Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[F:13][C:14]1[C:15]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:16][C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:18][CH:19]=1>C(Cl)Cl.CN(C=O)C>[C:33]([N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:17]3[N:16]=[C:15]([N:36]4[CH2:37][CH2:38][N:39]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:40][CH2:41]4)[C:14]([F:13])=[CH:19][N:18]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCNCC4)n3)cc2)CC1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCN(C(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.83 h
Yield: 63.9 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 50 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(5-fluoro-4-(piperazin-1-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (23 mg, 0.057 mmol) and TEA (0.400 mL, 2.87 mmol) in DMF (1 mL) was added drop wise. The mixture was then stirred at room temperature for 90 min. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (17 mg). MS 467.5 (M+H); UV 201.0, 269.4 nm
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.OS(O)(=O)=O.CCCCCC.[Pd]>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)c1cccc(Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated H2SO4 was added 10 grams of 5% Pd/C. The mixture was hydrogenated on a Parr apparatus under hydrogen (45 psi) overnight. The reaction mixture was then filtered through Hyflo, washing with ethyl acetate. The filterate was dried over Na2SO4, filtered and concentrated to give an oil. The oil was slurried in hexane and the resulting white solid was collected by filtration to afford 3-benzylbenzoic acid, which was used without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[O:8][CH:9]=2)=[N:22][CH:23]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Solvent: ClCCl
Product: CN1CCN(Cc2cc(=O)c(OCCCCCOc3ncnc4ccccc34)co2)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(quinazolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 20 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). 1-Methyl-piperazine (64 μL, 0.575 mmol) was added via syringe. The mixture was stirred at 45° C. for 1 h. CH2Cl2 (50 ml) was added and the solution was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The product was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=99:01. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one EHT 4063 was obtained (35 mg, 35%) as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:8]1=[O:21]
Reactant: ClCc1ccccn1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Agent: Cl
Product: O=c1c2sc3ccccc3c2n(Cc2ccccn2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-chloromethylpyridine hydrochloride and subsequently deprotected to provide the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([NH2:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[NH2:20]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(=O)C(N)Cc1ccccc1
Product: NC(=O)C(Cc1ccccc1)NC(=O)C(Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-propionamide to give the title compound in moderate yield.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:13][C:9]=2[C:8]=1[S:22](Cl)(=[O:24])=[O:23].Cl>CC(C)=O>[Cl:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:13][C:9]=2[C:8]=1[S:22]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])(=[O:24])=[O:23]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)S(=O)(=O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Diethylamine (102 parts) was added dropwise to a suspension of the 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonyl chloride (136 parts) in acetone (400 parts) cooled in an ice bath to maintain a temperature of about 30°C. After the addition of all the diethylamine, the mixture was stirred for 15 minutes and then poured into excess ice/water. The resulting solution was acidified with concentrated hydrochloric acid to precipitate a cream solid which was filtered off, washed with water and dried to give 5,6,7-trichloro-N,N-diethyl-2-trifluoromethylbenzimidazole-4-sulphonamide (144 parts, 97% yield), melting point 155°-157°C.
Reaction SMILES: [C:1]([C:7]#[N:8])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br.O.C(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:7]([NH2:8])=[O:12]
Reactant: O=C([O-])O
Reactant: CC(C)(C)C(=O)C#N
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C(=O)C(N)=O
Yield: 88 %

Procedure:
111.0 g (1 mole) of pivaloyl cyanide were added dropwise to 800 g of a 36% strength solution of hydrogen bromide in glacial acetic acid at room temperature, while stirring. When the addition had ended, the mixture was subsequently stirred at room temperature for 3 hours. 9 ml (0.5 mole) of water were then added dropwise at 20° to 25° C. and the mixture was subsequently stirred at room temperature for 1 hour. The reaction solution was then poured into an excess of saturated sodium bicarbonate solution. It was extracted three times with 200 ml of methylene chloride each time. The combined organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. After some time, the oil which remained crystallized completely. The recrystallization from petroleum ether gave 113.5 g (88% of theory) of trimethylpyruvic acid amide of melting point 69° to 70° C.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: CN(C)c1ccccc1I
Product: CN(C)c1ccccc1NC(=O)c1ccccc1
Yield: 94.7 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with N,N-dimethyl-2-iodoaniline (160 μL, 1.05 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 7:1; 15 mL fractions). Fractions 8–15 provided 239 mg (95% yield) of the product as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.42 (br s, 1H), 8.57 (dd, J=7.8, 1.4 Hz, 1H), 7.98–7.92 (m, 2H), 7.62–7.51 (m, 3H), 7.26 (dd, J=7.8, 1.4 Hz, 1H), 7.22 (td, J=7.8, 1.4 Hz, 1H), 7.12 (td, J=7.8, 1.4 Hz, 1H), 2.74 (s, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[CH2:12]([O:14][C:15](=[O:31])/[CH:16]=[C:17](/[O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[CH3:30])\[CH2:18]Br)[CH3:13].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][CH2:18]/[C:17](/[O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[CH3:30])=[CH:16]\[C:15]([O:14][CH2:12][CH3:13])=[O:31])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc2c1cnn2C
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C(\CN[C@@H](CC(C)C)C(=O)OC)Oc1cccc2c1cnn2C
Temperature: 90 °C
Yield: 62 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.043 g, 0.24 mmol), (E)-4-bromo-3-(1-methyl-1H-indazol-4-yloxy)-but-2-enoic acid ethyl ester (0.073 g, 0.22 mmol) and N,N-diisopropylethylamine (0.070 g, 0.54 mmol) in acetonitrile (6 mL) in a sealed tube was heated at 90° C. for 18 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 100% diethyl ether/hexanes) to afford (S)-2-[(E)-3-ethoxycarbonyl-2-(1-methyl-1H-indazol-4-yloxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.055 g, 66%).
Reaction SMILES: [CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16](Br)[N:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH3:38])[N:33]=[C:32]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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.[Cu]I>[CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=4)[N:34]([CH3:38])[N:33]=3)[N:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Cl)cc12
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(Cl)cc34)nc12)C(C)(C)C
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide (94 mg, 0.21 mmol) and 5-chloro-1-methyl-3-tributylstannyl-1H-indazole (367 mg, 0.40 mmol) were dissolved in DMF (1.9 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) and copper(I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-40% EtOAc) to afford 92 mg (82%) of 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as an off-white solid.
Reaction SMILES: C[Si]([O:5][Si](C)(C)C)(C)C.[K].C([O:13][C:14]([C:16]1[C:17](Cl)=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=1)=[O:15])C>COCCOC>[OH:5][C:17]1[C:16]([C:14]([OH:13])=[O:15])=[CH:21][N:20]=[C:19]([S:22][CH3:23])[N:18]=1
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [K]
Solvent: COCCOC
Product: CSc1ncc(C(=O)O)c(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A slurry of potassium trimethylsilyl oxide (90% tech., 40 g, 0.31 mol) in 1,2-dimethoxyethane (300 mL) was added, slowly over 20 min, to a solution of ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate (Aldrich, 15 g, 64 mmol) in 1,2-dimethoxyethane (100 mL). Said addition, being mildly exothermic, may warrant the use of an ice bath to maintain ambient temperature conditions during addition. After addition was complete, the resulting suspension was stirred at ambient temperature for 1 h, then warmed to reflux for 36 h, then allowed to cool to ambient temperature. Reaction mixture was quenched with 1 M HCl(aq), then extracted with ethyl acetate and dried using sodium sulfate to produce a crude solid (11 g). Said crude solid was then recrystallized in ethyl acetate to afford 4-hydroxy-2-methylsulfanylpyrimidine-5-carboxylic acid as a white solid (8.8 g, 47 mmol, 73% yield). MS (−ESI) m/z 185 (M−, 100). An aliquot of this material (3.00 g, 16.1 mmol) was diluted with thionyl chloride (90 mL) followed by DMF (0.20 mL) and the resulting solution was warmed to reflux. After 1 hour at reflux, the solution was allowed to cool to ambient temperature and was concentrated in vacuo to afford a beige solid which was triturated once from hot toluene and then once again from hot hexanes (i.e., in both instances the soluble material was the desired fraction). This afforded, after concentration in vacuo, the titled compound as a white solid (3.90 g, 15.6 mmol, 97% yield). 1H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 2.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccc(C(=C/C=C/C(=O)O)c2ccc(C)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
As in Example 115, (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid (7.25 g) and 4-nitrophenol (4.4 g) in dichloromethane (60 mL) was treated with 1,3-dicyclohexylcarbodiimide (5.36 g). The mixture was stirred at 0°-5° C. for 30 minutes and then at room temperature for 18 hours. After the usual work up, the ester was crystallized from 2-propanol to yield 8.9 g of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 153.5°-154.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[CH3:22][S:23]([O:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 84A from 250 mg (0.81 mmol) of tert-butyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 89A) in 20 ml of dichloromethane with 110 mg (0.97 mmol) of methanesulfonyl chloride and 0.23 ml (1.6 mmol) of triethylamine. The product is reacted without further purification.
Reaction SMILES: C([O:4][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:6])(C)C.[OH-].[Na+]>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:5]([OH:6])=[O:4])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred solution of 2.06 g (6.5 mmol) of 1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid isopropyl ester ( ) in 10 mL of methanol was added 2.3 mL (13 mmol) of 5N NaOH. After 2 hours, the solvent was removed in vacuo and the aqueous residue was acidified with 1N HCl and then extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1.69 g of the title compound as a white solid; ; mp 145-148° C.; 1H NMR (DMSO) δ 1.56-1.63 (m, 1H), 1.78-2.05 (m, 4H), 3.13-3.21 (m, 1H), 4.10-4.15 (m, 1H), 7.42-7.50 (m, 2H), 7.88-7.95 (m, 2H), 12.75 (bs, 1H); MS (ES) m/z 271.9 (MH−); HRMS for C11H12N2FO4S: 274.0543 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[O:38][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[C:32](=[O:33])[C:31]([O:34][CH3:35])=[CH:30][C:29](=[O:36])[C:28]=2[OH:37])=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.Cl(O)(=O)(=O)=[O:41].C(OCC)C>O1CCCC1>[CH3:35][O:34][C:31]1[C:32](=[O:33])[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([OH:41])[CH:18]([OH:38])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]2[C:4](=[O:39])[C:3]([O:2][CH3:1])=[CH:8][C:7](=[O:9])[C:6]=2[OH:10])=[C:28]([OH:37])[C:29](=[O:36])[CH:30]=1
Reactant: COC1=CC(=O)C(O)=C(CCCCCCCC2OC2CCCCCCCC2=C(O)C(=O)C=C(OC)C2=O)C1=O
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1=CC(=O)C(O)=C(CCCCCCCC(O)C(O)CCCCCCCC2=C(O)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
37 Milligrams of 1,16-bis(5-methoxy-2-hydroxy-1,4-benzoquinon-3-yl)-8,9-epoxyhexadecane was dissolved in 2 ml of tetrahydrofuran, to this solution was added 0.5 ml of 5% perchloric acid aqueous solution and the mixture was stirred at room temperature for 4 hours. Then, 30 ml of diethyl ether was added to the reaction mixture, and the organic layer was washed with a saturated sodium chloride aqueous solution in several times, and dried over anhydrous sodium sulfate. This extract was purified by means of a preparative thin layer chromatography [adsorbent: "Silica gel 60 F254 " manufactured by E. Merck A. G., developing solvent: chloroform-methanol (85:15 mixture by volume/volume)], then recrystallized from ethyl acetate-n-hexane to obtain 12 mg of 1,16-bis(5-methoxy-2-hydroxy-1,4-benzoquinon-3-yl)-8,9-dihydroxyhexadecane. Yellow powdery crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1csc(NC(C)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A mixture of ethyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (2 g), 2N sodium hydroxide (7 ml) and methanol (13 ml) was stirred at ambient temperature for 5 hours. The reaction mixture was neutralized by 1N hydrochloric acid (14 ml). The precipitated crystals were filtered and washed with water to give 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (1.3 g).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[C@@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([C@H:29]2[CH2:33][CH2:32][O:31][CH2:30]2)([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: I[C@@H]1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1([C@H]2CCOC2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in tetrahydrofuran (34.8 mL, 34.8 mmol) under N2 at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (4.0 g, 16 mmol) in tetrahydrofuran (20 mL). The resulting brown solution was stirred at −78° C. for 30 min before adding a solution of (3R)-3-iodotetrahydrofuran (3.75 g, 17.4 mmol) in THF (3 mL). The mixture was stirred for 10 min at −78° C. then kept in a freezer reading at −25° C. overnight. The reaction was quenched with saturated ammonium chloride, extracted with ether three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography (EtOAc/Hexane) to provide the desired product (1.6 g, 31%). MS calculated for C16H25NO5: (M+H) 312.2; found 312.2.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH3:13])[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: COc1cccc2c1CCNC2C
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1CCN(c1nc(Cl)nc(C)c1C)C2C
Yield: 67.8 %

Procedure:
After 1-methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline(0.9 g, 5.1 mmol) and triethylamine(0.7 ml, 5.1 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.64 mmol) in dimethylformamide, 1.0 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 70.3%)
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:31][NH:30][C:29](=[O:32])[C:4]=2[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.[ClH:33].O1CCOCC1>>[ClH:33].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:4]2[C:29](=[O:32])[NH:30][CH2:31][C:3]=2[C:2]=1[Br:1]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(Br)c3c2C(=O)NC3)cn1
Yield: 22.2 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-bromo-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (10 mg, 0.020 mmol) in HCl-dioxane (999 μL, 4.00 mmol) was stirred at RT for 2 h. The mixture was concentrated to a residue, diluted with Et2O (3 mL), and sonicated to yield a white precipitate, which was filtered and dried overnight in a lyophilizer to give an HCl salt of the title compound as a white solid (1.8 mg, 21%). [M+H] calc'd for C17H21BrN6O, 406. found, 406.