Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=N)[C:15]3([OH:18])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1.Cl.[OH2:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:22])[C:15]3([OH:18])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9]2=[S:19])=[C:4]([F:20])[CH:3]=1
Reactant: N=C1N(c2ccc(Cl)cc2F)C(=S)C2CCCCC12O
Reactant: O
Agent: Cl
Solvent: CCO
Product: O=C1N(c2ccc(Cl)cc2F)C(=S)C2CCCCC12O
Yield: 83 %

Procedure:
In 220 ml of ethanol was suspended 25.0 g of 2-(4-chloro-2-fluorophenyl)-3a-hydroxy-3-imino-octahydroisoindol-1-thione and 20 ml of concentrated hydrochloric acid was added to the suspension, followed by stirring at 50° to 60° C. for several minutes. After cooling, 200 ml of water was added to the mixture, and the resulting crystals were collected by filtration, washed with 50% ethanol and dried, thereby producing 20.8 g (yield of 83%) of the subject compound. Recrystallization from ethanol yielded slightly yellow crystals, m.p. 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]3[S:14][C:13]([C:15](OCC)=[O:16])=[N:12][N:11]=3)[NH:5][C:4]=2[C:3]=1[N:20]([CH3:29])[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:16][CH2:15][C:13]1[S:14][C:10]([C:6]2[NH:5][C:4]3[C:3]([N:20]([CH3:29])[S:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)(=[O:22])=[O:23])=[C:2]([CH3:1])[S:9][C:8]=3[CH:7]=2)=[N:11][N:12]=1
Reactant: CCOC(=O)c1nnc(-c2cc3sc(C)c(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc2cc(-c3nnc(CO)s3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of ethyl 5-{2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrol-5-yl}-1,3,4-thiadiazole-2-carboxylate (1.3 g) in tetrahydrofuran (20 mL) was slowly added lithium aluminum hydride (114 mg) in small portions. The mixture was stirred at room temperature for 1 hr, and water (0.15 mL), 15% aqueous sodium hydroxide solution (0.15 mL) and water (0.45 mL) were successively added to the reaction mixture under ice-cooling. The mixture was stirred for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated and crystallized from diethyl ether to give N-{5-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl}-N-methylthiophene-2-sulfonamide (370 mg, yield 31%) as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21].[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:23][CH2:19][CH:20]([CH3:22])[CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 78 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and isobutylamine (288 mg, 3.85 mmol) suspended in 1-butanol (10 ml) were heated at 100° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 1N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (89 mg, yield 78%).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOCC>[O:24]=[C:21]1[N:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: CCOC(=O)CCCCCCBr
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A yellow solution of 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one ((prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Example 12.1 step 1) (2.0 g, 6.07 mmol) and ethyl 7-bromoheptanoate (2.88 g, 12.14 mmol) in DMF (40 ml) under a nitrogen atmosphere was treated with potassium carbonate (4.20 g, 30.4 mmol) and the resulting suspension was stirred at room temperature for 23 hours. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water (×2) and brine, dried (MgSO4) and evaporated under reduced pressure to afford a yellow oil. The crude material was diluted with ether (50 ml) and washed with water (2×20 ml), brine, dried (MgSO4) and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][OH:11].[NH2:13][NH2:14]>O>[OH:11][CH2:10][CH2:9][NH:8][C:7]1[CH:6]=[C:5]([Cl:12])[N:4]=[N:3][C:2]=1[NH:13][NH2:14]
Reactant: OCCNc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: O
Product: NNc1nnc(Cl)cc1NCCO
Reaction time: 20 h

Procedure:
To 40 g of 3,6-dichloro-4-(2-hydroxyethylamino)pyridazine is added slowly with stirring 430 g of 97% hydrazine. The mixture is stirred for 20 hours and cooled. Water is added, and the precipitate, 4-(2-hydroxyethylamino)-6-chloro-3-hydrazino pyridazine (m.p. 168° to 172°C.), is collected by filtration
Reaction SMILES: F[C:2]1[CH:13]=[CH:12][C:5]([C:6]([CH2:8][CH2:9][CH2:10]I)=[O:7])=[CH:4][CH:3]=1.C(CCCI)(=O)C1C=CC=CC=1.[C:26]1([C:32]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:44]>>[ClH:44].[C:6]([CH2:8][CH2:9][CH2:10][N:35]1[CH2:36][CH2:37][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:33][CH2:34]1)(=[O:7])[C:5]1[CH:12]=[CH:13][CH:2]=[CH:3][CH:4]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: O=C(CCCI)c1ccc(F)cc1
Agent: Cl
Agent: O=C(CCCI)c1ccccc1
Product: O=C(CCCN1CCC(c2ccccc2)(c2ccccc2)CC1)c1ccccc1

Procedure:
When proceeding as described in Example 28, but replacing 3-(p-fluorobenzoyl)propyl iodide (used as the one reactant in said example) by 3-benzoylpropyl iodide and reacting 27.4 g. of said 3-benzoylpropyl iodide with 24.4 g. of 4,4-diphenylpiperidine, on addition of hydrochloric acid to the etheric solution of the diphenylpiperidine base 19.5 g. of 1-(3-benzoylpropyl)-4,4-diphenylpiperidine hydrochloride are obtained. On recrystallization from ethanol, the hydrochloride melts at 200° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl>O>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of glycine (100 mmol) and NaOH (100 mmol) in water (300 ml), at 5° C., o-chloro-benzoyl chloride (110 mmol) was added in small portions. The reaction mixture was stirred for 30 minutes at room temperature, then cooled again and acidified to pH=2 by addition of 6 M HCl. Extraction of the aqueous solution was performed with EtOAc. Then, the combined organic layers were dried over MgSO4 and the solvent was removed by reduced pressure. The residue was triturated in boiling chloroform, and the product was collected by filtration in 80% yield.
Reaction SMILES: [CH2:1]([C:7]1([CH:14]=[O:15])[CH2:12][CH:11]2[CH2:13][CH:8]1[CH:9]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([CH:7]1[CH2:12][CH:11]2[CH2:10][CH:9]([CH:8]=[CH:13]2)[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C=O)CC2C=CC1C2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCC1CC2C=CC(C2)C1=O
Temperature: -30 °C
Reaction time: 3.5 h
Yield: 71.8 %

Procedure:
Compound XII (236 g, 1.1 mol) was loaded into a three liter flask and dissolved in one liter of toluene. This mixture was then cooled to −30° C. Aluminum chloride (77 g, 0.56 mol) was then added in one portion. The reaction mixture exothermed moderately and changed color to light orange. The temperature was allowed to rise to −15° C., then held for 3.5 hours. After this time the reaction was complete as shown by GC measurements. The reaction mixture was then poured onto ice and 25% sulfuric acid, and the organic layers were separated and washed once with 10% sodium hydroxide solution. The methylene chloride solvent was then removed under reduced pressure, and the resulting oil was purified by simple distillation to yield 163 g (69% yield) of XIII.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S([CH:33](O)[CH2:34][Cl:35])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][CH2:34][Cl:35])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)C(O)CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
14 g of (S)-N-tert-butoxycarbonyltyrosine, dissolved in 140 ml of DMF, are placed in a three-necked flask under a nitrogen atmosphere. 4.8 g of 50% sodium hydride in oil are added slowly using a spatula. 16.87 g of 1-tosyl-2-chloroethanol are added after the mixture has been stirred for 2 h at room temperature. 2.4 g of 50% sodium hydride in oil, and a further 8.4 ml of 1-tosyl-2-chloroethanol, are added after the mixture has been stirred for 2 days. The same procedure is carried out after 24 h and the stirring is continued for a further 24 h. The reaction is stopped by adding 100 ml of distilled water, and the reaction mixture is concentrated to dryness under reduced pressure. The residue which is obtained is taken up in 100 ml of distilled water and then extracted with 3 times 100 ml of ethyl acetate. The aqueous phase is separated off after settling and acidified to pH3 with 50 ml of 1N HCl, and the product is extracted with 3 times 100 ml of ethyl acetate. The organic phases are combined, washed with 2 times 50 ml of water, separated off, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure in order to yield 13.51 g of (S)-N-tert-butoxycarbonyl-4-O-(2-chloroethyl)tyrosine in the form of a chestnut oil (Rf=0.5, toluene 70%/methanol 20%/diethylamine 10%), which is used as such in the following step.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[F:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1[N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: Nc1ncnc2nc[nH]c12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
Adenine (Mann Research Laboratories, Inc., 0.8 g, 5.9 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g; 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 10 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (2,400 I.U.) and purine nucleoside phosphorylase (3,900 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 6, the reaction was diluted to 100 ml with 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. On day 17, the suspension was filtered and the filtrate was evaporated. The residue was suspended in warm water. The suspension was filtered and the filtrate applied to a 1.5×12 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). The product was eluted with water. Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain the title compound that analyzed as a 0.6 hydrate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>COCCOC.O>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[F:9]
Reactant: COc1cccc(F)c1B(O)O
Reactant: Clc1ccccc1Br
Solvent: O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1ccccc1Cl
Yield: 122.2 %

Procedure:
Treatment of 2-bromochlorobenzene (9 mL, 77.6 mmol) with 2-fluoro-6-methoxybenzene boronic acid (10.0 g, 58.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 17.0 g of 2′-chloro-2-fluoro-6-methoxybiphenyl as a colorless oil.
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[NH:11]([C:13]1[N:14]=[C:15]([NH2:31])[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[NH2:12]>CC(O)C>[OH:22][C@@H:21]1[C@H:23]([OH:24])[C@@H:25]([CH2:26][OH:27])[O:28][C@H:20]1[N:19]1[CH:18]=[N:17][C:16]2[C:29]1=[N:30][C:13]([N:11]1[CH:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]=[N:12]1)=[N:14][C:15]=2[NH2:31]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CC(C)O
Product: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight. Yield 54.29 g, purity (by HPLC) 96.6%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)CCC>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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cccnc2)c2snc(-c3ccccc3)c2c1O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (180 mg, 0.47 mmol) in DMF (2.37 mL) was added 3-(tributylstannyl)pyridine (349 mg, 0.95 mmol) and PdCl2(PPh3)2 (33.3 mg, 0.047 mmol). The reaction mixture was stirred at 120° C. for 30 min. After cooling to r. t. the mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was washed with brine, water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2 gave the title compound as white solid (28 mg): MS (m/z) 378.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:21]([O-])=O)[C:12]1=[O:24])[CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].CO>[Pd]>[C:1]([O:4][CH2:5][C@H:6]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:21])[C:12]1=[O:24])[CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](CC(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@@H](CC(C)C)n1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a round bottom flask was combined (R)-4-methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)pentyl acetate (3.00 g, 0.00903 mol), palladium on C (0.1 g, 0.0009 mol), and methanol (170 mL, 4.1 mol). The reaction mixture was stirred under hydrogen at room temperature and was monitored for progress. At 40 minutes, the reaction was completed by the absence of any starting material in the LC-MS analysis. The mixture was filtered twice using a DryDisk system to remove the catalyst. Volatiles were removed under vacuum and the mixture was purified by column chromatography using an ethyl acetate:hexanes (0-100%) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([B:8])=[CH:5][CH:4]=1.S1C=CC=C1C[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[S:7][C:6]([B:8])=[CH:5][CH:4]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: [B]c1ccc(CO)s1
Reactant: c1csc(CN2CCOCC2)c1
Product: [B]c1ccc(CN2CCOCC2)s1

Procedure:
(5-Morpholin-4-ylmethyl-thiophen-2-yl)-boron acid is prepared analogously to (5-hydroxymethyl-thiophen-2-yl)-boron acid (described in example (2ab)) starting from 4-thiophen-2-ylmethyl-morpholine (1.83 g; 10 mmol).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.Cl[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28][OH:29].C(Cl)[Cl:34]>>[Cl:34][C:32]1[CH:31]=[CH:30][C:26]([CH2:27][CH:28]=[O:29])=[CH:25][CH:24]=1
Reactant: ClCCl
Reactant: OCCc1cccc(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: O=CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Dess-Martin periodinane (1.02 g, 2.4 mmol) was diluted in anhydrous CH2Cl2 (25 mL) under argon, and when solution was affected, 4-chlorophenethyl alcohol (33, 0.313 g, 2 mmol) was added dropwise. The mixture was stirred for 2 h and 15 min at room temperature, and was then quenched by addition of 20 mL sat. aq. Na2S2O3. After stirring at room temperature for 15 min, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with H2O and sat. aq. NaCl (50 mL each) and was dried over anhydrous sodium sulfate and concentrated. The resulting semisolid residue was triturated with 10% EtOAc in hexanes, and the solid was filtered and discarded. The filtrate was concentrated, and the oily residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 15% EtOAc in hexanes to afford the title compound as a clear yellow volatile oil (0.211 g, 88%). 1H-NMR (500 MHz; CDCl3): δ 9.75 (t, J=2.1 Hz, 1 H), 7.34 (d, J=8.3 Hz, 2 H), 7.15 (d, J=8.2 Hz, 2 H), 3.69 (d, J=2.0 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:40])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:37][CH2:38][CH3:39])=[CH:23][C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:41](Cl)([Cl:43])=[O:42]>C(N(CC)CC)C>[C:33]([C:24]1[C:25]([S:27](=[O:28])(=[O:29])[N:30]([CH3:31])[CH3:32])=[CH:26][C:21]([C:10]2[N:9]([C:41]([Cl:43])=[O:42])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:40])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]=2)=[C:22]([O:37][CH2:38][CH3:39])[CH:23]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)c(S(=O)(=O)N(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-N,N-dimethyl-benzenesulfonamide was reacted with phosgene in the presence of triethylamine to give rac-(4S*,5R*)-2-(4-tert-butyl-5-dimethylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride. The carbamoyl chloride was then reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) in the presence of triethylamine to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H53N5O6S2Cl2 [(M+H)+] 834.2887, observed 834.2878.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH:11]2[C:15](OCC)=[O:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C2C(=O)N(Cc3ccccc3)C(=O)C12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1C2CN(Cc3ccccc3)CC12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
Ethyl 3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (37.2 g, 136.3 mmol) was dissolved in dry THF (400 ml). This solution was added dropwise at 0° C. to a suspension of LiAlH4 (20.7 g, 545.3 mmol) in dry THF (200 ml). The resulting brown suspension was heated to 60° C. under nitrogen atmosphere for 36 h. The mixture was then cooled to 0° C. and quenched carefully with sat. NH4Cl. A grey solid formed and more THF was added to allow adequate stirring. Solid Na2SO4 was added to the mixture which was stirred at r.t. for 30 min. The mixture was then filtered through celite to give a pale yellow solution. This was concentrated in vacuo to give the title compound as an orange oil (14.1 g, 51%). m/z 204 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 2.25 (2H, d), 2.85 (2H, d), 3.20 (2H, t), 3.55 (2H, s), 4.35 (1H, t), 7.20-7.40 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][C:18]([O:33][CH3:34])=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc(-c2cccc3c2CCNC3C)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.