Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2].[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:4]([CH:18]=[O:20])=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2]
Reactant: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Formylation. 3-Ethyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (94 g, 0.405 mol) was stirred with glacial acetic acid (670 mL), and hexamethylenetetramine (102.6 g, 0.73 mol) was added in one portion. The mixture was heated at 95° C. for 3 h, hot water (670 mL) added, and the heating was continued for an additional 1.5 h at 100° C. The mixture was cooled to 20° C., toluene (200 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (3×150 mL), then neutralized with 5% NaHCO3 solution, and finally washed with brine (50 mL). The solvent was evaporated and the residue distilled to give 3-ethyl-2-formyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (77.9 g), bp 127°-132° C./0.5 mm, GLC purity 98%, 1H-NMR (CDCl3) δ12.87 (1H, s), 10.20 (1 H, s), 6.72 (1H, s), 2.89 (2H, q), 1.65 (4H, m), 1.44 (6H, s), 1.30 (3H, t), 1.29 (6H, s). 13C-NMR (CDCl3) δ194.3 (1C, d), 163.6 (1C, s), 156.7 (1C, s), 144.6 (1C, s), 130.8 (1C, s), 118.5 (1C, d), 115.2 (1C, s), 37.7 (1C, t), 35.5 (1C, s), 34.7 (1C, t), 34.0 (1C, s), 31.1 (2C, q), 27.7 (2C, q), 24.8 (1C, t), 16.9 (1C, q). IR (KBr) 1609 cm-1MS (m/e) 260.3 (M+, 22.6), 245.2 (100.0), 203.3 (18.2), 246.2 (17.0).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-:32].[K+].[K+].O>CN(C)C=O>[OH:32][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCO
Temperature: 60 °C
Reaction time: 120 h
Yield: 5.7 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (363 mg) and water (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. for 5 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]#[N:18]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
Mix 4-bromophenol (1.4 mmol) in acetonitrile (5 ml) and water (2 ml), add K2CO3 (3 mmol) and bromoacetonitrile (1.5 mmol) at room temperature under inert atmosphere. Heat the mixture to 80° C. for 16 h. Analyze by LC/MS for final product. Evaporate the solvent and add water. Extract product with DCM (3×) and combine and evaporate organic phases to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][C:24]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:38]2[CH2:37][CH2:36][N:35]([C:24]3[CH:25]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:40][CH2:39]2)=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1ccc(-c2ccccc2)cc1N1CCNCC1
Reactant: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2cc(-c3ccccc3)ccc2OC)CC1
Yield: 91 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and 1-(2-methoxy-5-phenylphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:37]=[C:38]=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:38]([NH:37][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCCCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 125 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-octyl isocyanate (1.55 g; 10 mmole). Recrystallization from methanol/ethanol/water provided the title compound (3.1 g; 62% yield) as colorless crystals, m.p. 229°-230° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([C:18]([NH2:20])=[O:19])[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([N+:15]([O-:17])=[O:16])=[C:12]([C:18]([NH2:20])=[O:19])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-Acetylphenyl)-2-nitrothiophene-3-carboxamide (0.21 g, 0.723 mmol) was taken up in MeOH (4 mL), followed by the addition of sodium borohydride (0.027 g, 0.723 mmol). The reaction mixture stirred at room temperature for 3 hours. Water was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)C>CO>[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:12]1[CH2:13][CH2:14][CH2:15][C:11]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:30])=[O:3])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cccc(C2=C(c3ccccc3OCc3ccccc3)CCC2)c1
Solvent: CO
Product: O=C(O)c1cccc(C2=C(c3ccccc3OCc3ccccc3)CCC2)c1

Procedure:
3-[2-(2-Benzyloxyphenyl)-cyclopent-1-enyl] benzoic acid ethyl ester (120 mg) was refluxed for 1 h in methanol/2N sodium hydroxide (10/10 mL). The reaction mixture was then evaporated down to 3 mL on a rotary evaporator. 2N Hydrochloric acid was added. The product was extracted with dichloromethane (2×10 mL), dried over magnesium sulphate and evaporated down to an oil which solidified on standing (wt: 100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]2[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C3CCCCO3)=[O:25])=[N:20][CH:21]=2)[CH2:11]1.[ClH:34]>CCO>[ClH:1].[ClH:34].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]2[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[N:20][CH:21]=2)[CH2:11]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCc3ccccc3Cl)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCc3ccccc3Cl)C2)cn1)NO
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-[5-({(3R)-1-[2-(2-chlorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (95 mg) in EtOH (1 mL) was added a 2N—HCl solution in EtOH (0.5 mL) and the mixture was stirred at 20-25° C. for 2 hours. After removal of EtOH by evaporation, IPE (2 mL) was added to the mixture to give a solid. The solid was collected by filtration and dried under reduced pressure to give (2E)-3-[5-({(3R)-1-[2-(2-chlorophenyl)ethyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamide dihydrochloride (86 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])=[N:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[O:32][CH3:33])=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])=[N:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[O:32][CH3:33]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
7-(3-(N-tert-butoxycarbonylamino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (610 mg, 1.28 mmol) was added slowly to TFA (10 ml). The reaction was stirred at ambient temperature for 2 hours and the volatiles were removed by evaporation and by azeotroping with toluene to give 7-(3-aminopropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline trifluoroacetate (455 mg, 94%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([CH:22]=[C:23]([C:32]#[N:33])[C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.[C-:34]#[N:35].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([C:22]([C:34]#[N:35])=[C:23]([C:32]#[N:33])[C:24]4[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=4)=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-n2c3ccccc3c3cc(C=C(C#N)c4cc(F)cc(F)c4)ccc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)c4cc(F)cc(F)c4)ccc32)cc1
Reaction time: 0.17 h

Procedure:
0.50 g (1.15 mmol) of N-(4-methoxyphenyl)-3-(2-cyano-2-(3,5-difluorophenyl)ethenyl) carbazole and 5 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.06 g (1.15 mmol) of sodium cyanide and 0.5 ml of water, which was stirred for 10 minutes. Further, 0.51 g (1.15 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 20 ml of chloroform was added. To the resultant solution was added 20 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a vermilion solid. The vermilion solid was recrystallized in the presence of ethanol to obtain 0.10 g of a vermilion crystal. The yield of the synthesized orange crystal was 19%, and its melting point was 140-142° C. The IR chart is shown in FIG. 23.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(=O)O[CH2:13][CH2:12][O:11]1.[H-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH2:13][CH2:12][OH:11]
Reactant: Oc1cc(F)cc(F)c1
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: OCCOc1cc(F)cc(F)c1

Procedure:
In a sealed Pyrex tube, a mixture of 3,5-difluorophenol (2.19 g, 16.8 mmol), ethylene carbonate (1.0 g, 11.4 mmol), a catalytic amount of NaH (60% in mineral oil) in DMF (1 mL) was reacted in a Labwell MW-10 microwave reactor at 50W for 3 min. The reaction mixture was diluted with toluene and washed with 5% aqueous NaOH. The organic phase was dried (MgSO4) and concentrated. This gave 1.59 g (80%) of the title compound as a light red oil. MS m/z 174 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1oc2cc(OCc3ccccc3)ccc2c(=O)c1-c1ccccc1

Procedure:
10 g of 7-hydroxy-2-methyl-isoflavone, 10 g of anhydrous potassium carbonate, 1 g of potassium iodide and 12.5 g of benzyl chloride are boiled in 200 ml of anhydrous acetone for 2 hours with stirring, under a reflux condenser. On subjecting the mixture to steam distillation, the crude product precipitating from the water is filtered, dried, and recrystallized from a mixture of 100 ml of methanol and 40 ml of acetone, affording white needle crystals of 7-benzyloxy-2-methyl-isoflavone, m.p. 139°-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.CN(C)C.S(Cl)(C)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1(O)CCOCC1
Agent: CN(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cnc1C1=CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.8 %

Procedure:
4-(5-Bromo-3-methylpyridin-2-yl)-tetrahydro-2H-pyran-4-ol (2.95 g), triethylamine (3 ml) and trimethylamine monohydrochloride (103 mg) were suspended in toluene (50 ml), mesyl chloride (1.26 ml) was added thereto under ice-cooling, then warmed to room temperature, and stirred for 72 hours. After completion of the reaction, water was added thereto, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (2.39 g) as a white solid. MS (ESI) m/z: 254, 256 (M+H)+.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]1[CH2:16][CH2:15]N2C(=NCCC2)[CH2:8][CH2:7]1.BrCCCCCBr>CN(C=O)C>[C:2]1([C:1]#[N:5])([C:3]#[N:4])[CH2:15][CH2:16][CH2:6][CH2:7][CH2:8]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: N#CCC#N
Agent: BrCCCCCBr
Solvent: CN(C)C=O
Product: N#CC1(C#N)CCCCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Malononitril (15.0 g) was dissolved in dry DMF (200 mL). Subsequently, DBU (75 mL) and 1,5-dibromopentane (34 mL) were added at 0° C. (ice bath). The ice bath was removed and the reaction was stirred for 2 h at 80° C. After cooling down, the reaction was poured into DCM. The organic layer was washed several times with 5% NaHCO3, the organic layer dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with PA:EtOAc (9:1) yielding 25.7 g white crystals. 1H NMR (400 MHz, CDCl3) δ 1.48-1.61 (m, 2H), 1.68-1.84 (m, 4H), 2.13 (t, J=6 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N:11]=O>C(O)C.ClCCl.[Pd]>[NH2:11][C:3]1[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH2:1]
Reactant: Cc1nn(CCO)c(N)c1N=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1nn(CCO)c(N)c1N
Reaction time: 2 h
Yield: 96.6 %

Procedure:
5-Amino-1-(2-hydroxyethyl)-3-methyl-4-nitrosopyrazole (0.9 g, 5.3 mmole) was dissolved in a mixture of ethanol (40 ml) and dichloromethane (40 ml) and hydrogenated over 10% Pd/C (0.1 g) at 20 p.s.i. and 20° C. for 2 hours. The catalyst was filtered onto Arbocel and the solvent removed under reduced pressure yielding the title compound as a foam (800 mg, 97%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]#[N:16])[CH:9]=1.N1CCCCC1>CO>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[CH:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:15]#[N:16])[CH:9]=1
Reactant: N#CCc1cccnc1
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=Cc1ccc[nH]1)c1cccnc1
Yield: 47.8 %

Procedure:
A mixture of pyrrole-2-carboxaldehyde (2.85 g; 30 mmol), 3-pyridylacetonitrile (3.54 g; 30 mmol), and piperidine (2 mL) in methanol (50 mL) was refluxed for 18 hours. The dark precipitate formed was separated by filtration. Dark solid was treated with charcoal in hot methanol to obtain 2.8 g (48%) of the title compound as a yellow solid, m.p. 139°-142° C. Anal. Calcd. for C12H9N3 : C, 73.83; H, 4.65; N, 21.52. Found: C, 73.71; H, 4.57; N, 21.76. Mass spectrum: (EI; M+) m/z 195. 1H-NMR (DMSO-d6 ; 200 MHz) δ 11.5 (s, 1H), 8.8 (d, 1H), 8.5 (d, 1H), 7.92-7.96 (m, 1H), 7.8 (s, 1H), 7.43-7.52 (m, 1H), 7.2 (d, 2H), 6.38-6.4 ppm (q, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:5][C:6]2[C:11]([CH2:12][CH:13]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[N:14]=[C:15]=S)[CH3:2].[N:17]([CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:22])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH2:5][C:6]2[C:7]([NH:14][C:15]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=4)=[CH:20][N:17]=3)=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH:13]=1)[CH3:2]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC1=CCc2cccc(N=C=S)c2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
A solution of the product of Example 1F (398 mg, 1.72 mmol), the product of Example 1G (473 mg, 2.07 mmol), and triphenyl phosphine (542 mg, 2.07 mmol) in dioxane (9 mL) was heated at 85° C. for 30 min. The solution was cooled to room temperature and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate-hexane to afford the title compound as a yellow solid (150 mg, 22%). 1H NMR (DMSO-d6) δ 9.38 (s, 1H), 7.76 (m, 4H), 7.65 (d, 1H, J=8.5 Hz), 7.62 (s, 1H), 7.18 (t, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.4 Hz), 4.85 (m, 1H), 3.79 (q, 2H, J=6.7 Hz), 3.49 (m, 2H), 3.36 (m, 2H), 1.26 (t, 3H, J=6.8 Hz); MS (ESI+) m/z 401 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]>>[Cl:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Product: CCOC(=O)c1sc(NS(=O)(=O)c2cc(-c3cc(F)ccc3F)c(Cl)s2)nc1C
Yield: 20 %

Procedure:
The product was prepared from ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (9 mg, 0.050 mmol) and 5-chloro-4-(2,5-difluorophenyl)thiophene-2-sulfonyl chloride (Intermediate 20) (17 mg, 0.050 mmol) according to the General Procedure 9, described in Example 123, using a slightly modified reaction temperature of 60° C. and a reaction time of one week. The title compound was obtained in 20% yield (4.7 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.36 (t, J=7.11 Hz, 3 H) 2.62 (s, 3 H) 4.32 (q, J=7.11 Hz, 2 H) 7.05-7.11 (m, 1 H) 7.13 (td, J=9.02, 4.63 Hz, 1 H) 7.16 (ddd, J=8.55, 5.62, 3.07 Hz, 1 H) 7.60 (d, J=1.83 Hz, 1 H). MS (ESI+) m/z 479 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:18]=[N:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:26]([Mg]Br)=[CH2:27].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH:26]=[CH2:27])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)S(=O)N=CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(NS(=O)C(C)(C)C)C1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
Under argon, 2.00 g (5.44 mmol) of 2-methyl-propane-2-sulfinic acid 8-(4-fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylmethyleneamide (105) were dissolved in 27 mL of absolute tetrahydrofuran. Then, 5.99 mL (5.99 mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were added dropwise at 0° C. and the reaction mixture was stirred for 17 h at room temperature. Another 3 mL (3.00 mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were added and the mixture stirred for 20 h at room temperature. The reaction mixture was cooled to 0° C. and 15 mL of saturated aqueous sodium sulphate solution were added. The suspension was filtered over celite, the organic layer was dried over magnesium sulphate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to yield 1.09 g of (106). Rt=0.96 min (Method 18). Detected mass: 396.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])=[CH:18][CH:17]=[C:16]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:28][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:16]([F:27])=[CH:17][CH:18]=[C:19]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(Br)c3c2)c1F
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
2,6-Difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.500 g, 1.268 mmol) was charged to a 100 mL round-bottom flask. CHCl3 (25 mL) was added to form a slurry. N-Bromosuccinimide (0.271 g, 1.52 mmol) was added and stirred for 20 minutes. The reaction mixture was filtered, washed with DCM, and dried under vacuum providing N-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.427 g, 71.2%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 12.12 (br s, 1H), 11.04 (s, 1H), 9.81 (br s, 1H), 8.41-8.43 (m, 1H), 8.34-8.35 (m, 1H), 7.74-7.76 (m, 1H), 7.53-7.59 (m, 1H), 7.25-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=473.0, 475.0.