Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]([CH3:20])[N:12]=2)=[CH:7][CH:6]=1>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:15]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)=[N:12][N:13]([CH3:20])[C:14]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: II
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nn1C
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1c(I)c(-c2ccc(OC)cc2)nn1C
Reaction time: 4 h

Procedure:
Silver sulfate (640 mg, 2.053 mmol) and iodine (0.106 mL, 2.053 mmol) were added successively to a solution of methyl 3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate (405.8 mg, 1.648 mmol) in EtOH (20.0 mL) at 25° C. and the reaction was stirred vigorously for 4 h. The reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (20 mL) and washed with satd Na2SO3 (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl 4-iodo-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate, as a colorless solid. Rf=0.33 (20% EtOAc/hexanes). LCMS calc.=373.01. found=372.89 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.68 (d, J=8.6 Hz, 2H); 6.97 (d, J=8.6 Hz, 2H); 4.22 (s, 3H); 3.96 (s, 3H); 3.85 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2]/[C:3](/[CH3:29])=[CH:4]/[C:5]1[CH:26]=[C:25]([F:27])[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:7]([F:28])[CH:6]=1.Cl.[N:31]1([CH:36](N)[NH2:37])C=CC=N1>C1COCC1>[F:28][C:7]1[CH:6]=[C:5](/[CH:4]=[C:3](\[CH3:29])/[CH2:2][NH:1][C:36]([NH2:37])=[NH:31])[CH:26]=[C:25]([F:27])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: NC(N)n1cccn1
Reactant: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCN(C)C)cc2)c(F)c1)CN
Agent: Cl
Solvent: C1CCOC1
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCN(C)C)cc2)c(F)c1)CNC(=N)N
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To a solution of (E)-4-(4-(3-amino-2-methylprop-1-enyl)-2,6-difluorophenoxy)-N-(2-(dimethylamino)ethyl)benzenesulfonamide (Intermediate 93.4, 39.3 mg, 0.092 mmol) in dry THF (460 uL, 0.2M) under N2 was added TEA (0.276 mmol, 27.9 mg) and (1H-pyrazol-1-yl)methanediamine hydrochloride (0.102 mmol, 14.9 mg). The resulting solution was stirred for 1 hour, at which point LCMS indicated complete conversion. The solvent was removed and the resulting residue brought up in 1:1 ACN:water and purified by preparative HPLC to give 16.9 mg of the title compound (26%) as a TFA salt. 1H-NMR (400 MHz, CD4OD): δ 7.87 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 3.92 (s, 2H), 3.62 (m, 2H), 3.29 (m, 2H), 3.17 (t, 2H), 2.01 (s, 6H), 1.91 (s, 3H). MS (m/z): 468.12 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=2[NH:10][C:9]1=[O:29])(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:7][C@@H:8]1[C:9](=[O:29])[NH:10][C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=2[N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the [(S)-1-(2-benzyloxy-ethyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with hydrochlorid acid (37%) in dioxane yielded the title compound as a light yellow foam; MS (m/e): 312 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:4]([O:3][CH2:1][CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: BrBr
Reactant: CCOc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4′-[(2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (6.15 g) and sodium acetate (1.46 g) in acetic acid (100 mL) was added bromine (0.91 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (7.12 g, 94%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@@H:13]1[O:18][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C=O>[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@@H:13]1[O:18][C@@H:17]([CH2:19][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3c(Cl)cccc3Cl)O2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1CO[C@H]1CCC[C@H](Cn2ccnc2)O1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
196 mg of 55% sodium hydride were added to a solution of 306 mg of imidazole in 14 ml of dimethylformamide and the mixture was stirred at 80° C. for 30 minutes. The mixture was then cooled to room temperature, after which 1.335 g of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran and 450 mg of sodium iodide were added thereto; the mixture was then stirred at 80°-85° C. for 2 hours. At the end of this time, the mixture was treated and purified essentially as described in Example 1(b), to give 965 mg of the title compound in the form of a colourless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[CH:5][C:4]=1[O:17][CH3:18])=[O:2].[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[C:4]([O:17][CH3:18])[CH:5]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Product: COc1cc(-c2ccc(O)cc2)ccc1C=O

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 4-formyl-3-methoxy-phenyl ester (11.0 mmol) with 4-tert-butyl-dimethylsilyoxyphenyl-boronic acid (3.50 g, 13.86 mmol) according to Method B to yield 880 mg (35%, over two steps) of yellowish solid: mp 159-161° C.; 1H NMR (DMDO-d6): δ 4.01 (3H, s), 6.89 (2H, d, J=8.62 Hz), 7.31 (1H, d, J=8.16 Hz), 7.36 (1H, d, J=1.15 Hz), 7.66 (2H, d, J=8.63 Hz), 7.72 (1H, d, J=8.09 Hz), 9.80 (1H, s), 10.34 (1H, s); mp 159-161° C.; IR 1660 cm−1; MS (ESI) m/z 227 (M−H)−, 229 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=1)=[O:7]
Reactant: Nc1cccc(-c2ccccn2)c1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1I
Temperature: 25 °C
Reaction time: 264 h

Procedure:
3-Iodo-4-methylbenzoic acid (154 mg, 0.59 mmol) was heated at 80° C. in thionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (3 ml), 2-(3-aminophenyl)pyridine (100 mg, 0.59 mmol) and sodium carbonate (400 mg) were added to the solution. The reaction was stirred at room temperature for 11 days, filtered and the filtrate reduced to dryness under vacuum. The residue was dissolved in ether and filtered through a bond-elut (1 g, silica), washing with ether. The solvent was evaporated from the combined filtrate and washings to give 3-iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide as a cream foam. NMR: δH CDCl3 8.70,(1H, dt), 8.33,(1H, d), 8.18,(1H, t), 7.93–7.89,(2H, m), 7.79–7.75, (4H, m), 7.50,(1H, t), 7.35,(1H, d), 7.26,(1H, m), 2.51,(3H, s).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.CO.[OH-].[Na+].Cl>O>[F:29][C:28]([F:30])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[OH:9])=[O:32])=[CH:23][CH:24]=1
Reactant: O=C(NCCCOc1ccccc1OC(=O)c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCCCOc1ccccc1O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a mixture of 0.87 g of 3-ethyl-5-methyl-4-(3-(4-(trifluoromethyl)benzamido)propyloxyphenyl benzoate and 10 ml of methanol was added a mixture of 0.16 g of sodium hydroxide and 2 m of water, while stirring at 0° C. After stirring at room temperature for 24 hours, the reaction mixture was made weak acidic by the addition of 10% hydrochloric acid, and extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.66 g of 3-ethyl-5-methyl-4-(3-(4-(trifluoromethyl)benzamido)propyloxyphenol (94% yield).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:28])[CH:6]([NH:15][C:16]([CH3:27])=[CH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:29][CH2:30][CH2:31]Br>C(O)C>[CH3:3][O:4][C:5](=[O:28])[CH:6]([NH:15][C:16]([CH3:27])=[CH:17][C:18](=[O:26])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:31][CH2:30][Br:29])=[CH:12][CH:13]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccc(F)cc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1ccc(F)cc1
Yield: 27 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[1-methyl-3-oxo-3-(4-fluorophenyl)-propenylamino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.05 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.37 g, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH2:23])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:30]1=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C[C@H](CCc1ccccc1)Nc1cc(C)ccc1N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)[nH]c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of (S)-3-(2-Amino-5-methyl-phenylamino)-5-phenyl-pentanoic acid ethyl ester (0.84 g, 2.6 mmol) in THF (15 mL) was added CDI (0.50 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.75 g of the desired product as a dark brown solid. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH:26]2[CH2:28][CH2:27]2)[N:22]=1.O>CN(C)C=O>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:20][C:21]2[O:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[N:22]=2)=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: ClCc1nc(C2CC2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Oc1ccc(OCc2nc(C3CC3)no2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
5 g of 4-(sec-butyloxy)-phenol and 6.2 g of potassium carbonate are stirred in 50 ml of anhydrous dimethylformamide for 1 hour at 80° C. Subsequently, 4.8 g of 5-chloromethyl-3-cyclopropyl-1,2,4-oxadiazole in 20 ml anhydrous dimethylformamide is dripped in and the mixture stirred for 8 hours at 80° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 100 ml of water and extracted three times with ethyl acetate, and the organic phases are dried over magnesium sulfate. The solvent is evaporated off and the crude product is purified by chromatography on silica gel using n-hexane/ethyl acetate (4:1) as eluant. There is obtained 6.7 g of 5-[4-(sec-butyloxy)-phenoxymethyl]-3-cyclopropyl-1,2,4-oxadiazole as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][CH2:5][CH:6]([OH:31])[CH2:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1.[N:37]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:36]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:3]([O:4][CH2:5][C@@H:6]([OH:31])[CH2:7][NH:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[N:20]=4)=[CH:13][CH:12]=3)[C:2]=2[N:1]=[N:37]1
Reactant: O=N[O-]
Reactant: Cc1ccc(-c2noc(CSc3ccc(CCNCC(O)COc4cccc(N)c4N)cc3)n2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2noc(CSc3ccc(CCNC[C@H](O)COc4cccc5[nH]nnc45)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of 1-(2,3-diaminophenoxy)-3-[[2-[4-[[[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]thio]phenyl]ethyl]amino]-2-propanol (0.077 g, 0.172 mmol.) in acetic acid (1.2 mL) at 5° C. was added a solution of sodium nitrite (0.013 g, 0.189 mmol) in water (0.5 mL). The mixture was stirred for 30 minutes and evaporated to dryness. The residue was purified by flash chromatography (silica gel; CH2Cl2/MeOH (3/1) to afford 0.079 g of the pure title compound. MP=110° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=S)[NH:9][C:10]=2[CH:11]=1.[NH3:16]>>[NH2:16][C:8]1[CH:7]2[CH2:13][CH2:14][CH2:15][CH:6]2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[N:9]=1
Reactant: N
Reactant: Cc1ccc2c(c1)NC(=S)C1CCCC21
Product: Cc1ccc2c(c1)N=C(N)C1CCCC21
Yield: 99 %

Procedure:
In a way that is similar to Example 4, 7-methyl-1,2,3,3a,5,9b-hexahy drocyclopenta[c]quinoline-4-thione (230 mg, 1.05 mmol) in 7N methanolic ammonia solution (25 ml) is reacted to form 210 mg (99%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][CH:16]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 35 h

Procedure:
50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol is mixed with 50 ml of 4-fluoroaniline and stirred for 35 hours at 60° C. After concentration by evaporation to half the volume, water and dichloromethane are divided up. After the organic phase is washed with 1N aqueous hydrochloric acid, it is dried on sodium sulfate, filtered and concentrated by evaporation. After chromatography on silica gel, 62.33 g (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine is obtained.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([OH:38])=O)=[CH:31][CH:30]=2.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([NH:2][CH3:1])=[O:38])=[CH:31][CH:30]=2
Reactant: O=C(O)c1ccc2cnc(Cl)cc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2cnc(Cl)cc2c1
Reaction time: 18 h
Yield: 60.4 %

Procedure:
HATU (17.6 mg, 0.046 mmol) was added to a solution of 3-chloroisoquinoline-6-carboxylic acid (Preparation 54, 8 mg, 0.039 mmol), DIPEA (54 uL, 0.31 mmol) and methanamine hydrochloride (15.6 mg, 0.231 mmol) in DMF (4 mL) and the reaction was stirred for 18 hours. The reaction was partitioned between EtOAc and brine, the separated organic phase was washed with saturated NaHCO3 solution, citric acid and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as yellow oil (5.2 mg, 61%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:27]>O1CCOCC1>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:27])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: N
Solvent: C1COCCO1
Product: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(N)ncnc2s1
Yield: 78 %

Procedure:
6-[4-(3-iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (200 mg) and concentrated aqueous ammonia (5 mL) was stirred in 1,4-dioxane (15 mL) for 17 hours. The solvent was evaporated and the residue purified by chromatography on silica eluting with a gradient of 0-50% EtOAc/DCM then 0-20% MeOH/DCM to give the title compound as a colourless solid (136 mg, 78%);
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:18]([Cl:17])=[O:20])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)Cl)CC1
Temperature: 0 °C

Procedure:
To solution of methyl piperazine (166 uL, 1.50 mmol) In anhydrous dichloromethane (2 mL), diisopropyl ethyl amine (300 uL, 1.72 mmol) was added. The reaction was cooled to 0° C. under N2. Triphosgene (240 mg, 0.809 mmol) was added and the reaction was allowed to warm to rt. The chloride was used immediately without purification.
Reaction SMILES: [OH-].[K+].[CH3:3][NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].C(O)[CH2:18][OH:19]>>[OH:19][CH2:18][CH2:12][O:11][C:9]1[CH:10]=[C:5]([NH:4][CH3:3])[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][C:8]=1[OH:13]
Reactant: CNc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Product: CNc1cc(OCCO)c(O)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
0.06 mol (3.9 g) of 85% pure potassium hydroxide pellets is dissolved in 60 ml of ethylene glycol on a boiling water bath. 0.03 mol (5.9 g) of 2-methylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 3, is added with stirring in the course of 5 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6](=[O:8])[CH:7]=1.IC.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:11])[C:6](=[O:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Cl)cn[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)cc1=O

Procedure:
A solution of 4-chloro-1H-pyridazin-6-one (6.000 mmol; 783.2 mg), Iodomethane (7.200 mmol; 1032 mg; 0.453 mL), and potassium carbonate (9.000 mmol; 1256 mg) in DMF (12 mL) was stirred at room temperature overnight. The mixture was filtered. The filtrate was partitioned between EtOAc and water. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 40% EtOAc in DCM to afford 5-chloro-2-methyl-pyridazin-3-one as an off-white solid (514.7, 59%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: O=Cc1cccnc1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1cccnc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with nicotinaldehyde (0.5 g, 4.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.102 g, 84%).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:17])=[O:16])[CH3:2]>CO.[Pd]>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:16])=[O:17])[CH3:34]
Reactant: CCN(CC)CCC/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCCCc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Yield: 81 %

Procedure:
A 1:1.2 mixture of Example 595C and Example 596A (408 mg, 0.84 mmol) was hydrogenated over 120 mg of 10% Pd/C in 16 mL of methanol for 1 hour. The reaction mixture was filtered through diatomaceous earth (Celite®), and concentrated to provide 332 mg (81%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.14 Hz, 6H) 1.42 (m, 2H) 1.67 (m, 8H) 2.62 (m, 2H) 2.72 (m, 8H) 2.88 (m, 2H) 3.75 (s, 3H) 7.03 (d, J=8.51 Hz, 1H) 7.18 (d, J=8.37 Hz, 1H) 7.22 (m, 1H) 7.29 (dd, J=7.75, 1.17 Hz, 1H) 7.44 (td, J=7.48, 1.37 Hz, 1H) 7.84 (dd, J=7.96, 1.37 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1.C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:11][CH:10]=2)[S:3]1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)s2)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(CC3SC(=O)NC3=O)s2)c1
Reaction time: 72 h
Yield: 18.5 %

Procedure:
1 g (2.5 mmol) of tert-butyl {3-[5-(2,4-dioxothiazolidin-5-ylidenemethyl)thiophen-2-yl]benzyl}methylcarbamate is placed in 20 ml of dioxane and 0.2 ml of acetic acid. The reaction medium is degassed and placed under 3 atm of hydrogen for 3 days. After filtration through Celite, 0.2 g (20%) of tert-butyl {3-[5-(2,4-dioxothiazolidin-5-ylmethyl)thiophen-2-yl]benzyl}methylcarbamate is obtained.