Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[NH:7][C:6]1([CH3:14])[CH3:13].[Cl:15]OC(C)(C)C>CO>[Cl:15][N:7]1[C:8]([CH3:12])([CH3:11])[C:9](=[O:10])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]1([CH3:14])[CH3:13]
Reactant: CC(C)(C)OCl
Reactant: COCCN1C(=O)C(C)(C)NC1(C)C
Solvent: CO
Product: COCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
A solution of 3-(2-methoxyethyl)-2,2,5,5-tetramethylimidazolidin-4-one (0.70 g, 3.5 mmol) in methanol (10 mL) was cooled in ice water for 10 minutes, before neat tert-butyl hypochlorite (0.59 mL, 5.25 mmol, 1.5 equiv.) was added in one portion. High pressure liquid chromatography-mass spectroscopy analysis after 5 minutes showed all starting amine had been consumed. After 20 minutes, the mixture was concentrated in vacuo to an oil. The oil absorbed was on silica (2.5 g) and was purified by silica gel flash chromatography (0-4% methanol in dichloromethane) afforded the N-chloro-imidazolidin-4-one as a colorless oil (0.78 g, 95%). 1H NMR (400 MHz, CDCl3) δ 3.55 (t, J=5.8 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 3.36 (s, 3H), 1.46 (s, 6H), 1.36 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.8, 82.0, 70.1, 65.3, 58.8, 40.5, 25.1, 23.5; LRMS (ESI/APCI) m/z 235 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].O1[CH2:15][CH2:14]OCC1>>[C:2]1([C:2]2[CH:7]=[CH:6][C:14]([CH3:15])=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Clc1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 102 mg (0.15 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 7), 1.13 g (10.0 mmol) of chlorobenzene, 2.04 g (15.0 mmol) of MeC6H4B(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 15 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of hexane. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the hexane and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.58 g (94% yield) of 4-phenyltoluene.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([OH:16])[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]=1[OH:17])C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1(=O)CCCC1.[I-].[K+]>[CH2:26]([O:16][C:14]1[CH:15]=[C:5]([C:4]([OH:3])=[O:18])[C:6]([O:17][CH2:7][CH2:6][CH2:5][CH2:15][CH3:14])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C1CCCC1
Product: CCCCCOc1cc(C(=O)O)c(OCCCCC)cc1C(=O)O
Temperature: 25 °C
Yield: 140.2 %

Procedure:
A mixture of 25.4 g of 2,5-dihydroxy terephthalic acid diethyl ester, 30.0 g potassium carbonate, 1 g potassium iodide and 31.5 g 1-bromopentane was heated to boiling-point in cyclopentanone for at least 24 hours. The solvent was withdrawn and 250 ml of 5 wt % caustic potash and 20 ml ethanol was added to the residue, which was then heated to boiling-point for at least 24 hours. After cooling to room temperature the product was precipitated by acidifying with hydrochloric acid and was recrystallized from methylene chloride. 23.7 g of 2,5-bis(pentyloxy) terephthalic acid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH2:18])[CH:5]=[CH:6][C:7]=1[F:8].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.CC(O)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:18][C:10]1[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Nc1nc2ccccc2n1-c1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1ccc(CNc2nc3ccccc3n2-c2ccc(F)c(F)c2)cc1F

Procedure:
1-(3,4-Difluorophenyl)-1H-benzoimidazol-2-ylamine, prepared as described in Procedure E (Scheme 5, Steps A-C), was dissolved in acetonitrile, added 3,4-difluorobenzaldehyde (1 eq), sodium triacetoxyborohydride (2 eq) and a catalytic amount of AcOH. The reaction mixture was heated in a sealed vial by means of MW irradiation at 100° C. for 25 min. Saturated aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative LCMS to give the title compound as the free base (solid, mp 158.5-159.5° C.). MS(ES+) m/z 372 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.50 (d, 2H), 6.85-6.92 (m, 2H), 6.99-7.15 (m, 2H), 7.20-7.46 (m, 5H), 7.68-7.74 (m, 1H), 7.78-7.83 (m, 1H).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH2:24][OH:25])[CH2:4][CH3:5])[CH3:2].C=O.[CH3:28]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([N:6]1[C:7]2[C:8](=[C:9]([NH:14][C:15]3[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])[N:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:24][O:25][CH2:28]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Agent: C=O
Solvent: Cc1ccccc1
Product: CCC(CC)N1COCc2c1cc(C)nc2Nc1c(C)cc(C)cc1C
Yield: 193.2 %

Procedure:
A mixture of [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol(280 mg, 0.82 mmol), 37% aqueous formaldehyde(0.35 ml) and p-TsOH (78 mg, 0.41 mmol) in 10 ml of toluene was heated at reflux using a Dean-Stark apparatus for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 280 mg of a green oil. The oil was purified through silica gel column chromatography using EtOAc as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 6.89 (s,2H), 6.09(s,IH), 4.51(s,2H), 4.19(s,2H), 3.53(m,1H), 2.25(s,6H), 2.15(s,6H), 1.55(m,4H), 0.90(t,6H)ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16](NN)[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]([NH2:28])=[O:27].O.Cl>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:25]=[C:26]([OH:27])[N:28]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(O)nc12
Temperature: 160 °C
Reaction time: 6 h

Procedure:
To the solution of 131 (3.27, 10 mmol) in anhydrous NMP (3.6 mL) under nitrogen is added urea (1.60 g, 26 mmol). The resulting mixture is heated to 160° C. and stirred for 6 hours. On cooling, the reaction mixture is poured into water (80 mL), pH is adjusted to 7 with hydrochloric acid, and the solution is extracted with dichloromethane (50 ml×4). The organic solution is dried with anhydrous sodium sulfate and concentrated to give the crude product 177 as an oil which is used directly in the next step reaction.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[Cl:6][C:7]1[CH:8]=[C:9]([C:16]([CH3:24])([CH3:23])[CH2:17][C:18](=[O:22])[CH:19]([F:21])[F:20])[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([CH:19]([F:20])[F:21])([OH:22])[CH2:4][C:3]#[CH:2])[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1
Reactant: CC(C)(CC(=O)C(F)F)c1cc(Cl)cc2c1OCC2
Reactant: C#CCBr
Agent: [Al]
Solvent: C1CCOC1
Product: C#CCC(O)(CC(C)(C)c1cc(Cl)cc2c1OCC2)C(F)F
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Aluminum foil (108 mg, 4.00 mmol) and mercuric chloride (ca. 1 mg, 0.01 mmol) in 3.5 mL of anhydrous THF were vigorously stirred for 20 minutes. Propargyl bromide (80% in toluene, 0.45 mL, 4.00 mmol) was added slowly (the reaction mixture became warm) and the resulting mixture was stirred at 40° C. for 1 hour. The dark gray propargyl aluminum sesquibromide solution was added to a solution of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1-difluoro-4-methylpentan-2-one (380 mg, 1.32 mmol) in 10 mL of anhydrous THF at 0° C. and the reaction was allowed to slowly warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo, quenched with ice and water, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 420 mg of the title product as an oil (97% yield), which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[CH3:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)[CH2:12][CH2:11]1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(CC(C)C)=O>[CH3:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([O:27][CH3:28])[CH:21]=2)[CH2:14][CH2:15]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20.7 g of potassium carbonate and 5 ml of methanol were added to a solution of 28.9 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131) in 600 ml of methylisobutylketone. The solution was reacted for 30 minutes, while it was refluxed. Next, 27.7 ml of ethyl bromoacetate was added dropwise into the solution over about 20 minutes by means of a dropping funnel. Thereafter, the solution was stirred for 4 hours. After reaction, the solution was allowed to cool to room temperature. After the potassium carbonate has been filtered out from the filtrate, the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 35.2 g of N-(trans-4-methylcyclohexyl)-4-(ethoxycarbonylmethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [O:1]=[C:2]1[N:13]2[CH2:14][CH2:15][N:4]([CH2:5][CH2:6][NH:7][CH2:8][CH2:9][N:10]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12]2)[CH2:3]1.Cl.[OH-:21].[Na+]>>[N:10]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:4]([CH2:3][C:2]([OH:21])=[O:1])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: [OH-]
Reactant: O=C(O)CN1CCNCCN2CCN(CC1)C(=O)C2
Agent: Cl
Agent: [Na+]
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCNCC1
Yield: 86.5 %

Procedure:
20 g (0.074 mol) of 12-oxo-1,4,7,10-tetraazabicyclo[8.2.2]tetradecane-4-acetic acid, prepared as described in example 5, are dissolved in 88.8 g of 10% NaOH. The solution is refluxed overnight, then cooled and acidified to pH 12 by addition of conc. HCl. The resulting solution is percolated on a column containing 600 ml of anionic exchanger resin IRA420 (Rohm & Haas), which is washed repeatedly with water, then eluted with 1N HCl. The fractions containing the product are combined and concentrated at reduced pressure to a volume of about 500 mL. The solution is percolated on a column containing 2 L of polyvinylpyridine resin (PVP), eluting with water, the fractions containing the desalted product are collected, combined and concentrated to dryness under vacuum. The crude solid is recrystallized from methanol/acetone=8/2, finally dried in a static drier at 50° C. under vacuum. 18.5 g (0.064 mol) of 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid are obtained.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH2:42][CH3:43])[C:32]1=[O:33])[CH2:29][CH3:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:1]([C:4]3[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH2:29][CH3:30])[C:32]1=[O:33])[CH2:42][CH3:43]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCOC(=O)COc1cc(C(=O)O)n(C)n1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methypyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-vloxy]acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)[C:5]([NH2:21])=[CH:4][CH:3]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:21]=[CH:23][N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[C:6]=2[CH:7]=1
Reactant: CSc1nc2ccc(CNc3cc(Br)ccc3N)cc2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CSc1nc2ccc(Cn3cnc4ccc(Br)cc43)cc2s1

Procedure:
6-((6-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a yellow solid (701 mg, 70%) using a procedure analogous to that described in Step 3 of Example 41, substituting 5-bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 389, 391 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(O)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2-hydroxyethyl)cyclopropanol (86 mg, 0.843 mmol) and triethylamine (136 mg, 1.35 mmol, Shantou Xilong chemical factory) in 10 mL of dichloromethane was stirred at −10° C. for 30 min. Methanesulfonyl chloride (106 mg, 0.927 mmol, Shanghai Haiqu chemical Ltd.) was then added via a syringe. The reaction was stirred at −10° C. for 1 hr at rt and then quenched with 1 mL ice-water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 2-(1-hydroxycyclopropyl)ethyl methanesulfonate as yellow oil (used in the next step without further purification).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:13]([O:20][C:21](=[O:31])[C@@H:22]([O:27][C:28](Cl)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([O:20][C:21](=[O:31])[C@@H:22]([O:27][C:28](=[O:29])[NH:2][C@H:3]([C:4](=[O:5])[N:6]([CH3:8])[CH3:7])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1
Reactant: CN(C)C(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](OC(=O)N[C@H](C(=O)N(C)C)C(C)(C)C)C(=O)OCc1ccccc1
Yield: 85.6 %

Procedure:
(2S)-2-Amino-3,3-dimethyl-N,N-dimethylbutyramide hydrochloride (0.25 g), (2S)-2-chlorocarbonyloxy-4-methylvaleric acid benzyl ester (0.36 g) and TEA (0.31 g) were reacted in ethyl acetate (10 ml) in a similar manner to that of Example 4-1) to give (2S)-2-[N-[(1S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyloxy]-4-methylvaleric acid benzyl ester (0.44 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCBr)ccc21
Yield: 63 %

Procedure:
In analogy to example 2.2, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and 1,5-dibromopentane were converted to yield 6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (63%) as colorless oil, MS: 397 (M, 1Br);
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.C(N)C#C.CO[C:18]1[C:22]([NH:23][C:24]#[C:25][CH3:26])=[N:21][S:20](=[O:28])(=[O:27])[N:19]=1.[CH3:29][C:30]1[NH:34][CH:33]=[N:32][C:31]=1[CH2:35][S:36][CH2:37][CH2:38][NH2:39]>>[CH3:29][C:30]1[NH:34][CH:33]=[N:32][C:31]=1[CH2:35][S:36][CH2:37][CH2:38][NH:39][C:18]1[C:22]([NH:23][CH2:24][C:25]#[CH:26])=[N:21][S:20](=[O:28])(=[O:27])[N:19]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CC#CNC1=NS(=O)(=O)N=C1OC
Agent: C#CCN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: C#CCNC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide wth one equivalent of 2-propynylamine and treating the resultant 3-methoxy-4-propynylamino-1,2,5-thiadiazole 1,1-dioxide with one equivalent of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine yields the title compound; identical to the product of Example 1.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[N:6]1([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O1CCCC1>[N:6]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17](=[O:19])[CH2:2][C:1]#[N:3])=[CH:21][CH:22]=2)[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(CN2CCOCC2)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
To a solution of acetonitrile (1.35 ml) in tetrahydrofuran (80 ml), cooled to 5° C., was added sodium hydride (0.94 g, 60% dispersion in oil). The mixture was stirred for 30 minutes before the addition of a solution of methyl 4-(morpholin-4-ylmethyl)benzoate (5.53 g) in tetrahydrofuran (20 ml). The resulting mixture was heated to 70° C. for 5 h. The mixture was cooled, quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with a 20–100% ethyl acetate/iso-hexane gradient to give 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile (0.97 g).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]C=C)([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:61])([C:57]([F:60])([F:59])[F:58])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56])[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:61])[C:57]([F:58])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]12C[C@H](CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10), 9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,5-pentafluoro-pentyl)-9-decenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[Br:15]Br.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[Br:15][CH2:13][C:12]([C:4]1[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:14]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(Cl)c1OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc(Cl)c1OC
Temperature: 25 °C

Procedure:
1-(3-Chloro-4,5-dimethoxyphenyl)-ethanone (31.6 g) was dissolved in chloroform (140 ml) and the solution was stirred at room temperature and treated dropwise with a solution of bromine (7.9 ml) in chloroform (60 ml). After a further 45 min the mixture was neutralised with aqueous potassium bicarbonate solution. The organic layer was separated and washed with sodium chloride solution, dried over sodium sulphate, then filtered and evaporated to dryness. The resultant oil (42.8 g) was crystallized from ether-hexane to give 2-bromo-1-(3-chloro-4,5-dimethoxyphenyl)-ethanone (32.0 g), m.p. 76.5°-78° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1C=CC=[C:6]([CH:10](C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)[CH3:34].C1(C(CC)C(Cl)=O)C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH:13]([C:5]1[CH:4]=[CH:2][CH:1]=[CH:10][CH:6]=1)[CH2:33][CH3:34]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CCC(C(=O)Cl)c1ccccc1
Product: CCC(C(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C)c1ccccc1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with 2-phenylbutyryl chloride, mp 142°-145° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])=[CH:15][CH:16]=3)[C:7](=[O:18])[C:6]=2[CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)coc2cc(O)c(O)cc12

Procedure:
6,7-Dihydroxy-3-(4-aminophenyl)-4H-1-benzopyran-4-one [see Example 51a] (538 mg) is dissolved in a mixture of dimethylformamide and water 15:85 (5 ml) and the solution is heated to 90° in the presence of benzenesulfonyl chloride (210 mg). After 15 minutes the pH has dropped to 3 and it is adjusted to 9 by addition of a 25% sodium hydroxide solution. Benzenesulfonyl chloride (additional 143 mg) and 25% sodium hydroxide solution (total amount used: 1 ml) are added in the same way until the pH does not vary any more. Aqueous hydrochloric acid is then added to lower the pH to 3 and the solution is cooled until precipitation occurs. The precipitate is filtered, washed with water and dried to give 6,7-dihydroxy-3-(4-phenylsulfonylaminophenyl)-4H-1-benzopyran-4-one, m.p. 285°-286°.