Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:7])([O-])=O.[OH-].[Na+].[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:7]
Reactant: [H][H]
Reactant: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
A solution was prepared from 19 g of 2-nitro-N-(1H-tetrazol-5-yl)benzamide in 100 ml of aqueous 1 N sodium hydroxide and 100 ml of ethanol. A 0.5-gram quantity of 5% Pd/C catalyst was added and the mixture was hydrogenated in a Parr apparatus at 1520 mm Hg pressure until uptake of hydrogen stopped. The catalyst was removed by filtration and the filtrate was treated with aqueous 1 N hydrochloric acid. The white solid which formed was separated by filtration and dried to give 2-amino-N-(1H-tetrazol-5-yl)benzamide melting at about 253°-254° C.
Reaction SMILES: O1C2C(=CC=CC=2)[C@H:4]([NH:11]C([C@@H]2CC3C(=CC([C@H]4C[C@@H](C(=O)N[C@H]5C6C(=CC=CC=6)CCC5)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C4)=CC=3)CN2C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O[C:75]([N:77](C)[C@@H:78]([CH3:152])[C:79]([NH:81][C@@H:82]([C:148]([CH3:151])([CH3:150])[CH3:149])[C:83]([N:85]1[CH2:89][C@@H:88]([C:90]2[CH:99]=[C:98]3[C:93]([CH2:94][C@@H:95]([C:121](=[O:133])[NH:122][C@H:123]4[C:132]5[C:127](=[CH:128][CH:129]=[CH:130][CH:131]=5)[CH2:126][CH2:125][CH2:124]4)[N:96]([C:100](=[O:120])[C@@H:101]([NH:106][C:107](=[O:119])[C@@H:108]([N:110](C(OC(C)(C)C)=O)[CH3:111])[CH3:109])[C:102]([CH3:105])([CH3:104])[CH3:103])[CH2:97]3)=[CH:92][CH:91]=2)[CH2:87][C@H:86]1[C:134]([NH:136][C@@H:137]([CH2:141][C:142]1[CH:147]=[CH:146][CH:145]=[CH:144][CH:143]=1)[C:138](O)=[O:139])=[O:135])=[O:84])=[O:80])=O)(C)(C)C.CC1OC([C@@H](N)CC2C=CC=CC=2)=NC=1.C(O)(C(F)(F)F)=O>>[CH3:104][C:102]([CH3:103])([CH3:105])[C@H:101]([NH:106][C:107](=[O:119])[C@@H:108]([NH:110][CH3:111])[CH3:109])[C:100]([N:96]1[C@H:95]([C:121]([NH:122][C@H:123]2[C:132]3[C:127](=[CH:128][CH:129]=[CH:130][CH:131]=3)[CH2:126][CH2:125][CH2:124]2)=[O:133])[CH2:94][C:93]2[C:98](=[CH:99][C:90]([C@H:88]3[CH2:87][C@@H:86]([C:134](=[O:135])[NH:136][C@H:137]([C:138]4[O:139][C:3]([CH3:2])=[CH:4][N:11]=4)[CH2:141][C:142]4[CH:143]=[CH:144][CH:145]=[CH:146][CH:147]=4)[N:85]([C:83](=[O:84])[C@@H:82]([NH:81][C:79](=[O:80])[C@@H:78]([NH:77][CH3:75])[CH3:152])[C:148]([CH3:149])([CH3:151])[CH3:150])[CH2:89]3)=[CH:91][CH:92]=2)[CH2:97]1)=[O:120]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Agent: Cc1cnc([C@@H](N)Cc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)c1ncc(C)o1)C(C)(C)C
Yield: 40 %

Procedure:
Following procedures analogous to those for the preparation of Compounds F and G of Example 46, (S)-2-((2S,4R)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidine-2-carboxamido)-3-phenylpropanoic acid (Compound D of Example 46, 45 mg, 0.044 mmol) and (S)-1-(5-methyloxazol-2-yl)-2-phenylethanamine, TFA (15 mg, 0.049 mmol) were converted to the title compound (19 mg, 40% over 2 steps). MS (ESI+) m/z 1001.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])C)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][OH:26].[OH-].[Na+].O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:22])[CH3:23])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:26][CH2:25][CH3:24])=[O:20])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
A mixture of 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}-N,N-3-oxapentamethyleneacetamide (4.9 g prepared as described in Example 214), ethylene glycol (30 ml) and 18N aqueous sodium hydroxide solution (10 ml) was heated under reflux for 21/2 hours and then cooled. Water (30 ml) was added and the aqueous mixture washed with ether. The ether extracts were washed with 5N aqueous sodium hydroxide solution and the alkaline washings combined with the aqueous reaction mixture and the resulting mixture neutralised by addition of concentrated hydrochloric acid. The neutralised mixture was evaporated and the residue dried by azeotropic distillation with methanol and then propan-2-ol. The residue was mixed with propan-2-ol and the mixture filtered. The filtrate was evaporated and the residue was heated at 63°/0.7 mm to remove excess ethyleneglycol and then dissolved in ethanol (50 ml). Thionyl chloride (3.5 ml) was added dropwise with stirring and the mixture allowed to stand for 16 hours under anhydrous conditions. The reaction mixture was then poured into a mixture of ice and excess aqueous sodium bicarbonate solution. The mixture was extracted with ether and the extracts were dried and evaporated to give an oil which was mixed with ether. The mixture was filtered and a solution of maleic acid in ether was added to the filtrate to produce a gum. The supernatent was decanted and the residual gum washed with ether, which was decanted, several times and then basified with sodium bicarbonate. The product was extracted with ether and the extracts were dried and evaporated to give ethyl 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetate. A sample of this material (2.8 g) was dissolved in methanol (300 ml). Ammonia gas was bubbled into the solution which was cooled in ice, saturated with ammonia gas and then evaporated and heated at 90°/20 mm to leave 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetamide a residual oil the boiling point of which was not determined.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)C(F)(F)F)=[CH:17][C:16]=3[CH2:28][CH2:29][C:30](OCC)=[O:31])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+].CO>C1COCC1>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)(=[O:13])=[O:14])=[C:16]([CH2:28][CH2:29][CH2:30][OH:31])[CH:17]=1
Reactant: CCOC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CCCO)c1
Temperature: 0 °C

Procedure:
A mixture of ethyl 3-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)propanoate (1.6 g, 3.2 mmol), and NaBH4 (0.48 g, 12.8 mmol) in THF (30 mL) was stirred at 0° C. Then CH3OH (1 ml) was added dropwise into the mixture and stirred at r.t. overnight. The solvent was evaporated and the residue was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC (column: YMC 150×30.0 mm, 20μ; liquid phase: [A-H2O; B-MeCN+0.1% TFA] B %: 12%-42%, 10 min) to give the title compound, which was dissolved in MeCN, acidified with aq. HCl and freeze-dried to give the product as hydrochloride salt (280 mg, yield 70%). 1H NMR (400 MHz, DMSO-d6): δ9.97 (s, 1H), 7.57-7.09 (m, 6H), 4.83 (s, 2H), 3.46-3.42 (m, 2H), 2.83-2.79 (m, 2H), 1.66-1.62 (m, 2H); ESI-MS m/z 385 (M+Na, positive); HPLC purity: 94.25% (MaxPlot 190-370 nm), 94.25% (220 nm).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:27])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:12].[ClH:10].[C:1]1([NH:7][C:8](=[SH:27][CH2:26][CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:29][CH:28]=3)[CH2:19][CH2:20]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 107.1 %

Procedure:
The procedure described in Example 2 was followed, using 4.3 g of phenyl isocyanate, 12.7 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 7.3 g of triethylamine and 100 ml of methylene chloride, to give 9.1 g (53% of theory) of N-phenyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. >230° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:26]([CH:29]=1)[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:27]([C:26]1[CH:29]=[C:22]([CH:23]=[CH:24][C:25]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:28]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCCC4)c(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 41 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (166.0 mg, 0.641 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (147.0 mg, 0.629 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (246.0 mg, 0.755 mmol). The mixture was stirred at room temperature for 41 h. The mixture was diluted with ethyl acetate, filtered through Celite®, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as a yellow foam (185.3 mg). LCMS m/z=457.5 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.18-1.28 (m, 1H), 1.30 (t, J=7.20 Hz, 3H), 1.41-1.52 (m, 4H), 1.79 (dd, J=12.82, 1.33 Hz, 1H), 1.85-1.93 (m, 4H), 2.06-2.15 (m, 1H), 2.50 (dd, J=16.80, 11.24 Hz, 1H), 2.68-2.86 (m, 4H), 2.94-3.04 (m, 1H), 3.49-3.61 (m, 1H), 4.16-4.25 (m, 2H), 5.06 (s, 2H), 6.82 (dd, J=8.78, 2.46 Hz, 1H), 6.97 (d, J=2.53 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.21 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H), 8.47 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C([O-])([O-])=[O:32].[K+].[K+].OO>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:32])[CH:8]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(3-fluoropyridin-2-yl)benzamide (Example 90, 100 mg, 0.24 mmol) in DMSO (3 mL) was added K2CO3 (66 mg, 0.48 mmol) and H2O2 (30% aqueous solution, 1.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with water (1 mL), and 2M aqueous HCl (3 mL) was added resulting in precipitation of a white solid. The solid was filtered, washed with water and dried to afford the title compound as a colourless solid (52.8 mg, 51%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])[CH:16]=[O:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (5.0 g), vanillin (3.27 g), potassium carbonate (2.97 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as crystals (7.25 g, yield 96%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:21]O>CN(C=O)C>[CH3:21][O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])=[O:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 190.0 g (0.77 mol) of 2-carboxy-5-nitrobenzenesulfonic acid, 10 ml of DMF and 250 ml (3.43 mol) of thionyl chloride is heated at boiling for 3 h. After separating off the insoluble constituents by filtration, the filtrate is concentrated. 200 ml (4.94 mol) of methanol are added to the residue which results. When addition is complete the reaction mixture is cooled to 0° C. The solid which precipitates is filtered off and dried. 70.9 g (35.3% of theory) of colorless, crystalline 2-methoxycarbonyl-5-nitrobenzenesulfonic acid (m.p.: 92°-94° C.) are thus obtained. By distilling off the volatile components from the mother liquor, a second fraction (62.5 g, 31.1% of theory) is obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:17]([C:18]1[CH:19]=[CH:20][C:21]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:22][CH:23]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: Ic1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Temperature: 110 °C

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 1-iodo-4-phenoxy-benzene (Aldrich, 296 mg, 1 mmol), Cul (Strem Chemicals, 19 mg, 0.1 mmol), 1,10-phenanthroline (Aldrich, 36 mg, 0.2 mmol), and Cs2CO3 (660 mg, 2.0 mmol) in toluene (anhydrous, Aldrich, 10 mL) and heated at 110° C. for two days. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×10 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:1, Rf. 0.20) as oil (220 mg, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 2.70–3.10 (m, 5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt, J=7.5, 1.0 Hz, 1H), 7.20–7.41 (m, 2H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]2[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]1=2)(=[O:4])=[O:3].[H-].[Na+].I[CH3:25]>CN(C=O)C>[CH3:1][S:2]([N:5]([CH3:25])[CH:6]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]2[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]1=2)(=[O:4])=[O:3]
Reactant: CI
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CC(C)(C)CC2N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 0.5 g (1.6 mmol) of methyl 5-methanesulfonylamino-7,7-dimethyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate in 5 ml of DMF was added dropwise to a suspension of 0.05 g (1.8 mmol) of 80 percent sodium hydride in 4 ml of DMF. After stirring at room temperature for 1 hr., 0.23 g (1.6 mmol) of iodomethane was added and the mixture was stirred at room temperature for 4 h. The reaction mixture was completely concentrated in vacuo and the residue was then taken up in EA and water and the organic phase was washed with dilute hydrochloric acid and sodium bicarbonate solution. After drying over magnesium sulfate and concentrating in vacuo; 0.5 g of methyl 5-(methanesulfonyl-methyl-amino)-7,7-dimethyl-5,6,7,8-tetrahydronaphthalene-1-carboxylate was obtained; m.p. 98-99° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[O:5][CH:6]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[OH:25][C:6]1[O:5][C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[N:3][C:2]=1[CH3:1]
Reactant: CCCCN(C(=O)C(C)C)c1nc(C)co1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCN(C(=O)C(C)C)c1nc(C)c(O)o1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
4-methyl-2(N-butylisobutyramido)oxazole (15 g., 0.067 m.) in dry methylene chloride (100 c.c.) was cooled to 0° C. during the addition of m-chloroperbenzoic acid (16 g., 0.023 m.) over 1 hour. The mixture was then stirred at room temperature for 40 hours. The precipitated m-chlorobenzoic acid was then filtered off and the filtrate evaporated to dryness. The residue was taken in ether (100 c.c.) and stirred with 5% aqueous sodium sulphite solution for1 hour. The organic phase was then separated and washed successively with aqueous sodium carbonate (×2) and water, and then dried and evaporated to give a brown oil, 13.9 g.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=3[C:16]#[N:17])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:22][C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH:21]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C#N)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C#N)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-[2-bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]-4-chloro-benzonitrile (Intermediate AB) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light brown solid. tR: 7.83 min (HPLC 2); ESI-MS: tR=1.32 min, [M+H]+ 516/518 (LC-MS 1); TLC: Rf=0.26 (1:4 EtOAc/hexanes).
Reaction SMILES: CS(O[CH:6](C)[C:7](OC)(OC)[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)(=O)=O.[C:25](=[O:28])(O)[O-:26].[Na+].CO>O>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:7]([CH3:6])[C:25]([OH:26])=[O:28])[CH:17]=[CH:16]2
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 70 °C

Procedure:
A mixture is prepared from the oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate, from Example 16, 20 g of sodium bicarbonate, 200 ml of methanol and 150 ml of water, and the mixture is heated at 70° C. with reflux for 14 hours. The methanol is removed under reduced pressure on a rotary evaporator and the oil remaining is extracted with ethyl ether. The organic and aqueous phases are separated and the aqueous phase is acidified with hydrochloric acid to afford 12.5 g of 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: ClC1C=CC(C(C2C=C[C:24]([O:27]C)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:51]2[CH:56]=[CH:55][C:54](Cl)=[CH:53][CH:52]=2)[C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:51]2[CH:56]=[CH:55][C:54]([O:27][CH3:24])=[CH:53][CH:52]=2)[C:37]2[C:45]3[C:40](=[C:41]([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(C(c2ccc(Cl)cc2)c2c[nH]c3c(CSC)cccc23)cc1
Reactant: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: COc1ccc(C(c2ccc(Cl)cc2)c2c[nH]c3c(CS(C)(=O)=O)cccc23)cc1

Procedure:
The title compound was prepared starting from 150 mg (0.37 mmol) of the compound from Example 282 in analogy to the synthesis of the compound from Example 312. 130 mg (80% of theory) of the target compound were obtained.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N[C:13]1C=CC(S(O)(=O)=O)=C[CH:14]=1.CO>C(O)(C)C>[CH2:13]=[CH:14][C:6]1[CH:5]=[CH:4][C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: CC(C)O
Product: C=Cc1ccc(S(=O)(=O)O)cc1
Yield: 73 %

Procedure:
Example 13 was repeated, but instead of aniline-2-sulphonic acid the same amount of aniline-4-sulphonic acid and instead of methanol the same volume of iso-propanol were used. 15.0 g (73%) of styrene-4-sulphonic acid, Na salt, were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]1([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][C:39]#[CH:40])[C:30]2=[O:41])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:40]#[C:39][CH2:38][N:31]3[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:30]3=[O:41])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCn1c(=O)n(-c2ccccc2)c2ccccc21
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)n(-c4ccccc4)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1,3-dihydro-1-phenyl 3-(2-propynyl)-2H-benzimidazol-2-one under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions were combined and evaporated and the residue was crystallized from methanol/ethyl acetate and recrystallized from methanol to yield off white crystals of 1-{3-[4-(2-chlorophenyl)-9-methyl-6H thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl }-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one with m.p.176°-179°. These crystals contained 0.66 mol of water according the analytical data.