Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]=[O:6].[N:8]([O-])=[O:9].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:7])[C:4](=[N:8][OH:9])[CH:5]=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)CC=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C=O)=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the respective 3-oxo-propionic acid methyl ester derivative (4.8 mmol, 1.0 eq.) in glacial acetic acid (1.9 mL) was cooled to 10° C. and at this temperature was added a solution of NaNO2 (5.6 mmol, 1.16 eq.) in water (0.68 mL). After the addition was complete (15 min), the solution was allowed to warm to rt and stirred for 2 h. Then the solution was poured into water (10 mL) and after a few minutes crystals begun to appear. This suspension was cooled in an ice-bath and crystals were collected by filtration. The cake was washed several times with cold water and the water was removed by the azeotrope of toluene-water in vacuo to give 2-hydroxyimino-3-oxo-propionic acid methyl ester derivatives which were dissolved in a mixture of acetic anhydride (1.4 mL) and glacial acetic acid (1.8 mL). To this solution was added sodium acetate (0.296 mmol, 0.06 eq.) and HgCl2 (0.01 mmol, 0.002 eq.). The mixture was refluxed for 1 h, then cooled to rt and filtered. The solid was rinsed with ether, the organic filtrate was recovered, washed 3 times with water and one time with 1M aq. K2CO3. The organic layer was dried over MgSO4, filtered and concentrated. The crude products were purified by flash chromatography to afford the corresponding 2-acetylamino-3-oxo-propionic acid methyl ester derivatives.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.C([Li])(C)(C)C.CCCCCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[C:2]([CH:28]=[O:29])[CH:3]=1
Reactant: Brc1ccc2c(c1)oc1ccccc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)oc1ccccc12
Temperature: -78 °C

Procedure:
Combine 3-bromodibenzofuran (0.5 g, 2.0 mmol) and tetrahydrofuran (30 ml). Cool to about −78° C. Add a solution of t-butyllithium, 1.6 M solution in hexane (2.2 ml, 3.0 mmol), then warm to about 0° C. for 10 min. Cool to about −78° C. and add dimethylformamide (0.5 ml, 5.9 mmol). Warm to room temperature, quench with water, and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH2:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[NH:10]1.[S:23]([NH2:27])([NH2:26])(=[O:25])=[O:24]>C(COC)OC>[NH2:26][S:23]([NH:27][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[N:10]1[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:18]([C:19]([NH:21][O:22][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:22])(=[O:25])=[O:24]
Reactant: NC(=O)C1c2ccccc2C(=O)NC1c1ccc(Cl)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: NS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a mixed liquid of 200 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-Nenzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed by stirring at 80° C. for 2 days. The reaction solution was concentrated, added with chloroform, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), crystallized from ethyl acetate, and collected by filtration to obtain 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[C:23]([OH:31])[C:24](=[CH:29][CH:30]=1)[C:25]([NH:27]O)=[O:26]>O1CCCC1>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25]([OH:26])=[N:27][O:31][C:23]=2[CH:22]=1
Reactant: O=C(NO)c1ccc(Cl)cc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1noc2cc(Cl)ccc12

Procedure:
A solution of 1,1'-carbonyldiimidazole (12.76 g, 78.5 mmol) and triethylamine (12.6 mL, 90 mmol) in tetrahydrofuran is slowly added to a refluxing suspension of 4-chlorosalicylohydroxamic acid (13.39 g, 71.4 mmol) in tetrahydrofuran. The reaction mixture is refluxed for 1 hour, cooled, concentrated in vacuo, diluted with water, acidified with concentrated hydrochloric acid (pH1) and filtered to obtain a solid. A solution of the solid in ether is extracted with saturated sodium hydrogen carbonate solution. The combined aqueous extracts are acidified with concentrated hydrochloric acid and the resultant precipitate is collected and dried overnight to give the title product as a white solid, mp 218°-219° C.
Reaction SMILES: I.CS[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[NH:14][C:15]([C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)=[NH:5].C([N:32](CC)CC)C>CO.O>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[NH:14][C:15]([C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])=[CH:8][CH:7]=1)(=[NH:32])[NH2:5]
Reactant: COC(=O)COc1ccc(C(=O)NC(=O)Nc2ccc(C(=N)SC)cc2)cc1
Reactant: CCN(CC)CC
Agent: I
Solvent: CO
Solvent: O
Product: N=C(N)c1ccc(NC(=O)NC(=O)c2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of the product of Example 1 (100 mg) in methanol (25 ml) was added a 1% (by volume) solution of triethylamine in water (25 ml). The reaction mixture was stirred at ambient temperature for 24 hours and filtered. The collected solid was washed thoroughly with methanol and dried to give the title compound (60 mg) as a cream solid; m.p. 285°-288° C. (decomposes); NMR Spectrum (TFA+DMSO-d6) 4.90 (2H, s), 7.14 (2H, d), 7.90 (8H, m), 8.07 (2H, d); Mass Spectrum m/Z 357 (M+H)+ ; Elemental Analysis: calculated for C17H16N4O5 : C, 53.5%; H, 4.97%; N, 14.7; found: C, 53.6%; H, 4.8%; N, 14.6%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)c3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), benzoyl chloride (47.1 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (111 mg, yield 89%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(CCO)ccc2o1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)c1cc2cc(CCO)ccc2o1
Temperature: 55 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 75 mg (0.189 mmol) (2-{[5-(2-Hydroxy-ethyl)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (58) in 3 ml THF were added 1892 μl of 4M solution of HCl in dioxane. The reaction was stirred at 55° C. for 2 h. The solvent was evaporated, ethylacetate was added and the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine and dried over Na2SO4. The solvent was removed to give 45 mg (0.152 mmol) 5-(2-Hydroxy-ethyl)-benzofuran-2-carboxylic acid (2-amino-phenyl)-amide (55); exact MW calc'd [M+H]: 297.12; MW found [M+H]: 297.1.
Reaction SMILES: NC1C=CC(C)=C(NC2O[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)C=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[NH:33][C:34](=[O:36])C.NC1C=CC(C)=C(NC(=O)C)C=1>>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[NH:33][C:34]1[O:36][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:12][N:13]=1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1C
Agent: CC(=O)Nc1cc(N)ccc1C
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Yield: 83 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(2-methyl-5-nitro-phenyl)-acetamide was used instead N-(5-Amino-2-methyl-phenyl)-acetamide. Yield=83%. m.p.>228° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[CH:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:4]([CH:3]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]1[C:1]([OH:6])=[O:11])(=[O:5])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: O=C1OC(=O)C2CCCCC12
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)C1CCCCC1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.7 %

Procedure:
In a 2.5 l sulfuration flask equipped with a mechanical stirrer, thermometer and a refrigerator, 154.17 g (0.5 mol) of hexahydrophtalic anhydride are dissolved in 800 ml of benzene. The solution is cooled in an ice bath and 133.34 g (1.1 mol) of AlCl3 are added portion wise over one hour while maintaining the temperature between 0° C. and 5° C. When the addition is complete, the ice bath is removed and the reaction mixture is stirred for 2 hours at room temperature and subsequently heated to reflux during one hour. After cooling to room temperature, the reaction mixture is poured onto a mixture of ice and water while stirring with a mechanical stirrer. The precipitated product is filtered off and washed several times with water until the pH of the wash water is neutral. The material is dried in vacuum and the remaining product dissolved in chloroform. The solution is filtered over hyflo and the volume of the filtrate reduced in vacuum. The product precipitates as an off-white solid that is filtered off, washed with additional solvent and dried in vacuum. 66 g (57% yield) of the product are obtained as a white solid with a melting point of 130-132° C. 1H-NMR analysis is in agreement with the presence of a compound possessing the cis configuration of the substituents on the cyclohexane ring.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH:15]=[C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].[Cl-].C([NH+](CC)CC)C>C(OCC)C.CN(C1C=CC=CN=1)C>[C:34]([O:26][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH:12]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:17]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: CC[NH+](CC)CC
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Yield: 84.3 %

Procedure:
To a stirred suspension of finely powdered 17-(3-pyridyl)androsta-5,16-dien-3β-ol (3.50 g, 10 mmol) in dry diethyl ether (150 ml) containing triethylamine (2.3 ml, 16 mmol) and dimethylaminopyridine (0.012 g, 0.1 mmol) was added acetyl chloride (1.0 ml, 14 mmol). The mixture was then stirred at ambient temperature for 12 h, over which time a thick white precipitate of triethylammonium chloride had formed. The mixture was then filtered and the filtrate concentrated to afford the crude product which was recrystallised firstly from ethanol/water (1:1), then finally from hexane to afford the title compound (3.30 g, 84%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@H:15]([O:29][CH2:30][CH2:31]OS(C)(=O)=O)[C@@H:16]2[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:37]([CH2:31][CH2:30][O:29][C@@H:15]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C@@H:16]1[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]1)=[N+:38]=[N-:39]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCOS(C)(=O)=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2c(F)cccc2[C@H](OCCN=[N+]=[N-])[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Temperature: 70 °C
Yield: 89.9 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-(methylsulfonyloxy)ethoxy)methyl)morpholine-4-carboxylate (554 mg, 1.0 mmol) in anhydrous DMF (18 mL), solid NaN3 (230 mg, 3.51 mmol) was added and the reaction mixture was heated to 70° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (110 mL), and water (30 ml). The organic phase was washed with water (3×30 mL), dried over Na2SO4 and evaporated to give (R)-tert-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (423 mg, 90%). MS (E/Z): 471 (M+H+)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@@H:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([CH2:21][C:22]#[N:23])[CH2:6][CH2:5]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][C@@H:4]1[CH2:9][C@@H:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([CH2:21][C:22]#[N:23])[CH2:6][CH2:5]1
Reactant: N#CC[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#CC[C@H]1CC[C@H](N)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a mixture of benzyl [(1R,2R,5S)-5-azido-2-(cyanomethyl)cyclohexyl]carbamate (45 mg, 0.14 mmol) in tetrahydrofuran (1.5 mL) was added water (13 μL, 0.73 mmol) and resin of triphenylphosphine (150 mg, 0.29 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried in vacuo to give 32 mg of crude product. LCMS calculated for C16H22N3O2 (M+H)+: m/z=288.2. Found: 288.0. The crude was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[OH:7][CH2:8][C:9](=O)[CH3:10]>[Pt](=O)=O>[OH:7][CH2:8][CH:9]([NH:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[CH3:10]
Reactant: CC(=O)CO
Reactant: CC[C@H](N)CO
Agent: O=[Pt]=O
Product: CC[C@@H](CO)NC(C)CO
Reaction time: 30.5 h
Yield: 72928.5 %

Procedure:
A mixture of (S)-2-aminobutan-1-ol (14.5 g, 0.163 mmol), 1-hydroxypropan-2-one (13.3 mL, 0.195 mmol) and platinum(IV) oxide (100 mg, 0.440 mol) were stirred under a hydrogen atmosphere (1 atm). After 30.5 h, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by distillation to give (S)-2-(1-hydroxypropan-2-ylamino)butan-1-ol (17.5 g, 74%) as a colorless oil. 1H NMR consistent.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Cl.[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Reactant: Nc1cc(CO)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: OCc1cc(Nc2nccc3nc(-c4c(Cl)cccc4Cl)sc23)ncn1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), (6-aminopyrimidin-4-yl)methanol hydrochloride salt (0.052 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (20 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.71 (s, 1H), 8.63 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 7.85-7.66 (m, 5H), 5.58 (m, 1H), 4.49 (d, J=5.5 Hz, 2H). LCMS (Method B): RT=4.84 min, m/z: 404.0 [M+H+].
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.O1CCCC1>[O:9]=[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][N:3]1[NH:2][C:18](=[O:19])[O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN1CCCNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NN1CCCNC1=O)OCc1ccccc1

Procedure:
3-Aminotetrahydro-2(1H)-pyrimidinone, monohydrochloride (30 g, 0.198 mol) was dissolved in a mixture of 240 ml water and 200 ml tetrahydrofuran. The pH was adjusted to 8.5 and benzylchloroformate (33.8 g, 0.198 mmol) was added dropwise while keeping the pH between 8 and 9. After the pH remained constant, the mixture was stirred for an additional hour. The tetrahydrofuran was removed in vacuo and the resulting crystals were filtered off with suction, triturated with ether and dried in vacuo. Yield 35.6 g, melting point 161°-163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[CH:11]=1.CI.[Mg].[C:15](=[O:17])=[O:16]>CCOCC>[CH3:10][C:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:15]([OH:17])=[O:16])=[CH:11][C:6]=2[S:7][CH:8]=1
Reactant: O=C=O
Reactant: Cc1csc2cc(Br)ccc12
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: Cc1csc2cc(C(=O)O)ccc12
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-3-methylbenzo[b]thiophene (16.8 g) and methyl iodide (23.8 g) was added dropwise to a stirred mixture of dry ether (150 ml) and magnesium (11.06 g) at such a rate that gentle reflux was maintained. When the addition was complete, the mixture was heated under reflux with stirring for 30 minutes, then cooled and poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated, 2N hydrochloric acid (100 ml) was added and the mixture was shaken. The ether layer was separated and the aqueous layer was extracted with ether. The ether solutions were combined, dried (Na2SO4) and evaporated to give a solid which was crystallized from ethyl acetate to give 3-methylbenzo[b]thiophene-6-carboxylic acid (7.71 g), m.p. 230°-232° C.
Reaction SMILES: [C:1]([N:4]1[C:8]([C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([CH2:19][CH3:20])[N:6]([C:21](=[O:23])[CH3:22])[C:5]1=[O:24])(=[O:3])[CH3:2].[S:25]([O-])([O-])(=O)=O.S(O)(O)(=O)=O.S(O)(O)(=O)=O.S(O)(O)(=O)=O.S(O)([O-])(=O)=O.[P+3]>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:8]([C:9](=[S:25])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([CH2:19][CH3:20])[N:6]([C:21](=[O:23])[CH3:22])[C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: CCc1c(C(=O)c2ccccc2OC)n(C(C)=O)c(=O)n1C(C)=O
Reactant: O=S(=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [P+3]
Solvent: Cc1ccccc1
Product: CCc1c(C(=S)c2ccccc2OC)n(C(C)=O)c(=O)n1C(C)=O

Procedure:
In 100 ml Toluene are suspended 10 g of 1,3-diacetyl-1,3-dihydro-4-ethyl-5-(2-methoxybenzoyl)-2H-imidazole-2-one and 20 g phosphorus pentasulfate. The mixture is refluxed 6 hours and the solvent evaporated to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#N.[PH2]([O-])=[O:13].[Na+].C(O)(=O)C.N1C=CC=CC=1>[Ni].O>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=[PH2][O-]
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1ccc2[nH]ccc2c1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Raney nickel (6.7 g) was added to a solution of 5-cyanoindole (Aldrich, 10.0 g) and sodium hypophosphite (20.0 g) in a mixture of water (73 ml), glac. acetic acid (73 ml) and pyridine (145 ml) at 45° C. The resulting mixture was stirred at 45° C. for 2 hours, then cooled and filtered through Hyflo. The filtrate was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, 10% aqu. citric acid, 1N aqu. HCl, water and brine, dried and evaporated in vacuo to give the desired product as a buff solid which was recrystallised from chloroform (7.5 g).
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-fluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (2.0 eq.). ESI (m/z): 331 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27]>C1COCC1.CCOCC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]3[NH:24][C:26](=[O:27])[NH:25][C:20]=3[CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C#CCCN2CCC(Cc3ccccc3)CC2)cc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(C#CCCN3CCC(Cc4ccccc4)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A mixture of 4-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-benzene-1,2-diamine (Example 70) (333 mg, 1 mmol) and carbonyl diimidazole (243 mg, 1.5 mmol) in THF (5 mL) is stirred at room temperature for 1 hr. A precipitate forms; the mixture is diluted with ether (10 mL), filtered and the solid washed with ether to give the title compound as a white powder (233 mg): mp 221-223° C.