Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[NH:23][CH:27]=[CH:26]4)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]ccc4c3O2)cc1

Procedure:
A mixture of 3.75 g (9.2 mmole) of [(2R)-7-nitro-8-(2-oxoethyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate and 3.0 g of platinum oxide in 50 mL of ethyl acetate was treated with 45 psi of hydrogen on a Parr hydrogenation apparatus for 6 hours. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on silica gel with first 10% hexane/methylene chloride, then 1% methanol/methylene chloride and finally 2% methanol/methylene chloride to give 1.50 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 145° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](Cl)=[O:33]>>[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:33]
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Product: O=C(CCNC(=O)c1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylcarbonyl)amino]-1-oxopropyl]hydrazide (31) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared in the manner described above in Example 9, and 2-furoyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.37 g (43%) of product. Analysis calculated for C22H19N4O5Cl (M.W. 454.87): C, 49.26; H, 4.36; N, I2.77; Cl, 7.79. Found: C, 49.05; H, 4.40; N, 12.66; cl, 7.58.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].I[C:31]1[CH:32]=[N:33][N:34]([C@H:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:31]3[CH:32]=[N:33][N:34]([C@H:36]4[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]4)[CH:35]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
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: O
Solvent: C1COCCO1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](O)CC4)c3)cc12

Procedure:
A mixture of 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60.0 mg, 0.138 mmol), trans-4-(4-iodo-pyrazol-1-yl)cyclohexanol (52.4 mg, 0.179 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol), potassium carbonate (57.2 mg, 0.414 mmol) and 4:1 dioxane:water (7 mL) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel, extracting with DCM and sat. NaHCO3 solution. The organic layer was dry-loaded onto silica gel, and column chromatography was used to purify, eluting with 3-4% (7N NH3 in MeOH)/DCM. The resulting solid was triturated with MeOH to give the title compound. 1H NMR (400 MHz, CD3OD): δ=1.47-1.59 (m, 2 H), 1.88 (d, J=6.8 Hz, 3 H), 1.90-2.03 (m, 2H), 2.10-2.22 (m, 4 H), 3.66 (tt, J=10.9, 4.2 Hz, 1 H), 4.17 (tt, J=11.6, 4.0 Hz, 1 H), 5.27 (q, J=7.0 Hz, 1 H), 7.18 (dd, J=8.4, 8.8 Hz, 1 H), 7.38 (d, J=1.3 Hz, 1 H), 7.44 (d, J=2.0 Hz, 1 H), 7.46 (br. s., 1 H), 7.54 (d, J=0.8 Hz, 1 H), 7.87 (d, J=0.8 Hz, 1 H), 8.32 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 473.01/475.04 (100/70) [MH+]. HPLC: tR=3.36 min (ZQ3, polar—5 min). This material was redissolved in DCM. 2.0 M of HCl in Et2O (0.8 mL) was added at rt and stirred for 20 min. The mixture was concentrated in vacuo to afford the title compound as an HCl salt.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1ccc(I)cc1C(=O)O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
Reflux 2-amino-5-iodo-benzoic acid (Aldrich; 10 g, 38 mmol) in formamide (30 mL) at 120° C. for 18 h. Upon cooling to room temperature, the product is crystallized from the solvent. The product is collected via filtration and the resulting crystals are washed with ether providing the desired 9.2 g (89%) of the titled compound as a pale solid. MS ES+ m/e 273.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1([CH2:32]O)[CH2:31][O:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC1(CO)COC1
Product: CC1(COc2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)COC1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and (3-methyl-oxetan-3-yl)-methanol in analogy to Example 9c): MS (ISN): 478.1 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: C1COCCO1
Reactant: O=C1Cc2cc(Oc3ccc(Cl)cc3)ccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)cc2)cc1CC(=O)[O-]

Procedure:
A mixture of 2-oxo-5-(4-chlorophenoxy)indoline (4.2 g.), sodium hydroxide (2.6 g.), dioxane (20 ml.) and water (40 ml.) was refluxed under heating for 5 days with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in water (50 ml.) and filtered. The filtrate was washed with diethyl ether and evaporated. The residue was dissolved in ethyl acetate (200 ml.) under warming and filtered. The filtrate was cooled, and the precipitating crystals were collected by filtration, washed with ethyl acetate and then recrystallized from a mixture of ethanol and ethyl acetate to give the captioned compound (3.4 g.). mp 206° to 209° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:25][OH:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:43](O)(=[O:45])[CH3:44].C(=O)([O-])O.[Na+]>O1CCCC1.O>[C:43]([O:26][CH2:25][C:10]1[C:11]2[C:12](=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:27])(=[O:45])[CH3:44]
Reactant: Cc1c(CO)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccccc3)nncc12

Procedure:
A solution of 1.65 g (4.59 mmol) of 1-benzyl-7-benzyloxy-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 3.8 g (18.6 mmol) of dicyclohexylcarbodiimide and 1.6 ml (27.4 mmol) of glacial acetic acid in 50 ml of anhydrous tetrahydrofuran is stirred at room temperature for 18 h. The solution is then treated with 50 ml of water, rendered neutral with saturated sodiumhydrogen carbonate solution and extracted with 3×50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: ethyl acetate). After crystallization from diisopropyl ether, 1.3 g (71%) of the title compound are isolated. M.p.: 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][OH:25])=[CH:21][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenylethanol and DBU in dioxane. ES-MS m/e (%): 362 (M{81Br}+H+, 96), 360 (M{79Br}+H+, 100), 258 ([M{81Br}+H-PhCH═CH2]+, 55), 256 ([M{81Br}+H-PhCH═CH2]+, 52).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[CH2:8][CH2:7][CH:6]=2>[Pd].C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C2=c3cc(O)ccc3=CCC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3ccc(O)cc23)CC1
Yield: 34.7 %

Procedure:
10% Palladium on carbon (1.16 g) and 7-hydroxy-1-(4-methyl-1-piperazinyl)-2,3-dihydronaphthalene (1.48 g, 6.06 mmol) were slurried in toluene (100 mL) and refluxed 16.5 h. The mixture was cooled, filtered, and concentrated. The product was purified by flash chromatography on silica gel (1×6 inches). Elution with 50% ethyl acetate/hexane followed by 100% ethyl acetate gave 0.51 g (34%) of the title product as a light pink foam. A sample was recrystallized from ether to give a cream colored solid for analysis: mp 184-185° C. Analysis calculated for C15H18N2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.05; H, 7.03; N, 11.42.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12](S(C)(=O)=O)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24]>>[C:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=4)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1C(=O)N(c2ccccc2)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2ccccc2)C3)cc1
Temperature: 175 °C
Yield: 10.1 %

Procedure:
A mixture of 100 mg (0.31 mmol) of 3-phenyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 170-180° C. for 10 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residual solid was purified by crystallisation from cyclohexane/ethyl acetate to give 14 mg (10%) of 3-phenyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 141-144° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=1.C(C1NC=CN=1)([C:29]1[NH:30]C=CN=1)=O.CN>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([NH:30][CH3:29])=[O:25])[CH:16]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1c(C(=O)c2cccc(OCC(=O)O)c2)cnn1-c1ccc(F)cc1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of 5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (0.5 g, 1.43 mmol) in tetrahydrofuran (10 ml) was added carbonyl diimidazole (0.3 g, 1.85 mmol) and the reaction mixture was heated at 60° C. After 1 h, methylamine (10 ml, 5 mmol, 0.5 M solution in tetrahydrofuran) was added and reaction was continued at 60° C. overnight. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient: 20-30% acetone/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonyl-methyloxy)benzoyl]pyrazole (0.25 g, mpt. 195.6-196.3° C.) as a solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[Cl:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][N:23]=[C:24]1[C:28]2([CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)[CH2:27][NH:26][CH2:25]1.C(#N)C>C(N(CC)CC)C>[C:35]([O:34][C:32]([N:30]1[CH2:31][C:28]2([C:24](=[N:23][O:22][CH3:21])[CH2:25][N:26]([C:11]3[C:12]([Cl:14])=[C:13]4[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:16])[CH2:27]2)[CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 4 h
Yield: 31.6 %

Procedure:
300 mg of 1cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 530 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2 g of Amberlite® IRA-420 were added to 10 ml of acetonitrile and thereto 1 ml of triethylamine was added by dropping. The resulting mixture was refluxed for 72 hours and then the resulting solid was filtered off. The filtrate was concentrated under the reduced pressure and thereto 10 ml of ethylacetate was added and the resulting solution was stirred for 4 hours. The precipitated solid was filtered and dried to give 169 mg of the titled compound(yield: 31.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1nsc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3snc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of {3-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester obtained from method 31 alternative procedure above in chloroform (300 ml), diisopropylethylamine (6 g, 46.5 mmol) was added and the reaction mixture was heated to 60° C. To the hot solution a solution of the p-toluoyl chloride (3.78 g, 24.4 mmol) in chloroform (150 ml) was added dropwise and the resulting solution was refluxed overnight. The TLC showed the disappearance of most of the SM. The reaction mixture was washed with water (2×100 ml), satd, NaHCO3 (200 ml) brine (100 ml) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 10-30% EtOAc in hexanes as eluent. Yield=6.14 g (62%) of {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester. White foam, mp. 70-71° C. m/z 604 (MH+), 1H NMR (DMSO-d6, 300 MHz, 95° C.) δ: 0.48 (d, 3H), 0.90 (d, 3H), 1.26 m, 1H), 1.28 (s, 9H), 2.33 (s, 3H), 2.47 (d, 2H), 2.72-2.64 (m, 1H), 2.72 (s, 3H), 3.24 (t, 2H), 5.08 (d, 1H), 5.60 (d, 1H), 5.90 (d, 1H), 7.20-7.40 (m, 9H).
Reaction SMILES: C([Li])CCC.[C:6]1([CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:29][S:30]SC.O>O1CCCC1>[C:6]1([CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][CH:14]([P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[S:30][CH3:29])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOP(=O)(CCC(c1ccccc1)c1ccccc1)OCC
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)C(CC(c1ccccc1)c1ccccc1)SC
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (2.5M in n-hexane, 132 ml, 33 mmol) was added dropwise over 10 minutes to a stirred solution of diethyl 3,3-diphenylpropylphosphonate (9.96 g, 30 mmol) in dry tetrahydrofuran (100 ml) cooled to -60° C. under nitrogen atmosphere. After 20 minutes at -60° C. a solution of dimethyl disulphide (2.96 ml, 33 mmol) in dry tetrahydrofuran (5 ml) was added in one portion turning the solution colour from orange to pale yellow immediately. After 30 minutes at -60° C., water (200 ml) was added and the mixture extracted with diethyl ether (2×100 ml). The ether extracts were washed with saturated aqueous sodium bicarbonate (2×100 ml), brine solution (100 ml), dried, filtered and evaporated to a yellow oil (13 g). Chromatography on flash silica eluting with diethyl ether gave the title product as a colourless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1ccccn1
Product: COc1ccc(-c2ccccn2)cc1C=O

Procedure:
The title compound was prepared by employing the method described in Example 111, Step A with (3-formyl-4-methoxyphenyl)boronic acid and the commercially available 2-bromopyridine.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([CH3:29])[C:23]=1[S:24][CH2:25][N+:26]([O-:28])=[O:27])[NH2:20].O>O1CCCC1>[CH3:29][C:22]1[CH:21]=[C:19]([NH:20][S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])[CH:18]=[C:17]([CH3:16])[C:23]=1[S:24][CH2:25][N+:26]([O-:28])=[O:27]
Reactant: Cc1cc(N)cc(C)c1SC[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1SC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.7 %

Procedure:
0.75 g (7.49 mmol) of calcium carbonate and then 1.0 g (5.66 mmol) of benzenesulphonyl chloride are added to a solution, maintained under a nitrogen atmosphere, of 0.80 g (3.77 mmol) of 3,5-dimethyl-4-[(nitromethyl)thio]aniline in 30 ml of anhydrous tetrahydrofuran. After stirring for 3 days at room temperature, the reaction medium is poured into water and extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium Sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 0.9 g (68%) of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]benzenesulphonamide.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:6].N#N.Cl[C:32]1[CH:40]=[C:39](Cl)[CH:38]=[CH:37][C:33]=1C(Cl)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][C:11]=1[N:12]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:33]=1)=[O:6]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
Sodium Hydride (60% dispersion in oil, 80 mg, 1,5 mmol) was added to an ice-cold solution 5-Phenyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester (2) (230 mg, 0,74 mmol) in 20 ml of N,N-dimethylformamide in an atmosphere of N2. After 5 min, 2,4-Dichloro-benzoyl chloride (310 mg, 1.48 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 16 h at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×10 mL) and the combined ether layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (30% EtOAc/Hexane) to obtain 58 mg (16%) of 3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65-7.10 ppm (m, 14H, Haro); 3.77 ppm (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[I-:18].[Na+].O>CC(=O)CC>[I:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: ClCCOc1ccc(Cc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: ICCOc1ccc(Cc2ccccc2)cc1
Yield: 72.9 %

Procedure:
A solution of 1-(2-chloroethoxy)-4-(benzyl)benzene (734 mg, 2.97 mmol) and sodium iodide (1.78 g, 11.9 mmol) in 2-butanone (30 mL) was heated at reflux for 16 hours. After cooling, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 732 mg of 1-(2-iodoethoxy)-4-(benzyl)benzene, 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 2H), 7.19 (dd, 1H), 7.18 (d, 2H), 7.11 (d, 2H), 6.84 (d, 2H), 4.23 (t, 2H), 3.94 (s, 2H), 3.41 (t, 2H) ppm.