([C:23]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)=[O:24])[CH2:26][CH2:27]1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: O=C(C1CCCCO1)N1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(=CN1CCN(C(=O)C3CCCCO3)CC1)C(=O)N2

Procedure:
5.00 g. of 5,6-dimethoxy-3-hydroxymethylene oxindole, 5,6 g. 1-(tetrahydropyran-2-carbonyl)piperazine and 2.1 g. acetic acid in 60 ml. benzene was reacted as described in Example 5 to give 6.18 g. of product, m.p. 208°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])=[CH:5][CH:4]=1.COC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)=CC=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 56 h
Yield: 95 %

Procedure:
Ethyl (1RS,2RS,3SR)-1-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (0.72 g, 1.7 mmol) in EtOH (30 ml) was added 10% palladium on activated carbon (1 g). The resulting suspension was stirred under an atmosphere of H2 for 56 h and filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (0.70 g, 95%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.[NH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][NH:16][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15]
Reactant: NCCO
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Product: O=C(NCCO)c1nc(Cl)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid from example A-1 d) and 2-amino-ethanol in analogy to example 2; MS-(−)-ion: M−1=265.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([NH2:31])=[CH:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:12]=2[CH:30]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([NH:31][S:40]([C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)(=[O:42])=[O:41])=[CH:10][C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:12]=2[CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
4-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]butanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:38]2=[CH:39][N:40]=[N:41][C:42](=[O:43])[C:37]2=[N:36][CH2:35]1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[C@@H:11]1([N:34]2[C:38]3=[CH:39][N:40]=[N:41][C:42](=[O:43])[C:37]3=[N:36][CH2:35]2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C1N=NC=C2C1=NCN2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1N=NC=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
1-(2,3,5-tri-O-Benzoyl-β-D-ribofuranosyl)imidazo[4,5-d]pyridazin-4-one (555 mg, 0.9 mmol) was added to a solution of sodium methylate (205 mg) in methanol (25 mL) and stirred at 20° C. for 2 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was concentrated under pressure. The crude product was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (220 mg) as a white powder.
Reaction SMILES: [OH2:1].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([CH2:27][CH2:28][CH:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32])(C(C)(C)C)(C)C>O1CCCC1>[OH:1][CH2:27][CH2:28][CH:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32]
Reactant: CC(C)(C#N)C(O)CC[Si](C)(C)C(C)(C)C
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C#N)C(O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate is added to a solution that consists of 3 g (11.65 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitrile of the title compound of Example 6a, dissolved in 40 ml of tetrahydrofuran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum. The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:28][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1
Reactant: Cc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 39.8 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.39 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (110 mg, 0.59 mmol), 4-dimethylaminopyridine (72 mg, 0.59 mmol), methane sulfonamide (110 mg, 1.17 mmol) in dichloromethane (5 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (71 mg, 40%) as a light yellow solid: LC/MS m/e calcd for C24H31N3O4S (M+H)+: 458.6, observed: 458.2.