Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][OH:7].[CH2:8]([O:15][C:16]1[C:17]([CH3:25])=[N:18][N:19]([CH3:24])[C:20]=1[CH2:21][C:22]#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH2:26]>>[CH2:8]([O:15][C:16]1[C:17]([CH3:25])=[N:18][N:19]([CH3:24])[C:20]=1[CH2:21][C:22]([O:7][CH3:6])=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nn(C)c(CC#N)c1OCc1ccccc1
Reactant: O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(OCc2ccccc2)c(C)nn1C
Yield: 33 %

Procedure:
Concentrated sulfuric acid was added to a solution of methanol (9.5 ml) and water (0.5 ml) under ice-cooling, and (4-benzyloxy-1,3-dimethylpyrazol-5-yl)acetonitrile (1.6 g, 6.6 mmol) was added thereto and the resulting mixture was heated for 6 hours under reflux. It was then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate, successively washed with water, aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel (eluent; ethyl acetate/n-hexane=1:2) to obtain methyl (4-benzyloxy-1,3-dimethyl-pyrazol-5-yl)acetate (0.6 g, 2.2 mmol, 33%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[S:16])[CH3:13]
Reactant: NCCNCc1cnccn1
Reactant: CCN=C=S
Product: CCNC(=S)NCCNCc1cnccn1

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3 and chromatographing gives N-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3 gives N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]guanidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=1)[C:5](O)=[O:6].[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][C:25]=12>>[CH:21]1[CH:22]=[CH:23][N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([C:11]4[CH2:16][C:15]([CH3:17])([CH3:18])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=4)=[C:2]([CH3:1])[CH:3]=3)=[O:6])[CH2:26][C:25]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CC(C)(C)CC(C)(C)C1
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CC(C)(C)CC(C)(C)C1
Yield: 80.4 %

Procedure:
3-Methyl-4-(3,3,5,5-tetramethyl-cyclohex-1-en-1-yl)-benzoic acid of Step B (0.100 g, 0.349 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.071 g, 0.384 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.123 g) as white crystals, m.p. 158° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.BrC1C2[O:19][CH:18]=[CH:17]C=2C=CC=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.O>C1(C)C=CC=CC=1>[O:8]1[C:4]2[CH:3]=[C:2]([C:18](=[O:19])[CH3:17])[CH:10]=[CH:9][C:5]=2[CH:6]=[CH:7]1
Reactant: Brc1ccc2ccoc2c1
Reactant: Brc1cccc2ccoc12
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc2ccoc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of 6-bromobenzofuran and 7-bromobenzofuran (1.12 g, 5.68 mmol) in toluene (19 mL), tetrakistriphenyl phosphine palladium (650 mg, 0.57 mmol) and tributyl(1-ethoxyvinyl)tin (2.11 mL, 6.25 mmol) were added, and the mixture was stirred at 100° C. overnight. The reaction solution was added water at room temperature, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica-gel column chromatography (hexane). The title compound (280 mg) was obtained as a yellow crystal.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44].C(Cl)[Cl:50].CO>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:48]([Cl:50])=[CH:40][CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35 with 72 μl (0.5 15 mmol) of triethylamine and 60 μl (0.468 mmol) of 3-chlorobenzoyl chloride to give the product. TLC: methylene chloride/methanol/conc. ammnonia (700:50:1) Rf =0.71, FD-MS: M+ =566.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:18]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:27]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CCCCCCC1=C(C=O)C(O)CC1=O

Procedure:
A convenient procedure for manufacture of the 2-formyl compounds consists of cleaving the glycol structure of the corresponding 2-(α,β-dihydroxyphenethyl) substances. 3-Acetoxy-5-oxo-2-(α,β-dihydroxyphenethyl)cyclopent- 1-eneheptanoate in ethanol is contacted with aqueous sodium periodate, thus affording 3-acetoxy-2-formyl-5-oxocyclopent-1-eneheptanoate. The 2-formyl compounds are alternatively produced from the corresponding 2-styryl derivatives by combining the hydroxylation and cleavage processes. Methyl 3-hydroxy-5-oxo-2-styrylcyclopent- 1-eneheptanoate in aqueous dioxane is thus allowed to react with osmium tetroxide and sodium periodate to afford methyl 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:35]=[CH:34][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:21]4[CH:22]=[CH:23][C:24](=[O:27])[CH:25]=[CH:26][C:20]4=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:18]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])C.C(O)C.[OH-].[K+]>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:21]4[CH:22]=[CH:23][C:24](=[O:27])[CH:25]=[CH:26][C:20]4=[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:18]=3)[CH2:13][CH2:12]2)=[CH:34][CH:35]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
To a stirred suspension of 3-[4-(4-ethoxycarbonyl benzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (1.2 g), prepared as described in Example 20, and ethyl alcohol (30 cc) under an atmosphere of nitrogen, a solution of potassium hydroxide (0.2 g) in distilled water (3 cc) is added at a temperature of about 20° C. in the course of 5 minutes. The reaction mixture is then heated to 60° C. for 4 hours. After the solution is cooled, 1N aqueous potassium hydroxide solution (10 cc) is added and the mixture is washed 3 times with methylene chloride (150 cc in total). The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (5 cc) and the solution is poured into silica (40 g) contained in a column 1 cm in diameter. Elution is first performed with a mixture of cyclohexane and ethyl acetate (50:50 by volume) (2.5 liters and the corresponding eluate is rejected. Elution is then performed with methanol (1 liter and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization in 2-methyl-2-butanol, 3-[4-(4-carboxybenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (0.6 g) is obtained in the form of its potassium salt.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:27](Cl)(Cl)Cl.CO.C(O)=O>CO>[Br:1][C:2]1[CH:22]=[C:21]([C:23]([O:25][CH3:27])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: CCCCc1nc2cc(Br)cc(C(=O)O)c2n1Cc1ccccc1Cl
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: CCCCc1nc2cc(Br)cc(C(=O)OC)c2n1Cc1ccccc1Cl

Procedure:
A mixture of 5-bromo-2-n-butyl-1-(2-chlorophenyl)-methyl-1H-benzimidazole-7-carboxylic acid (prepared in Example 1)(1.0 g, 2.4 mmol) in methanol (15 mL) was cooled in ice and then saturated with dry hydrochloric acid. The reaction mixture was refluxed for 14 hours, and TLC on silica with 9:1 chloroform/methanol containing a trace of formic acid gave an Rf 0.87 for the product; the starting material had an Rf 0.65. The methanol was evaporated, the residue was diluted with ice water and the solid was separated, washed with water and dried at 92° C. at high vacuum to provide 0.88 g of methyl 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1)#[N:23]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 61.4 %

Procedure:
2.0 g (0.01 mol) of 1-benzyl-4-hydroxypiperidine and 1.4 ml (0.01 mol) of triethylamine were dissolved in 100 ml of toluene and treated with 1.6 g (0.00966 mol) of 4-cyanobenzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetatelhexane (1:1). 1.9 g (61%) of 1-benzyl-piperidin-4-yl 4-cyano-benzoate were obtained as brownish crystals; m.p. 110°-111°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[N:12]1[C:20]2[C:15]3[C:16](=[CH:21][CH:22]=[CH:23][C:14]=3[C:13]=1S)[CH:17]=[CH:18][CH:19]=2.C(O)C.C(Cl)(Cl)Cl>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:11])[CH2:8][CH2:9][NH:10][C:13]2[C:14]3[CH:23]=[CH:22][CH:21]=[C:16]4[C:15]=3[C:20](=[CH:19][CH:18]=[CH:17]4)[N:12]=2)=[CH:3][CH:2]=1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: CC(CCN)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(CCNC1=Nc2cccc3cccc1c23)c1ccncc1

Procedure:
The title compound was prepared by the procedure of Example 55, utilizing 3.1 grams of 3-(4-pyridinyl)butanamine, 3.9 grams of benz(cd)indol-2-thiol, 6.4 grams of mercuric acetate, and 300 ml of ethanol. Chloroform (200 ml) was utilized as the partitioning solvent in place of dichloromethane. When the chloroform was being removed in vacuo, crystallization of the title compound suddenly occurred. The precipitate was collected, washed with a little chloroform, and dried. The yield was 3.9 grams; mp 220° C.-221° C. with decomposition.
Reaction SMILES: [OH-:1].[K+].[OH:3][OH:4].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:5]([O:3][O:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: [OH-]
Reactant: OO
Agent: [K+]
Solvent: O
Product: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.01 h
Yield: 63 %

Procedure:
Giving Benzoyl Peroxide as Major Product: A beaker was loaded with 1.23 g ~85% KOH pellets (19 mmoles) dissolved up to 15.9 ml with water, 2.04 ml of 30% aqueous hydrogen peroxide (20 inmoles), 50 ml of Freon® E1, and 2.32 ml of benzoyl chloride (20 mmoles) with ice bath cooling. An ultrasonic horn connected to a 40 Khz, 150 watt Dukane power source was started up at maximum power and lowered into the reaction mixture. After 25 seconds, ultrasonication was stopped, the solids filtered off, washed with water, and sucked dry on the filter. This gave 1.52 g of white solid, a 63% yield of benzoyl peroxide based on starting benzoyl chloride. The filtrate was brought to pH ~1 by the addition of concentrated sulfuric acid and then extracted three times with methylene chloride. The three methylene chloride extracts had a combined volume of 80 ml, 10.0 ml of which took 0.2 ml of 0.1 N thiosulfate in iodometric peroxide titration. The failure to find significant amounts of peroxide in the methylene chloride extracts indicates that little if any benzoyl hydroperoxide [C6H5 (C=O)OOH] was formed during the reaction.
Reaction SMILES: N1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=3)[CH2:8][CH:7]=2)CCCC1.[C:16]([O:20]C)(=[O:19])[CH:17]=[CH2:18].C(O)(=[O:24])C.Cl>O1CCOCC1>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH:7]([CH2:18][CH2:17][C:16]([OH:20])=[O:19])[C:6]2=[O:24])=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(c1)C(N1CCCC1)=CC2
Reactant: CC(=O)O
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCC1Cc2ccc(Cl)cc2C1=O

Procedure:
Twenty-two (22) grams of 3-pyrrolidino-5-chloroindene and 18 g of methyl acrylate were dissolved in 70 ml of dioxane, refluxed for 5 hours and freed of the solvent by distilling it off, to obtain a residue. The thus obtained residue was incorporated with 100 ml of acetic acid and 100 ml of hydrochloric acid and heated for 3 hours. After the end of the reaction, the resulting reaction mixture was freed of the solvent by distilling it off under a reduced pressure and incorporated with iced water to precipitate crystals. The crystals so precipitated were filtered off, washed with water, dried and then recrystallized from ethyl acetate to obtain 16 g of 6-chloro-1-oxo-2,3-dihydro-2-indene propionic acid in the colorless needle form.
Reaction SMILES: C1(C[O:8][C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)C=CC=CC=1.I[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH:28]([CH3:30])[CH3:29])[C:25](Cl)=[O:26])=[CH:20][CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH:28]([CH3:30])[CH3:29])[C:25]([N:10]2[C:9](=[O:8])[N:13]([CH3:16])[C:12](=[O:14])[O:11]2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=c1[nH]c(OCc2ccccc2)no1
Reactant: CI
Reactant: CC(C)N(C(=O)Cl)c1ccc(Cl)cc1
Solvent: CC#N
Product: CC(C)N(C(=O)n1oc(=O)n(C)c1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
A 50 mL round bottom flask, equipped with a thermometer, a stirrer and nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (0.5 g, 2.6 mmol), 1,8-diazabicyclo[5.4.0]unded-7-ene (0.5 g, 3.28 mmol), iodomethane (0.5 g, 3.54 mmol) and acetonitrile (5 mL). The mixture was stirred at room temperature for 18 h. To the mixture was added (4-chlorophenyl)(1-methylethyl)carbamic chloride (0.7 g, 3 mmol) and N,N′-dimethylamino-pyridine (0.367 g, 3 mmol), and the resulting mixture was heated to reflux for 2 h. It was then cooled to room temperature and flash chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide 150 mg (18%) of the title compound as a white solid melting at 121-123° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][C:23]([OH:27])([CH3:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>O1CCCC1.O.CO>[OH:27][C:23]1([CH3:26])[CH2:22][CH2:21][CH:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@@H](C)CC1)C1CCC(C)(O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)CCC(N(c2cc(-c3ccccc3)sc2C(=O)O)C(=O)[C@H]2CC[C@@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cis-3-[(4-Hydroxy-4-methyl-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (70.0 mg, 0.149 mmol, 1 eq) in tetrahydrofuran (1 mL), water (0.5 mL) and methanol (0.5 mL) was added lithium hydroxide (19.0 mg, 0.447 mmol, 3 eq). The resulting mixture was stirred 3 h at room temperature and was then extracted with ether (2×10 mL). Aqueous phase was separated and combined organic phases were discarded. Aqueous phase was acidified to pH 1 and extracted with dichloromethane (3×30 mL). Organic phases of dichloromethane were combined, dried over sodium sulfate and concentrated. The crude was purified by chromatography (10% methanol/dichloromethane) to give 50 mg (74%) of cis-3-[(4-Hydroxy-4-methyl-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (CDCl3, 400 MHz): 7.60 ppm (d, 2H); 7.39 ppm (m, 3H); 7.03 ppm (s, 1H); 4.51 ppm (bs, 2H); 2.00 ppm (m, 1H); 1.80-1.20 ppm (m, 15H); 1.12 ppm (s, 3H); 0.71 ppm (d, 3H); 0.60 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.NC1C2N(C([C@@H]3CCCN3C(OCC3C=CC=CC=3)=O)=NC=2Br)C=CN=1.[F:57]C1C=CN=C(NC(=O)C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([F:57])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Agent: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4cc(F)ccn4)cc3)c12
Yield: 93 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2b, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-fluoropyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 4b) to afford the title compound (331 mg, 93%).
Reaction SMILES: [N:1]#[C:2][Br:3].[CH3:4][C:5]1[C:6]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:7]([NH2:19])[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]=1[CH3:11].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[BrH:3].[CH3:11][C:10]1[N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[N:19]=[C:2]([NH2:1])[N:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:6]=2[C:5]=1[CH3:4]
Reactant: N#CBr
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Br
Product: Cc1nc(Oc2ccccc2)c2nc(N)n(CC(C)C)c2c1C
Temperature: 90 °C
Yield: 42.4 %

Procedure:
Cyanogen bromide (1.11 g, 10.5 mmol) was added to a solution of 5,6-dimethyl-N4-(2-methylpropyl)-2-phenoxypyridine-3,4-diamine (2.5 g, 8.8 mmol) in ethanol (50 mL), and the solution was heated overnight at 90° C. An analysis by LC/MS indicated the presence of starting material, and additional cyanogen bromide (100 mg) was added. The reaction was heated for one additional hour and allowed to cool to ambient temperature. Ethyl acetate and saturated aqueous sodium bicarbonate were added. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 2-5% methanol in dichloromethane) to provide 1.46 g of 6,7-dimethyl-1-(2-methylpropyl)-4-phenoxy-1H-imidazo[4,5-c]pyridin-2-amine hydrobromide as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN(C)[CH:36]=[C:37]([N:43]1[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[N:44]1)[C:38](OCC)=[O:39]>O>[F:11][C:12]1([F:17])[CH2:16][CH2:15][N:14]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:38](=[O:39])[C:37]([N:43]4[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[N:44]4)=[CH:36][NH:9]3)[CH:7]=2)[CH2:13]1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1
Reactant: FC1(F)CCNC1
Reactant: NNc1cc(Cl)ncn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCC(F)(F)C4)ncn3)c2=O)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (1.4 mmol) of the compound from Example 11A, 238 mg (1.7 mmol) of 3,3-difluoropyrrolidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 325 mg (1.4 mmol) of the compound from Example 7A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 137 mg (27% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[OH:27][C:28]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:28]=4[OH:27])[CH2:33]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 18.9 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 89 (18.9% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.77 and 2.90 (2t, 2H), 3.52 and 4.05 (2t, 2H), 3.74-3.80 (m, 6H), 3.87 and 3.92 (2s, 6H), 4.40 and 4.92 (2s, 2H), 6.31-6.92 (m, 2H), 7.67-8.17 (m, 6H), 8.70 and 8.73 (2s, 1H); MS (ESI) m/z 502 ([M+H]+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C>O1CCCC1>[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of 1.89 g of methanesulfonyl chloride in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 2.32 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 g of triethylamine in 40 ml of dried tetrahydrofuran at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and to the residue were added 30 ml of water and 30 ml of diethyl ether. After cooling, the resulting white crystals were separated by filtration, washed successively with cool water and cool diethyl ether and dried under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolineamide.