Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1)=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CNC(=O)c1ccc(C)c(I)c1
Reaction time: 5 h

Procedure:
A solution of 1.0 mmol of 3-iodo-4-methylbenzoic acid, 1.2 mmol of TsCl, and 25 mmol of Py was stirred for 3 h and then 5 mmol of methylamine hydrochloride was added and stirring continued for 5 h. Chromatography provided N-methyl-(3-iodo-4-methylphenyl)carboxamide.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.Cl.[F:15][C:16]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:36])[C:32]([F:34])([F:35])[F:33])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)(F)C(F)(F)COc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)NC(=O)NC1=O
Reaction time: 16 h
Yield: 17.8 %

Procedure:
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (0.188 g) was added to a solution of 4-{4-(2,2,3,3,3-pentafluoropropoxy)phenoxy]-piperidine hydrochloride (0.30 g) in dichloromethane (10 ml) and triethylamine (0.70 ml) at ambient temperature. Stirred for 16 hours and evaporated to dryness. The residue was purified by prep HPLC (using λ230 nm as the detecting wavelength) eluting with 0-95% acetonitrile, H2O, +0.2% trifluoroacetic acid. Yielded a solid product, which was dried under vacuum at 50° C. to give the title compound (0.076 g). NMR: (DMSOd6) δ 10.7 (s, 1H), 8.0 (s, 1H), 7.0 (m, 4H), 4.75 (t, 2H), 4.45 (m, 1H), 3.5 (d, 1H), 3.3 (m, 3H), 3.1 (m, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.35 (s, 3H). Mass Spectrum: M−H− 513.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15]/[CH:16]=[CH:17]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol (0.152 g, 0.49 mmol), iodobenzene (0.06 mL, 0.49 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.05 mmol), and triethylamine (0.68 mL, 4.9 mmol) were combined in DMF (4 mL) and the mixture was purged with N2 (g) for 5 minutes. The reaction was then sealed and stirred at 100° C. overnight. After aqueous workup, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[CH2:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[C:14](O)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C(OC(=O)CCCC)(=O)CCCC>>[OH:19][C:14](=[C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(=O)O
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2O1
Agent: CCCCC(=O)OC(=O)CCCC
Product: CCCCC(O)=C1C(=O)Oc2ccc([N+](=O)[O-])cc21

Procedure:
In a further process disclosed in EP-A 1 116 719, 5-nitro-2(3H)-benzofuranone is reacted in the presence of pentanoic acid and pentanoic anhydride to give 3-(1-hydroxypentylidene)-5-nitro-2(3H)-benzofuranone which reacts under acidic conditions to give 2-(n-butyl)-5-nitrobenzofuran. The disadvantage of this process is that 5-nitro-2(3H)-benzofuranone is used as precursor, which makes industrial application uneconomic.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccoc1
Product: O=C(OCc1ccccc1)C1C=COC1

Procedure:
Synthesis takes place first of all by Birch reduction of 3-furancarboxylic acid followed by esterification with benzyl bromide to form benzyl 2,3-dihydrofuran-3-carboxylate (in accordance with G. Lowe, St. Swain; J. Chem. Soc. Perkin Trans I (1985), 391) ##STR29## b) The end product from a) is reduced with lithium aluminum hydride to give 3-hydroxymethyl-2,3-dihydrofuran
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CCOC(OCC)/C(C)=C/CBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(OCC)/C(C)=C/COc1ccc(NC(C)=O)cc1
Reaction time: 96 h
Yield: 57.9 %

Procedure:
A solution of 1.0 g (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene in 10 ml of sieve dried dimethyl formamide is treated with 0.7 g of p-acetylaminophenol and 0.64 g anhydrous potassium carbonate. The suspension is stirred under nitrogen for four days and the mixture is then poured into 100 ml water and the hazy solution extracted with two 100 ml portions of benzene. The benzene extract is washed with water and dried with sodium sulfate. The benzene extract is concentrated and vacuum dried to give 0.75 g of (E)-4-(4-acetylaminophenoxy)-1,1-diethoxy-2-methyl-2-butene which is dissolved in about 5 to 10 ml acetone and treated with about 1 ml water and a spatula of p-toluenesulfonic acid monohydrate. The resulting solution is agitated occasionally for 30 minutes and the solution is evaporated at room temperature giving a solid, ethylether insoluble residue. The residue is dissolved in about 150 ml methylene chloride and washed twice with water. The residue is dried with sodium sulfate and concentration gave 0.45 g of a solid. The material is filtered in about 50 ml of hot carbon tetrachloride-benzene then boiled down to about 10 ml. The product is filtered and washed with room temperature carbon tetrachloride giving 0.2 g white solid, m.p. 127°-30° C. Elemental Analysis. Calculated for C13H15NO3 : C,66.94; H,6.48; N,6.00. Found: C,66.64; H,6.29; N,5.75.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C)C=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]cnc2cc(Cl)ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2cc(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
In a dried round bottom flask under N2 atmosphere was added 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3, 9.0 g, 49.56 mmol) to dimethylformamide (50 mL). The solution was stirred at 0° C. and sodium hydride (1.78 g, 74.35 mmol) was added portion-wise over 10 min. The anionic suspension was stirred for 1 h at 0° C. followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (12.4 g, 74.35 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 h. After consumption of starting materials as indicated by TLC, the reaction mixture was quenched with ice. A solid precipitates. It was filtered and washed with excess n-pentane. The solid was dried under vacuum to afford 7-chloro-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one (4) as a brown solid. Yield: 9.1 g, 59%; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.72 (s, 1H), 7.79 (s, 1H), 5.49 (s, 2H), 3.65 (t, J=16 Hz, 2H), 0.90 (t, J=16 Hz, 2H), −0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]#[C:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][C:10]#[CH:9]
Reactant: Oc1ccccc1Br
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromophenol (50.0 g, 289 mmol) and progargyl bromide (41.3 g, 347 mmol) in dry ACN (500 mL) was added K2CO3 (47.9 g, 347 mmol) and the solution was stirred overnight at rt. The solvent was removed and the residue was poured into water and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give compound P34a (60 g, 98%) as an oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:15](Cl)(=[O:17])=[O:16]>O.CC(C)=O>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:15]([N:1]=[N+:2]=[N-:3])(=[O:16])=[O:17]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of sodium azide (3.1 g, 44 mmol) in water (10 ml) was added dropwise at RT to a stirred solution of 2-naphthalenesulfonyl chloride (10 g, 44 mmol) in acetone (60 ml) and stirring was continued for 2 hours. Water (50 ml) was added and the resulting mixture was decanted. The surnatant was discarded, while the brown oily residue was recrystallized from light petroleum producing after drying pure title compound (7.67 g, 32.9 mmol, yield 74.7%) as white needles, m.p.=45°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:14])[CH3:13])=[O:9])[CH:5]=[CH:4][C:3]=1[S:23](Cl)(=[O:25])=[O:24].[S:27]1[C:31]([NH2:32])=[N:30][CH:29]=[N:28]1.[OH-].[Na+].O1CCOCC1.O>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:23]([NH:32][C:31]1[S:27][N:28]=[CH:29][N:30]=1)(=[O:25])=[O:24])[C:8]([NH:10][CH2:11][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH3:13])=[O:9]
Reactant: Nc1ncns1
Reactant: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Cl)c(F)c1)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(CNC(=O)c1ccc(S(=O)(=O)Nc2ncns2)c(F)c1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
2-Fluoro-4-({[2-(4-fluorophenoxy)-2-methylpropyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 95, 242 mg, 0.599 mmol) was added portion-wise to a solution of 1,2,4-thiadiazol-5-amine (182 mg, 1.80 mmol) and sodium hydroxide (71.9 mg, 1.80 mmol) in 1,4-dioxane (1.9 mL, 24 mmol) and water (0.37 mL, 21 mmol). After stirring 30 min at ambient temperature, the reaction was quenched with 2 N HCl. The mixture was partitioned with methylene chloride. The aqueous layer was washed with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated onto Celite. The residue was purified via automated flash chromatography (12 g SiO2, chloroform to 20% MeOH in chloroform). The product containing fractions were concentrated in vacuo, and the residue was dissolved in 1 mL of DMSO, filtered, and purified via reverse-phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The product containing fractions were lyophilized to afford the product as a white powder (48 mg, 16%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=O.[CH:11]([NH2:13])=O>O>[OH:2][C:3]1[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[N:10]=[CH:11][N:13]=1
Reactant: NC=O
Reactant: COC(=O)c1sccc1N
Solvent: O
Product: Oc1ncnc2ccsc12
Temperature: 200 °C
Reaction time: 2 h

Procedure:
3-aminothiophene-2-carboxylic acid methylester (1.6 g, 10 mmol) was added to formamide (3.4 ml), and the mixture was stirred at 200° C. for 2 hours. The reaction mixture was returned to room temperature, and water was added thereto, which was extracted with chloroform. The solid obtained by distilling off the solvent under reduced pressure was washed with ethyl acetate to obtain 4-hydroxythieno[3,2-d]pyrimidine (60 mg, 0.39 mmol).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([O:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:19]=[N:20][CH:21]=1)([CH3:14])[CH3:13]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:27][C@H:25]([CH2:24]/[CH:23]=[CH:22]/[C:18]2[CH:19]=[N:20][CH:21]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[CH:17]=2)[CH3:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, p-toluenesulfonyl chloride (11.45 g, 60.06 mmol) was added to a stirring solution of (2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (7.00 g, 31.63 mmol) in dry triethylamine (30 mL) at 0° C. After stirring and warming to ambient temperature over 18 h, the mixture was concentrated on a rotary evaporator. The crude product was stirred with saturated NaHCO3 solution (100 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford 10.00 g (84.2%) as a dark-brown oil, which was used without further purification.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:51]([C:53]1[N:54]=[C:55]([C:66]([O-])=[O:67])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=1)#[N:52].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:66]([C:55]2[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:57]=[C:53]([C:51]#[N:52])[N:54]=2)=[O:67])=[C:13]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A solution of 267 mg (0.732 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid tert-butyl amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 512 mg (1.10 mmol) of PyBroP, 246 mg (0.806 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)) and 383 μL (2.20 mmol) of DIEA. The mixture was stirred at RT for 3 h, diluted with CH2Cl2 (20 mL), and washed with saturated aqueous NaHCO3 (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 311 mg (69%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.73 (br s, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.76 (s, 1H), 7.13 (dd, 1H, J=8.4, 2.0 Hz), 7.02 (d, 1H, J=2.0 Hz), 5.94 (s, 2H), 5.77-5.72 (m, 1H), 4.07 (br s, 1H), 3.69-3.62 (m, 2H), 3.35-3.27 (m, 2H), 3.14-3.06 (m, 2H), 2.31-2.23 (m, 2H), 2.12-2.07 (m, 2H), 1.58 (t, 2H, J=6.4 Hz), 1.34 (s, 9H), 1.10 (s, 6H), 1.00-0.94 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:30](O)=[O:31])[CH2:8][CH2:7][N:6]([CH2:9][C:10](=[O:29])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:5]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:70]3[C:65](=[CH:66][CH:67]=[C:68]([NH2:71])[CH:69]=3)[NH:64][N:63]=2)=[CH:58][CH:57]=1>CN(C=O)C>[F:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[C:70]3[C:65](=[CH:66][CH:67]=[C:68]([NH:71][C:30]([C:4]4([CH2:3][O:2][CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][C:10](=[O:29])[N:11]5[CH2:12][CH2:13][N:14]([C:17]6[CH:18]=[CH:19][C:20]([C:23]7[N:28]=[CH:27][CH:26]=[CH:25][N:24]=7)=[CH:21][CH:22]=6)[CH2:15][CH2:16]5)[CH2:5]4)=[O:31])[CH:69]=3)[NH:64][N:63]=2)=[CH:60][CH:61]=1
Reactant: COCC1(C(=O)O)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
The 3-methoxymethyl-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (0.049 mmol), 1-hydroxybenztriazole (7 mg, 0.052 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (10 mg, 0.052 mmol) were dissolved in dry DMF (1 ml). 3-(4-Fluoro-phenyl)-1H-indazol-5-ylamine (12 mg, 0.053 mmol) was added and the reaction mixture was stirred overnight and directly subjected to purification by reversed phase HPLC to obtain 9.15 mg of the title product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Cl>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: ClCc1ccccn1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccn3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and pyridin-2-yl-methyl chloride. The crude product is purified by column chromatography eluting with 2% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]([N:18]([CH3:20])[CH3:19])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]([N:18]([CH3:20])[CH3:19])([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(F)cc1
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCO)cc1
Reaction time: 12 h

Procedure:
10.0 g (0.035 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-propan-1-one and 18.4 g (0.25 mol) of 3-amino-1-propanol are dissolved in 20 ml of dry dimethylacetamide, and the solution is heated up to 150° C. together with 9.7 g (0.07 mol) of potassium carbonate, and stirred overnight (about 12 hours). After the solution is cooled down, it is poured into 300 ml of water and extracted with toluene. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the toluene, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:1) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]:1.14 (s, 3H), 1.50 (br, 1H), 1.93 (m, 2H), 2.33 (s, 6H), 2.96 (d, 1H), 3.37 (m, 2H), 3.42 (d, 1H), 3.85 (m, 2H), 4.45 (br, 1H), 6.56 (d, 2H), 6.89-6.91 (m, 2H), 7.10-7.12 (m, 3H), 8.45 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:11]([N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH3:18])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(NC2CCCC2)c1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C2CCCC2)c1Br
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a stirred solution of methyl 2-bromo-3-(cyclopentylamino)benzoate (1.4 g, 4.69 mmol) in acetonitrile (20 mL), cesium carbonate (3.0 g, 9.2 mmol) and methyl iodide (3.38 g, 23.4 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered and the residue washed with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford desired methyl 2-bromo-3-(cyclopentyl(methyl)amino)benzoate (1.1 g, 75%).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])=[CH:31][CH:32]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CC(C)NC(=O)OC(C)(C)C)cc1
Yield: 55.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (260 mg, 0.80 mmol) was reacted with tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamate (430 g, 1.2 mmol) to afford the desired product (212 mg, 55%) as a yellow oil: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [CH:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[I:15])=[CH2:2].Cl[CH2:17]I.C([Zn]CC)C>ClCCCl>[CH:1]1([O:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:5]=2[I:15])[CH2:17][CH2:2]1
Reactant: ClCI
Reactant: C=COc1ccc(OC(F)(F)F)cc1I
Agent: CC[Zn]CC
Solvent: ClCCCl
Product: FC(F)(F)Oc1ccc(OC2CC2)c(I)c1
Temperature: 0 °C
Yield: 73.9 %

Procedure:
1-(Vinyloxy)-2-iodo-4-(trifluoromethoxy)benzene (Description 11; 7.6 g, 23 mmol) and chloroiodomethane (5.4 mL, 74 mmol) were dissolved in 1,2-dichloroethane (40 mL) and cooled to 0° C. Diethyl zinc (3.8 mL, 36.8 mmol) was then added dropwise. The solution was allowed to warm to room temperature for 10 minutes, then cooled back to 0° C. when it was quenched with saturated aqueous ammonium chloride solution (50 mL). The suspension formed was extracted with 50% diethyl ether/hexane (2×100 mL) and the extracts dried (MgSO4). Concentration yielded a yellow oil which was purified by silica chromatography to give the title compound as a clear oil (5.84 g, 17 mmol).
Reaction SMILES: [C:1]([OH:9])(=O)[CH:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:10]([N:17]1[C:1](=[O:9])[CH:2]([OH:3])[CH2:4][C:5]1=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CC(O)C(=O)O
Solvent: CCO
Product: O=C1CC(O)C(=O)N1Cc1ccccc1

Procedure:
Heating malic acid with benzylamine in ethanol at 170° C. to give N-benzyl-3-hydroxysuccinimide and reducing with lithium aluminum hydride to give N-benzyl-3-pyrrolidinol.