Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:154][CH2:155][O:156][Si](C(C)(C)C)(C)C)[S:12]([C:15]1[CH:20]=[C:19]([S:21](=[O:44])(=[O:43])[N:22]([CH2:33][CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][C:16]=1[Bi:45]([C:100]1[CH:105]=[CH:104][C:103]([S:106](=[O:129])(=[O:128])[N:107]([CH2:118][CH2:119][O:120][Si](C(C)(C)C)(C)C)[CH2:108][CH2:109][O:110][Si](C(C)(C)C)(C)C)=[CH:102][C:101]=1[S:130](=[O:153])(=[O:152])[N:131]([CH2:142][CH2:143][O:144][Si](C(C)(C)C)(C)C)[CH2:132][CH2:133][O:134][Si](C(C)(C)C)(C)C)[C:46]1[CH:51]=[CH:50][C:49]([S:52](=[O:75])(=[O:74])[N:53]([CH2:64][CH2:65][O:66][Si](C(C)(C)C)(C)C)[CH2:54][CH2:55][O:56][Si](C(C)(C)C)(C)C)=[CH:48][C:47]=1[S:76](=[O:99])(=[O:98])[N:77]([CH2:88][CH2:89][O:90][Si](C(C)(C)C)(C)C)[CH2:78][CH2:79][O:80][Si](C(C)(C)C)(C)C)(=[O:14])=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:80][CH2:79][CH2:78][N:77]([CH2:88][CH2:89][OH:90])[S:76]([C:47]1[CH:48]=[C:49]([S:52](=[O:75])(=[O:74])[N:53]([CH2:64][CH2:65][OH:66])[CH2:54][CH2:55][OH:56])[CH:50]=[CH:51][C:46]=1[Bi:45]([C:100]1[CH:105]=[CH:104][C:103]([S:106](=[O:129])(=[O:128])[N:107]([CH2:118][CH2:119][OH:120])[CH2:108][CH2:109][OH:110])=[CH:102][C:101]=1[S:130](=[O:153])(=[O:152])[N:131]([CH2:142][CH2:143][OH:144])[CH2:132][CH2:133][OH:134])[C:16]1[CH:17]=[CH:18][C:19]([S:21](=[O:43])(=[O:44])[N:22]([CH2:33][CH2:34][OH:35])[CH2:23][CH2:24][OH:25])=[CH:20][C:15]=1[S:12](=[O:13])(=[O:14])[N:11]([CH2:10][CH2:9][OH:8])[CH2:154][CH2:155][OH:156])(=[O:98])=[O:99]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc([Bi](c2ccc(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c2ccc(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc2S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c(S(=O)(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc([Bi](c2ccc(S(=O)(=O)N(CCO)CCO)cc2S(=O)(=O)N(CCO)CCO)c2ccc(S(=O)(=O)N(CCO)CCO)cc2S(=O)(=O)N(CCO)CCO)c(S(=O)(=O)N(CCO)CCO)c1)N(CCO)CCO
Temperature: -30 °C
Yield: 94.7 %

Procedure:
A solution of 1.38 g of the tris(2,4-bis(N,N-bis(2-t-butyldimethylsilyloxyethyl)sulfamoyl)phenyl)bismuthine preparation obtained in Example 5 in 15 ml of tetrahydrofuran was cooled to -30° C., and 5.88 ml of a 1 M/1 tetrahydrofuran solution of tetra-n-butylammonium fluoride was gradually added droprise under stirring. After removal of the cooling bath, it was stirred further for 2 hours. Water and n-hexane were added to the reaction solution, and after vigorous shaking, the aqueous layer was separated out. The aqueous layer was washed with chloroform three times, and lyophilized. As a result, 0.67 g of the title compound as obtained. NMR (D2O)δ: 8.49 (3H,s), 7.38, 6.82 (each 3H,A Bq), 3.65 (24H,m), 3.44 (12H,t), 3.29(12H,t)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:29]([O-])=O)[C:5]([C:12](=[O:28])/[C:13](/[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][N:23]=2)=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl>CO.[Fe]>[F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]2[C:12](=[O:28])[CH:13]([C:22]3[N:26]([CH3:27])[N:25]=[CH:24][N:23]=3)[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[NH:29][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C(=O)/C(=C/c1ccc(F)cc1)c1ncnn1C
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Yield: 15.1 %

Procedure:
To a solution of (E)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)acryloyl)-3-nitrobenzoate (9) (214 mg, 0.5 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37%, 1 mL), then reductive Fe powder (140 mg, 2.5 mmol) was added slowly to the reaction system. After the addition was complete the resulting mixture was refluxed for 24 hours. The reaction mixture was then filtered, concentrated, neutralized with saturated NaHCO3 (20 mL), and extracted with ethyl acetate (10 mL×3). The residue was purified by chromatography (ethyl acetate:petroleum ether=1:1) to give the title compound (5) (30 mg, yield 15%) as an off-white foam. LC-MS (ESI) m/z: 399 (M+H)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CN(C)C=O.[C@@H:14]12[C:23](=O)[O:22][C:20](=[O:21])[C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2.[OH-].[K+]>O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:1]2[C:20](=[O:21])[C@H:15]3[C@H:14]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:23]2=[O:22])=[CH:4][CH:5]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NCc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1Cc1ccncc1
Yield: 43.8 %

Procedure:
To 17.0 g (157 mmoles) of 4-aminomethylpyridine was added 40 mL of dimethylformamide and 24.2 g (157 mmoles) of cis-1,2-cyclohexanedicarboxylic anhydride. The mixture was heated under reflux for 2 hours. The cooled solution was diluted with water, made basic with aqueous potassium hydroxide, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated to afford 16.8 g of 2-(4-pyridinylmethyl)-cis-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione, m.p. 91°-92°; NMR (CDCl3): δ8.53-8.63 (d, 2H); 7.19-7.29 (d, 2H); 4.63 (s, 2H); 2.80-3.00 (m, 2H); 1.78-2.00 (m, 2H); 1.63-1.78 (m, 2H); 1.33-1.58 (m, 4H) .
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.[H-].[Na+].C(OP([C:21](=[CH2:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(OCC)=O)C.O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:27][O:10]2)=[CH:8][CH:9]=1
Reactant: C=C(C(=O)OCC)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2ccc(Cl)cc2OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
4-Chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., Vol. 53, p. 258, 1999) (510 mg) was dissolved in tetrahydrofuran (40 ml), sodium hydride (60% in oil, 157 mg) was added, and the mixture was stirred at room temperature for 2 hours. A tetrahydrofuran solution (10 ml) of ethyl 2-diethylphosphonoacrylate (J. Org. Chem., Vol. 43, P. 1256, 1978) (769 mg) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 2 hours and then heated overnight under reflux. After the reaction mixture was cooled to room temperature, water and diethyl ether were added to conduct liquid separation. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the title compound (247 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)=[CH:8][CH:7]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:22]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)=[CH:8][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added benzaldehyde (22 μL) and sodium hydrogen carbonate (27.4 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (21.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[N+:13]([O-])([O-:15])=[O:14].[K+].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCCc2c(F)cccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C1CCCc2c(F)ccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
14 gm of the compound prepared in (7) above was dissolved into 100 ml of concentrated sulfuric acid. After cooling the solution, a solution of 9.05 gm of potassium nitrate in 80 ml of concentrated sulfuric acid was added dropwise while maintaining the internal temperature below 5° C. The stirring was continued for a further 30 minutes. The resultant reaction mixture was poured into ice-cooled water and extracted with chloroform. The extract was washed with saturated aqueous solution of sodium bicarbonate, water, and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated and residue was recrystallized in methanol to obtain 9.15 gm of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].O[CH2:28][CH:29]1CC1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:29][CH2:28]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCC1CC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 5 h

Procedure:
A mixture of 8.0 g (24 mmol) of ethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 0.5 g (7.7 mmol) of potassium cyanide and 60 ml of hydroxymethyl-cyclopropane is stirred at 130° for 5 hours, during this time a small amount of solvent being distilled off four times by the application of a slight vacuum. The mixture is subsequently evaporated in vacuo, the residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are washed three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is crystallized from ethyl acetate and there is obtained cyclopropylmethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of decomposition point 183°-185° (partially racemized).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20][C:21](=[O:24])[O:22]C)[C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].CC(O)=O.O>CN(C=O)C>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[NH:20][C:21](=[O:22])[O:24][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC(=O)NC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nc(-c2[nH]c(=O)oc2-c2ccccc2)ccc1=O
Temperature: 72.5 °C
Yield: 70.2 %

Procedure:
A solution of methyl [1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]carbamate (2.46 g) in DMF (10 ml) was added to a suspension of NaH (60% dispersion in mineral oil) (314 mg) in DMF (15 ml) and the mixture was heated at 70-75° C. for 3 hours. A mixture of AcOH (0.5 ml) and water (75 ml) was added to the mixture to give a precipitate. The precipitate was collected by filtration and dried under reduced pressure to give 2-isopropyl-6-(2-oxo-5-phenyl-2,3-dihydro-oxazol-4-yl)-3(2H)-pyridazinone as a solid (1.56 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:17])([F:18])[F:16])[CH:7]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-pheyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (20.83 g, 35.6 mmol) in CH2Cl2 (300 ml) was added under argon NEt3 (12.5 ml, 89 mmol) and at 0-5° C. trifluoroacetic anhydride (6.15 ml, 42.7 mmol). After stirring for 4 h at 25° C. the reaction mixture was added to a cold NaHCO3 solution and the product was extracted with CH2Cl2. Combined extracts were washed with cold 0.1 N aqueous HCl, water and saturated NaHCO3 solution, dried over MgSO4, filtered and concentrated to provide the title compound as a yellow oil, which was used as such for the next step: TLC (hexane-EtOAc 1:1): Rf=0.73; HPLC RtH5=1.364 min; ESIMS: 571, 573 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.89 (d, 1H), 7.62 (ddd, 1H), 7.57 (ddd, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 6.58 (dd, 1H), 6.19 (s, 1H), 4.17 (s, 2H), 1.81 (s, 3H), 1.72 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1.CS(C)=O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 2.0 g (7.7 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 1.7 g (8.47 mmol) piperidin-4-yl-carbamic acid tert-butyl ester using 1.07 ml (7.7 mmol) triethylamine in 3 mL NMP and 12 mL DMSO. 200 mL ethyl acetate and 100 mL half concentrated aqueous Na2CO3 solution are added and the phases are separated. The aqueous phase is extracted 2 times with ethyl acetate (100 mL each). The combined organic layers are dried over sodium sulfate and the solvent is removed under reduced pressure. The crude product is used without further purification in the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:31])C>OO>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:28])(=[O:27])[NH2:26])[C:17]=1[S:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:31])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Sc1ccccc1
Reactant: CC(=O)O
Agent: OO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1S(=O)c1ccccc1

Procedure:
To a suspension of 3-benzylamino-4-phenylthio-5-sulphamyl-benzoic acid (0.8 g) in acetic acid (20 ml), perhydrol (1.5 ml of 30% hydrogen peroxide in water) was added while stirring. The reaction mixture was stirred for an additional 75 hours at room temperature, after which the 3-benzylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid was collected by filtration and washed with acetic acid. After recrystallization from aqueous methanol and drying, the acid had a melting point of 234° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23][CH2:22]2>CN1C(=O)CCC1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:23][CH2:22]2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: COc1ccc2c(c1)CCCN2
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(OC)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (700 mg, crude) in NMP (2 mL) was added 6-methoxy-1,2,3,4-tetrahydroquinoline (1.0 g, 6.13 mmol) with stifling for 3 h at 150° C. The reaction mixture was cooled to room temperature. The product was precipitated by the addition ethyl acetate and the solids were collected by filtration to afford methyl 3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (450 mg), which was used to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 60 h

Procedure:
To an ice cooled solution of 2-Methoxy-5-trifluoromethylaniline (311 mmol, 59.4 g) in 500 ml dry dimethylformamide is added sodiumhydride (438 mmol, 17.5 g 60%) followed by slow addition of 2-chloro-5-trifluoromethyl-nitrobenzene (311 mmol, 47.4 ml) and the mixture is stirred for 60 hours. More sodiumhydride (10 g 60%) is added and after stirring for additional two hours is another portion of 2-chloro-5-trifluoromethyl-nitrobenzene (5 ml) and sodiumhydride (2 g 60%) added. Upon completion is the reaction mixture poured into water and a black precipitate is formed. The crude product is filtered of and is washed with 1M HCl and petroleum ether yielding the title compound as grey crystals, M.p. 86°-88° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:32]1[CH2:31][CH2:30][N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])[CH2:34][CH2:33]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCN(c2ccccc2Cl)CC1
Yield: 81.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.091 g, 0.243 mmol) obtained in Example 22, step 3 and 1-(2-chlorophenyl)piperazine (0.057 g, 0.239 mmol), the title compound (0.102 g, 69%) was obtained.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[C:12]3[CH:13]=[CH:14][S:15][C:16]=3[CH2:17][C:10]=2[C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[N:8]1.Cl>CO>[S:15]1[CH:14]=[CH:13][C:12]2[C:11]3[NH:7][N:8]=[C:9]([C:18]4[CH:19]=[CH:20][C:21]([C:24]5[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=5)=[CH:22][CH:23]=4)[C:10]=3[CH2:17][C:16]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(O)cc3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: Oc1ccc(-c2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-biphenyl-4-ol (0.06 g, 0.13 mmol) was dissolved in MeOH and treated with concentrated HCl (0.3 mL, 10 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 4′-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-biphenyl-4-ol (0.03 g, 0.08 mmol) as brown solid in 61% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CC(C)([O-])C.[K+].Br[C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][C:43]=4[CH3:44])[C:35]([NH:37][CH:38]4[CH2:40][CH2:39]4)=[O:36])[CH:28]=3)[C:23]2=[O:45])=[CH:17][CH:16]=1>C1COCC1>[CH:38]1([NH:37][C:35](=[O:36])[C:34]2[CH:41]=[CH:42][C:43]([CH3:44])=[C:32]([C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:45])[N:22]([CH2:21][C:18]3[CH:19]=[N:20][C:15]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:16][CH:17]=3)[CH:31]=[CH:30]4)[CH:33]=2)[CH2:39][CH2:40]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(Br)nc3)ccc2c1
Reactant: CN(C)CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCN(C)C)nc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To solution of 3-(dimethylamino)propan-1-ol (0.03 mL) in THF (1 mL) was added potassium tert-butoxide (28 mg) and the reaction stirred at room temperature for 10 minutes. A solution of the product of step i) (100 mg) in THF (2 mL) was added, and the mixture heated at reflux for 100 hours.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]\[CH3:19]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH3:19]
Reactant: C/C=C\c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of methyl 5-methyl-4-{1-methyl-4-[(1Z)-1-propen-1-yl]-1H-pyrazol-5-yl}-2-thiophenecarboxylate (243 mg, 0.88 mmol) in methanol (6.8 ml) was added Pd(OH)2 (49 mg, 0.35 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N2, filtered through Celite and concentrated affording methyl 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (217 mg, 0.69 mmol, 78% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H)+.