Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH:28]=[CH:29][N:30](C)C)[CH:27]=[C:19]1[C:18]2([CH3:34])[CH3:33])=[O:12])([CH3:9])([CH3:8])[CH3:7].NOS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO.O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH2:28][C:29]#[N:30])[CH:27]=[C:19]1[C:18]2([CH3:34])[CH3:33])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)C=CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Agent: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1=CC=C2C(=[C+]1)C(C)(C)C1=CC(CC#N)=CCN21
Reaction time: 48 h

Procedure:
2-(tert-Butoxycarbonylamino-methyl)-8-(2-dimethylamino-vinyl)-10,10-dimethyl-10H-pyrido[1,2-a]indolylium perchlorate (14 g, 0.028 mol; Sigma-Aldrich) was placed into 500-mL conical flask equipped with magnetic stir bar followed by 400 mL of 1:1 MeOH—H2O mixture. Stirring was started and hydroxylamine-O-sulfonic acid (14 g, 0.12 mol; Aldrich) was added to the flask in one portion. In about 2 hours all solid was dissolved and stirring was continued for additional 48 hours at room temperature. Sodium bicarbonate (2.00 g) was added to the reaction mixture to adjust pH equal to 7.0. The reaction mixture was transferred into 1-L round bottom one-necked flask and 80% of the reaction solvent was evaporated under vacuum. The product deposited on flask wall as a slightly yellow tar. The aqueous solution (ca 80-100 mL) that contained excess of hydroxylalamino sulfonic acid was discarded and the deposited tar was washed with water (2*60 mL) and dissolved in 250 mL water-methanol (1:1) mixture. Most of the solvent was again removed in vacuum, aqueous solution (approximately 50 mL) discarded, the separated organic residue was washed with water (2*60 mL), ether and dried. The crude product was used in the next step without additional purification. The yield of crude material was 13.1 g (100% of theory).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([N:48]2[CH2:57][C:56]3[CH:55]=[N:54][N:53]([CH3:58])[C:52]=3[NH:51][C:50]3[CH:59]=[C:60]([Cl:63])[CH:61]=[CH:62][C:49]2=3)=[O:47])=[CH:42][C:41]=1[F:64].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C:34](=[O:36])[NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([N:48]2[CH2:57][C:56]3[CH:55]=[N:54][N:53]([CH3:58])[C:52]=3[NH:51][C:50]3[CH:59]=[C:60]([Cl:63])[CH:61]=[CH:62][C:49]2=3)=[O:47])=[CH:42][C:41]=1[F:64])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)CNC(=O)OC(C)(C)C)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
HBTU (165 mg, 0.44 mmol) was added to a solution of N-(tert-butoxycarbonyl)glycine (65 mg, 0.37 mmol) in DMF (10 ml) and the mixture was stirred for 30 min at room temperature. (4-Aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (100 mg, 0.22 mmol) and DIEA (0.228 ml, 1.31 mmol) were added and the mixture was stirred for 24 h at room temperature. The solution was diluted with EtOAc, washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane then 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (123 mg, 100%).
Reaction SMILES: [CH:1]([N:4]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I[C:19]1[N:23]2[C:24]3[N:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:25]=3[O:26][CH2:27][CH2:28][C:22]2=[N:21][CH:20]=1.ClCCl.C([O-])(=O)C.[K+].COCCOC>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([N:4]1[C:8]([C:20]2[N:21]=[C:22]3[CH2:28][CH2:27][O:26][C:25]4[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[N:32][C:24]=4[N:23]3[CH:19]=2)=[CH:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cnc2c(c1)OCCc1ncc(I)n1-2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cnc2c(c1)OCCc1nc(-c3ccnn3C(C)C)cn1-2

Procedure:
A mixture of 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (117.1 mg, 0.4958 mmol), methyl 10-iodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate (92.0 mg, 0.248 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (20.24 mg, 0.02479 mmol) and 1.0 M of Potassium acetate in water (0.49 mL) in 1,2-Dimethoxyethane (5.0 mL, 48 mmol) was degassed. The reaction was microwaved on 200 watts, 140° C. for 40 minutes. The reaction mixture was filtered, washed with DME, mixed with water and extracted with EtOAc. Combined organic extracts were washed with 1% aq NaOH to remove a phenolic byproduct, then 5% aq citric acid, water, brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified on 4 g silica column, eluting with 60-70% of EtOAc in heptane. Yield 21 mg. MS (ESI+): 354.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([CH3:29])=[CH2:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc2c(cc1OC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A suspension of 3-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.030 g, 0.070 mmol) and 10% Pd/C (10 mg) in MeOH (10 mL) was stirred under H2 (50 psi) at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.016 g, 53%). LC/MS (Table 1, Method 2) Rt=1.275 min.; MS m/z: 431 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[NH:13][CH:12]=1)[OH:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)=[O:10]
Reactant: OC(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To (2,4-dichloro-phenyl)-(5-phenoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (33, 48 mg, 0.12 mmol) in tetrahydrofuran (15 mL), Dess-Martin periodinane (58 mg, 0.137 mmol) was added. The reaction was stirred at room temperature for 40 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The crude material was suspended in acetonitrile (1˜2 mL). The precipitated material was collected with vacuum filtration to provide the compound (P-0036, 24 mg, 50%). MS (ESI) [M+H+]+=383.1 and 385.1.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=4)=[CH:15][C:14]=3[O:29][C:30]([F:33])([F:32])[F:31])[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.O.O.[OH-].[Li+]>C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=4)=[CH:15][C:14]=3[O:29][C:30]([F:31])([F:32])[F:33])[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(OC(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
Combine methyl 4′-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)-3′-(trifluoromethoxy)biphenyl-4-carboxylate (9.15 g, 19.2 mmol), THF (175 mL) and water (175 mL) in a 500 mL flask equipped with a magnetic stir bar. While stirring in an ice bath treat the mixture with lithium hydroxide monohydrate (2.42 g, 57.7 mmol). Stir the reaction for 30 minutes, warm to room temperature and stir an additional 16 hours. Dilute with ethyl acetate (250 mL) and wash with water (250 mL). Add hydrochloric acid (2N) to the aqueous layer until it is acidic then extract with ethyl acetate (2×300 mL). Wash the extracts with aqueous saturated sodium chloride solution (1×250 mL), dry over anhydrous magnesium sulfate and concentrate to afford 6.98 g (79%) of the product as a white solid: MS (m/z): 462 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32]>C(O)C.C(OCC)C.[Pd]>[CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:17][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
Compound 4 (125 mg, 0.344 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (36.2 mg, 0.034 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows complete conversion to compound 5, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 5 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (127.5 mg, 0.447 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 48 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a off-white precipitate that was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 8-9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to afford beige foam 6 (75 mg, 49.3%); 1H NMR (DMSO-d6) δ 7.71 (d, 1H, J=3.7 Hz), 7.58 (d, 1H, J=5.2 Hz), 7.35-7.20 (m, 6H), 7.09 (m, 1H), 6.92 (s, 1H), 6.64 (d, 1H, J=8.5 Hz), 6.23 (brs, 2H), 6.10 (s, 1H), 4.14 (s, 2H), 3.99 (t, 2H, J=8.0 Hz), 2.90 (quintet, 1H, J=4.6 Hz), 2.10 (s, 3H), 2.05-1.97 (m, 2H), 1.91-1.80 (m, 1H), 1.69-1.56 (m, 3H), 1.49-1.35 (m, 2H); ESI-MS (m/z, %): 443 (M+1, 70%), 219 (100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[NH:17][C:16]2[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[C:21]([Cl:34])[CH:20]=3)=[N:14][CH:13]=[N:12][C:11]=2[CH:10]=1)(C)(C)C.[ClH:36].C(O)C>O1CCCC1>[ClH:34].[ClH:36].[NH2:7][CH2:8][C:9]1[NH:17][C:16]2[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[C:21]([Cl:34])[CH:20]=3)=[N:14][CH:13]=[N:12][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate (500 mg) in tetrahydrofuran (12 mL) was added 2N hydrochloric acid (6.0 mL) at room temperature. The mixture was stirred at 60° C. for 2 hrs, ethanol was added to the reaction system and the mixture was concentrated under reduced pressure. The resultant crystals were collected by filtration and washed with diisopropyl ether to give the title compound (481.4 mg) as pale-yellow powder crystals.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][S:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:9][S:8][CH2:7][C:5]1[O:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(Br)oc1CSC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CSC
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of methyl 5-bromo-2-[(methylsulfanyl)methyl]furan-3-carboxylate (5.3 g), 4-(trifluoromethyl)phenylboronic acid (4.6 g), tetrakis(triphenylphosphine)palladium(0) (1.2 g), 2N aqueous sodium carbonate solution (24 mL) and 1,2-dimethoxyethane (50 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 75%) as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[C:12](=[O:25])[CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:8][CH3:9].CS([C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][N:31]=1)(=O)=O.[OH-].[Na+]>CS(C)=O>[C:7]([C:11]1[C:12](=[O:25])[CH2:13][CH:14]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][N:31]=3)=[CH:22][CH:23]=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(O)cc2)CC1=O
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(=O)C1=C(O)CC(c2ccc(Oc3ccc(S(C)(=O)=O)cn3)cc2)CC1=O
Reaction time: 0.17 h

Procedure:
A solution of 3.3 g (0.029 mol) of potassium t-butoxide in 40 mL of dimethyl sulfoxide was treated with 3.5 g (0.013 mol) of 2-propionyl-3-hydroxy-5-(4-hydroxyphenyl)cyclohex-2-en-1-one at room temperature. The mixture was stirred for 10 minutes and 4.1 g (0.017 mol) of 2,5-bis(methylsulfonyl)pyridine was added. The resulting mixture was stirred for 1 hour, becoming dark and homogeneous. The mixture was poured into 200 mL of cold, dilute (0.1N) NaOH and washed with 50 mL of diethyl ether. The aqueous alkaline layer was removed and acidified (pH 2) with 1N HCl and the solution was extracted 4 times with 50 mL portions of ethyl acetate. The organic layers were combined and washed with an aqueous saturated NaCl solution, dried over MgSO4, filtered and the solvent removed by evaporation leaving a solid residue. Recrystallization of the residue from a 1:4 ethyl acetate/absolute ethanol mixture gave the above named product as a beige-white solid in a yield of 4.5 g (80 percent of theoretical). The product melted at 163°-164.5° C.; 1H NMR (CDCl3): δ 1.13 (t, 3H, CH3 --), 2.63-3.75 (m includes at 3.07 for CH3SO2 --, 7H ring protons and --CH2CH3), 7.03-7.42 (m, 5H, ArH's), 8.25 (dd, 1H, ArH), 8.77 (d, 1H, ArH), 18.2 (s, 1H, enol H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11]([C:16]([N:18]3[CH2:24][C:23]4([CH3:26])[CH2:25][CH:19]3[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22]4)=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)C.[OH-].[Na+].Cl>C(O)C>[CH3:26][C:23]12[CH2:25][CH:19]([N:18]([C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:10]=3[CH:9]=[CH:8][N:7]4[CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[O:17])[CH2:24]1)[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22]2
Reactant: CCOC(=O)CCn1ccc2c(C(=O)N3CC4(C)CC3CC(C)(C)C4)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC2CC(C)(CN2C(=O)c2cccc3c2ccn3CCC(=O)O)C1
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 3-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester (25 mg, 0.063 mmol) in ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the resulting solution stirred for 2 h. The solution was acidified with 1N hydrochloric acid solution before the organic volatiles were removed in vacuo and the aqueous residues were extracted with DCM (3×5 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 10 mg (43%) of the title compound as a solid. MS-ESI m/z 369; 1H NMR (400 MHz, DMSO) δ 0.81-0.99 (m, 6H), 1.08-1.10 (m, 4H), 1.18-1.22 (m) and 1.50-1.54 (m, 1H), 1.30-1.36 (m, 3H), 1.71-1.73 (m, 1H), 2.24-2.28 (m) and 3.02-3.12 (m, 1H), 2.65 (t, 2H), 3.29 (dd) and 3.68 (dd, 1H), 3.93-3.95 (m) and 4.60-4.62 (m, 1H), 4.29 (t, 2H), 6.24-6.29 (m, 1H), 6.94-6.96 (m, 1H), 7.00-7.12 (m, 2H), 7.27 (d, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(Cl)c4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,3-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:20](=[O:21])[CH:19]([Br:18])[CH3:23])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(Br)C(=O)Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C)Br)cc1

Procedure:
To a solution of 1.1 g of 4-Amino-benzoic acid methyl ester in 17 ml of toluene were added 2.2 ml of pyridine and 1.5 g of 2-Bromo-propionyl bromide at room temperature. After 16 h the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2 g.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33][NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and phenylhydrazine according to the method described for example 43. MS: M=413.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]([NH:28][OH:29])=[NH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:38][C:39](Cl)=O)[CH:34]=[CH:35][C:36]=1[Cl:37]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:26]1[N:27]=[C:39]([CH2:38][C:33]2[CH:34]=[CH:35][C:36]([Cl:37])=[C:31]([Cl:30])[CH:32]=2)[O:29][N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(NO)c1nc2ccc(N3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Product: O=c1c(OCc2ccccc2)c(-c2noc(Cc3ccc(Cl)c(Cl)c3)n2)nc2ccc(N3CCOCC3)cn12

Procedure:
Using the product of example 20 and 3,4-dichlorophenylacetyl chloride following the procedure of example 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2cnccc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2cnccc2[nH]1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-c]pyridine and methanesulfonic acid chloride.