Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.[C:38]1([C:44](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>C1(C)C(C)=CC=CC=1>[C:4]1(=[O:25])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][C:13]2[N:35]([C:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:36]=[N:37][N:14]=2)[C:1](=[O:30])[C:2]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:3]12
Reactant: N#CCCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCN(CCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
To a solution of 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butyronitrile (336 mg, 0.84 mmol) in xylene (5 ml) was added trimethyltin azide (378 mg, 1.84 mmol). The mixture was stirrred at 115° C. for 18 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was dissolved with 17% THF/CH2Cl2 (2.4 ml). To the solution was added 10 N NAOH solution (107 μl, 1.07 mmol). After srirring at RT for 30 min, triphenylmethyl chloride (297 mg, 1.07 mmol) was added, and the mixture was stirred at RT for 7 h, After adding water, the mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. Concentrating under vacuum gave 3-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro 1-naphthyl)amino]-1-[1-(triphenylmethyl)tetrazol-5-yl]propane (125 mg, 22%) which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:13]([CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:30]([C:32]1[N:33]([CH2:42][CH2:43][CH2:44]Cl)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])#[N:14]>CN(C=O)C>[C:13]([CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:30]([C:32]1[N:33]([CH2:42][CH2:43][CH2:44][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])#[N:14]
Reactant: C1COCCN1
Reactant: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2n1CCCN1CCOCC1
Reaction time: 48 h
Yield: 27.1 %

Procedure:
To a stirred slurry of morpholine (0.05 ml, 0.51 mmol) and potassium carbonate (0.09 g, 0.68 mmol) in DMF (1.2 ml) was added 6-Chloro-1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide from Example 19 (0.17 g, 0.34 mmol) at room temperature. The reaction was stirred for 48 hours before being partitioned between ethyl acetate and 1N NaOH. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting crude oil was chromatographed (5% MeOH/dichloromethane) to yield 6-chloro-1-(3-morpholin-4-yl-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (0.05 g, 27%); [M+H=543].
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([NH:22][C:23]([C:25]2[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=2)=O)=[CH:10][N:9]=1)(C)(C)C.[C:35](O)(=O)C>>[CH2:15]([N:14]1[C:12]2[CH:13]=[C:8]([NH:7][C:6](=[O:5])[CH3:35])[N:9]=[CH:10][C:11]=2[N:22]=[C:23]1[C:25]1[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)O
Reactant: Cc1cc(C(=O)Nc2cnc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Product: CC(=O)Nc1cc2c(cn1)nc(-c1cc(C)c(=O)n(C)c1)n2Cc1ccccc1
Temperature: 170 °C

Procedure:
{4-Benzylamino-5-[(1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-amino]-pyridin-2-yl}-carbamic acid tert-butyl ester II-16″ (2.000 g; 4.315 mmol) is suspended in acetic acid (5.190 g; 86 mmol) in a microwave vial and heated in a CEM microwave at 170° C. for 5 h. The reaction mixture is then concentrated under reduced pressure. The residue is used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[N:15]=[CH:14][C:13](B(O)O)=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[OH2:19].OO>C1COCC1.[Cl-].[Na+].O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[N:15]=[CH:14][C:13]([OH:19])=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O
Reactant: OB(O)c1cnc(CCCCn2ccnn2)nc1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnc(CCCCn2ccnn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-[1,2,3]Triazol-1-yl-butyl)-pyrimidine-5-boronic acid (0.099 g, 0.40 mmol) is dissolved in THF (0.5 ml) and water (0.5 ml) and hydrogen peroxide (30 wt %) (0.054 g, 0.48 mmol) is added. After stirring the solution at r.t. for 2 h, brine (3 ml) is added and the mixture is extracted with THF (2×10 ml). The combined organic phases are dried over MgSO4 and concentrated in vacuo yielding 2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidin-5-ol as a off-white solid. Yield 85 mg (97%).
Reaction SMILES: O[CH:2]=[C:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([CH3:16])([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl.[NH2:18]O>C(O)C.O>[CH3:16][C:5]1([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C:3]2[CH:2]=[N:18][O:9][C:8]=2[CH:7]=[CH:6]1
Reactant: CC1(C#C[Si](C)(C)C)C=CC(=O)C(=CO)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C#C[Si](C)(C)C)C=Cc2oncc2C1
Yield: 99.5 %

Procedure:
To a solution of 6-(hydroxymethylene)-4-methyl-4-((trimethylsilyl)ethynyl)-cyclohex-2-enone (147 mg, 0.63 mmol) in ethanol (15 mL) was added a solution of hydroxylamine hydrochloride (452 mg) in water (0.65 mL). The mixture was heated under reflux for 1 h. To the mixture was added water (50 mL). The aqueous mixture was extracted with methylene chloride/ether (1:2, 50 mL ×3). The extract was washed with saturated aqueous sodium bicarbonate solution (50 mL ×1) and brine (50 mL ×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 9 as a crystalline solid (145 mg, quantitative yield): 1H NMR (CDCl3) δ 8.06 (1H, s), 6.47 (1H, d, J=9.9 Hz), 6.03 (1H, d, J=9.9 Hz), 3.07 (1H, d, J=16.1 Hz), 2.77 (1H, d, J=16.1 Hz), 1.37 (3H, s), 0.14 (9H, s). This material was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1.Cl.CN(C)[CH2:21][CH2:22][CH2:23][N:24]=[C:25]=NCC.N1CCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][C:2]1([CH3:1])[CH2:15][C:6]2=[C:7]([C:12]([N:24]3[CH2:25][CH2:21][CH2:22][CH2:23]3)=[O:14])[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CC(C)(C)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a stirred solution of 6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylic acid (1.0 g, 3.7 mmol), 4-dimethylaminopyridine (0.75 g, 6.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) in DCM (30 mL) was added pyrrolidine (0.34 mL, 4.1 mmol). The mixture was stirred for 18 h then the solution was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, washed with 1M HCl (2×20 mL) and sat. K2CO3 (20 mL). The organic layer was separated, dried (MgSO4) and evaporated. The residue was triturated with hexane/ether to afford the title amide (905 mg, 76%) as a colourless solid. mp 153-155° C. C16H21NO2S2 requires: C, 59.41; H, 6.54; N, 4.33%. Found: C, 59.70; H, 6.73; N, 4.77%, 1H NMR (360 MHz, CDCl3) δ1.05 (6H, s), 1.94-2.04 (4H, m), 2.40 (2H, s), 2.59 (3H, s), 2.84 (2H, s), 3.59-3.62 (4H, m). MS (ES+) 324 (M+1).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1([F:23])[CH2:10][CH:9]1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[OH:12].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:24]([O:12][CH:11]([CH:9]1[CH2:10][C:8]1([F:23])[F:7])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.23 ml (2.86 mmol) of pyridine was added dropwise to 2.40 g (9.52 mmol) of the compound from Example 190A and 1.94 g (19.0 mmol) of acetic anhydride, and the mixture was stirred at RT overnight. The reaction mixture was then added to ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated, and the organic phase was concentrated, and the crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6/1). 2.66 g (95% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:4]5[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (115 mg, 0.92 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (20 μL, 0.26 mmol) and oxalyl chloride (80 μL, 0.92 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure and ethanol (10 mL) was added to the residue. The mixture was stirred with heating at 75° C. and cooled to room temperature, and the precipitate was collected by filtration to give the title compound (144 mg, 54%) as a white powder.
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[OH-:8].[K+].[CH2:10]([O:12][CH2:13][CH3:14])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:8])[CH2:14][CH:3]1[CH2:4][O:5][CH2:6][CH2:7][NH:2]1)[CH3:11]
Reactant: [OH-]
Reactant: CCOCC
Reactant: ClN1CCOCC1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC1COCCN1
Temperature: 16 °C
Reaction time: 2 h

Procedure:
N-chloromorpholine (24 g) in diethyl ether (20 ml) was added drop-wise over 2.5 h to a vigorously stirred solution of potassium hydroxide (22.1 g, 0.37 mol) in ethanol (130 ml) at 90° C. Heating was continued at 80° C. for 2 h. After standing at room temperature for 48 h the mixture was filtered to remove the inorganics and the solvent removed from the filtrate in vacuo. The residue was partitioned between diethyl ether and brine, dried (Na2SO4) and the solvent removed in vacuo. The resulting brown oil was dissolved in acetonitrile (100 ml). Triethylamine (25 ml) and monoethyl malonate (25 g) were added and the mixture heated at 16° C. for 16 h. The volatiles were removed in vacuo and the residue partitioned between saturated aqueous potassium carbonate and diethyl ether. The organic phase was dried (Na2SO4) and the solvent removed in vacuo to afford the title compound as a brown oil (3.5 g).
Reaction SMILES: [CH2:1]1[S:3][CH:2]1[CH2:4]Cl.[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:6]([O:10][C:11](=[O:19])[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:4][CH:2]2[CH2:1][S:3]2)[CH2:15][CH2:14]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: ClCC1CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC2CS2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 114 %

Procedure:
Epithiochlorohydrine (268 mg, 2.40 mmol, 1.0 eq) is added at room temperature to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (500 mg, 2.40 mmol, 1.0 eq) in N,N-dimethylformamide (15 mL), followed by potassium carbonate (335 mg, 2.40 mmol, 1.0 eq). After 24 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (1-thiiranylmethyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a white solid (745 mg, 57% yield).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:9])[CH2:6][CH2:7]Cl.[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[C:13]2=[CH:23][S:24][CH:25]=[C:12]12>CN(C)C=O>[CH3:4][N:5]([CH3:9])[CH2:6][CH2:7][N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([CH3:10])[C:12]2=[CH:25][S:24][CH:23]=[C:13]2[C:14]1=[O:22]
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.4 g. of 55% sodium hydride-mineral oil dispersion 0.5 g. of 2-dimethylaminoethylchloride hydrochloride and 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring at room temperature is continued for 18 hours. The reaction mixture is cooled, quenched with water, acidified, decolorized and filtered. The filtrate is made alkaline and extracted with chloroform. The dried chloroform extracts are concentrated to give a solid which is recrystallized from chloroform-hexane to give off-white crystals, m.p. 147°-149°C.
Reaction SMILES: [CH2:1]([C:3]1([CH3:21])[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[O:4]1)[CH3:2].CCN(CC)CC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([C:3]1([CH3:21])[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:39]([C:33]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[CH:32]=3)(=[O:41])=[O:40])[CH:9]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)C=Cc2cc(CNc3ccccc3)ccc2O1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(C)C=Cc2cc(CN(c3ccccc3)S(=O)(=O)c3ccc(OC)c(OC)c3)ccc2O1
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of 9 (80 mg, 0.29 mmol) in DCM (3 mL) was added Et3N (0.12 mL, 0.85 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (135 mg, 0.573 mmol). After 24 h, sat. NH4Cl was added to the reaction mixture and the aqueous layer was extracted with DCM (5×2 mL). The organic layers was combined, dried over MgSO4 and concentrated under vacuum. The crude product was purified by column (silica gel, 5:1 Hx/EtOAc) to give a white solid (42.6 mg). Yield: 32%. 1H NMR (CDCl3): δ 7.35 (dd, J=6.4 Hz, 2.0 Hz, 1H), 7.25-7.23 (m, 3H), 7.02-6.98 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.91-6.88 (m, 2H), 4.62 (s, 2H), 3.98 (s, 3H), 3.77 (s, 3H), 1.71-1.65 (m, 2H), 1.43 (s, 3H), 0.94 ppm (t, J=7.6 Hz, 3H). 13C NMR (CDCl3): δ 152.8, 152.5, 148.7, 139.2, 130.5, 129.8, 129.3, 129.2, 128.8, 127.9, 127.8, 126.6, 122.8, 121.4, 121.1, 115.8, 110.4, 79.0, 56.2, 56.1, 54.3, 34.0, 26.0 ppm. MS (ESI) m/z 502 [(M+Na)+]. HPLC: ret. time=5.9 min, 98.9%.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=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>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 34 %

Procedure:
A mixture of 3-(1-adamantyl)-4-methoxy-1-bromobenzene (1.000 g, 3.11 mmol, prepared in a similar manner as described by Charpentier, B. et al. in J. Med. Chem. 1995, 38, 4993–5006), 4-formylphenylboronic acid (0.559 g, 3.73 mmol) and potassium carbonate (1.719 g, 12.44 mmol) in 10.5 mL of DME and 1.5 mL of water was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.16 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ethyl acetate, 95:5) to give 0.372 g of 4-[3-(1-adamantyl)-4-methoxyphenyl]benzaldehyde (34%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), [2.10 (brs), 216 (s), 9 H], 3.91 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.48 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H), 10.04 (s, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:14][O:15][CH2:16][C:17](O)=O>>[CH3:14][O:15][CH2:16][C:17]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: COCC(=O)O
Product: COCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with methoxyacetic acid, Y and Z. LC-MS-conditions 02: tR=0.81 min; [M+H]+=234.45.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([SH:16])=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.I[C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[CH:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:18]4[CH:26]=[CH:25][C:24]5[C:20](=[CH:21][N:22]([CH3:27])[N:23]=5)[CH:19]=4)=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc2cc(I)ccc2n1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5nn(C)cc5c4)n3n2)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (2.3 g, 10.0 mmol) in DMF (20 mL) is added 5-iodo-2-methyl-2H-indazole (2.6 g, 10.0 mmol), tris(dibenzylideneacetone) dipalladium(0) (460 mg; 502.7 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (580 mg, 1.0 mmol), diisopropylethylamine (4 mL, 22.9 mmol). The mixture is purged with N2 and stirred at 100° C. for 18 h. DMF is removed under vacuum, and the residue is purified by flash column chromatography (Combi-Flash, silica gel) eluting with DCM/methanol (20:1) to give a crude product. The crude product is suspended in 20 mL of DCM to give slurry, and the pure product is collected by filtration to afford the title compound (1.9 g, 52.5%) as a yellow solid. MS (m/z): 363.1 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([OH:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:22][C:19]1[C:18]([F:23])=[CH:17][C:13]([C:14]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[C:12]([F:11])[C:20]=1[OH:21]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Oc1c(F)c(F)cc(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4,5-trifluoro-3-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.63-7.76 (m, 2 H), 8.44 (dt, J=7.9, 2.0 Hz, 1 H), 8.83 (dd, J=4.8, 1.6 Hz, 1 H), 9.25 (d, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:23]2[O:27][C:26](C)(C)[C:25](C)(C)[O:24]2)=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:32](C)([O-:34])=[O:33].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:23]([OH:27])[O:24][CH:25]([CH2:26][N+:32]([O-:34])=[O:33])[C:15]=2[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(B2OC(C)(C)C(C)(C)O2)c1OCCCOCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1OCCCOCc1ccccc1)B(O)OC2C[N+](=O)[O-]

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.36 g, 7.88 mmol), nitromethane (1.28 mL, 23.66 mmol), NaOH (0.22 g, 5.52 mmol), THF (6 mL), water (18 mL). Purification: flash column chromatography (30% EtOAc/hexanes): yield 1.2 g (41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 7.40-7.22 (m, 5H), 7.22-7.04 (m, 2H), 5.68 (dd, J=9.4, 2.7 Hz, 1H), 5.29 (dd, J=13.4, 2.5 Hz, 1H), 4.52 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.25 (t, J=6.2 Hz, 2H), 3.75 (s, 3H), 3.61 (t, J=6.2 Hz, 2H), 1.92 (quin, J=6.5 Hz, 2H).