Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:16].[OH-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH2:16])([OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0° C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4].[CH3:17][NH2:18]>>[CH3:17][NH:18][C:9]1[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CN(C)S(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CN
Product: CNc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O

Procedure:
A mixture of 5-dimethylsulfamoyl-2-fluorobenzoic acid (10 g) and 40% aqueous methylamine solution (85 ml) is refluxed for 24 hours and then evaporated under reduced pressure. The residue is adjusted to the pH of about 4 with acetic acid. The precipitate is collected, washed with water, and dried to give the title compound (6.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:25]([O:31][C@@H:32]1[C@H:36]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:35]([CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[O:34][C@H:33]1[N:50]1[CH:57]=[CH:56][C:54]([NH2:55])=[N:53][C:51]1=[O:52])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:55][C:54]2[CH:56]=[CH:57][N:50]([C@@H:33]3[O:34][C@H:35]([CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:47])[CH3:48])[C@@H:36]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])[C@H:32]3[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:51](=[O:52])[N:53]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](OC(=O)C(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ccn([C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OS(C)(=O)=O)[C@H]3OC(=O)C(C)(C)C)c(=O)n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
4,4'-Dimethoxytrityl chloride (685 mg, 2.02 mmol) was added to a solution of Compound C5 (825 mg, 1.69 mmol) in anhydrous pyridine (4 ml) and the mixture was stirred at room temperature for 3 hours. After cooling, aqueous 50% pyridine was added to decompose an excess of the reagent, and the mixture was extracted with ether containing a small amount of chloroform. The organic layer was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The organic solvents were evaporated, the remaining pyridine was removed as the toluene azeotrope and the residue was subjected to silica gel chromatography [eluant; chloroform-ethyl acetate-triethylamine (80:20:1)] to give 1.280 g of the desired compound, C6 (yield 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:10]=2[S:9][C@@H:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[C@@H:7]([OH:32])[C:6]1=[O:33].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([O:32][C@H:7]1[C:6](=[O:33])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:34])[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]=2[S:9][C@H:8]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1F

Procedure:
455 mg of (±)-cis-5-(2-dimethylaminoethyl)-2-(3- fluoro-4-methoxyphenyl)-2,3-dihydro-3-hydroxy-8-phenoxy-1,5-benzothiazepin-4(5H)-one (prepared as described in Example 3) were acetylated in the same manner as described in Example 2 in 2 ml of pyridine using 1 ml of acetic anhydride and the product was isolated and purified also as described in Example 2, to give 480 mg of the title compound as a gum.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:13]1)=[O:11])([CH3:8])[CH3:7]>C(O)(=O)C>[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[C:15]([Cl:4])[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:13]1)=[O:11])([CH3:8])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC(C)C
Solvent: CC(=O)O
Product: Cc1c(Cl)c(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Sulfuryl chloride (0.24 g, 1.8 mmol) was added to a solution of N-isopropyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.56 g, 1.5 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-isopropyl-4-chloro-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.60 g, yield: 98.4%). mp: 89-91° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (d, J=6.6 Hz, 6H), 2.63 (s, 3H), 3.90-4.10 (m, 1H), 6.40-6.65 (m, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.85 (dd, J=2.0 and 8.7 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[C:6]([F:18])[CH:5]=1.[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[ClH:1].[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][S:25]([CH2:28][C:29]([NH:3][C:4]2[CH:17]=[CH:16][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=3)=[C:6]([F:18])[CH:5]=2)=[O:30])(=[O:26])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Agent: Cl
Product: Nc1cc(Oc2ccc(NC(=O)CS(=O)(=O)Cc3ccc(F)cc3)cc2F)ccn1
Yield: 45.6 %

Procedure:
4-(4-Amino-2-fluorophenoxy)pyridin-2-amine dihydrochloride (50 mg, 0.17 mmol) was coupled with 2-(4-fluorobenzylsulfonyl)acetic acid (33 mg, 0.14 mmol) in a manner similar to that which is described in Step C of Example 1 to give 2-(4-fluorobenzylsulfonyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride salt (30 mg, 45% yield). 1H NMR (DMSO-d6) δ 13.40 (s, 1H), 11.15 (s, 1H), 7.97 (d, 1H, J=7.0 Hz), 7.80-7.90 (m, 3H), 7.47 (m, 4H), 7.26 (t, 2H, J=8.5 Hz), 6.72 (d, 1H, J=7.0 Hz), 6.14 (d, 1H, J=2.0 Hz), 4.69 (s, 2H), 4.27 (s, 2H); MS(ESI+): m/z 434.15 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][N:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1cnc(I)cc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 86 mg (0.21 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 125 mg (0.54 mmol) of 2-iodo-4,5-dimethyl-pyridine in 1 mL THF with 0.28 mL 2M isopropylmagnesium chloride using. Yield: 21 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 2.2 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]([O:20][C:21](=[O:47])[CH:22]([N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[CH:23]1[NH:27][CH:26]([C:28]([OH:30])=[O:29])[C:25]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[S:24]1)([CH3:19])([CH3:18])[CH3:17].Cl>CN(C)C=O>[CH2:1]([O:30][C:28]([CH:26]1[C:25]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[S:24][CH:23]([CH:22]([N:36]2[C:40](=[O:41])[C:39]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]3[C:37]2=[O:46])[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:47])[NH:27]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCCCC2)S1)N1C(=O)c2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCCCC2)S1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 82.7 %

Procedure:
8.5 g. (0.05 mole) of benzyl bromide are first added all at once and then 3.43 g. (0.034 mole) of triethylamine are added to a solution of 12 g. (0.026 mole) of tert-butyl-4-carboxy-alphaphthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate in 130 ml. of anhydrous dimethylformamide. The reaction mixture is left to stand overnight at ambient temperature and then it is poured on to ice and 10 ml. of 6N hydrochloric acid are added followed by extraction with benzene. The organic phase is first washed with a 5% aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, filtered and finally evaporated to dryness. After recrystallization from a mixture of diethyl ether and hexane (50/50), 12 g. (0.0215 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate are obtained. Yield: 82.7%. M.P. 165°-166° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>C1COCC1>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][CH2:5][NH:4][CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: CNCCO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCOc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Sodium hydride (8.81 g, 220.38 mmol) was added portionwise to 2-(methylamino)ethanol (16.55 g, 220.38 mmol) in THF (500 mL) at 0° C. over a period of 10 minutes under an atmosphere of argon. The resulting solution was stirred at 0° C. for 1 hour and then 2-amino-6-fluorobenzonitrile (20 g, 146.92 mmol) was added in one portion and the mixture heated at 85° C. for 2 hours. The mixture was quenched with water and then evaporated. The residue was dissolved in EtOAc (300 mL), and the mixture washed sequentially with water (2×300 mL), and then with a saturated solution of NaCl (300 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-10%, of a 7M solution of NH3 in MeOH, in CH2Cl2. Fractions containing product were evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzonitrile (12.08 g, 43% yield); Mass spectrum: m/z (ESI+) (M+H)+=192.43. b) Potassium hydroxide (32 g, 570.35 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzonitrile (16 g, 83.67 mmol) in ethanol (160 mL). The resulting mixture was heated at 90° C. for 2 days. The mixture was then diluted with water (1000 mL) and acidified to ˜pH1 with 2M HCl. The mixture was loaded onto an SCX column and the product was eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzoic acid which was used without further purification. c) HATU (35.0 g, 92.04 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzoic acid (17.59 g, 83.67 mmol) and DIPEA (15.92 mL, 92.04 mmol) in DMF (200 mL) and the resulting solution was stirred for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (500 mL). The mixture was washed sequentially with a saturated solution of Na2CO3 (500 mL), water (500 mL), and finally with a saturated solution of NaCl (500 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 6-amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (1.635 g, 10% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.09 (s, 3H), 3.44 (t, 2H), 4.20 (t, 2H), 5.74 (br s, 2H), 6.22 (dd, 1H), 6.52 (dd, 1H), 7.08 (appt t, 1H); Mass spectrum: m/z (ESI+) (M+H)+=193.41.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)([Cl:15])=[O:14]>O1CCCC1>[Cl:15][C:13]([N:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCN1c1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCN(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
16.2 parts by wt. of 1-phenyl-2-oxo-imidazolidine were suspended in 160 parts by vol. of tetrahydrofurane and 12.0 parts by wt. of phosgene, dissolved in 30 parts by vol. of tetrahydrofurane, were added dropwise at 10° C. The mixture was then stirred for a further 4 hrs. at 10° C and left to stand overnight at 20° C, and the precipitate present was then filtered off, washed with tetrahydrofurane and dried.
Reaction SMILES: [CH3:1][N:2]1[C:7](Cl)=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].COCCOC.[Li+].[N:29]1[CH:34]=[CH:33][C:32](B([O-])[O-])=[CH:31][CH:30]=1.[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]1[C:7]([C:32]2[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=2)=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21]
Reactant: Cn1c(Cl)c(-c2ccccc2)nc(-c2ccccc2)c1=O
Reactant: [O-]B([O-])c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1c(-c2ccncc2)c(-c2ccccc2)nc(-c2ccccc2)c1=O

Procedure:
To a solution of 1-methyl-3,5-diphenyl-6-chloro-1H-pyrazin-2-one (0.5 g) in 3:1 ethylene glycol dimethylether:water (30 cm3), under nitrogen, was added sequentially 4-pyridyl boronic acid lithium salt (0.42 g), sodium carbonate (0.72 g) and tetrakis-triphenylphosphine palladium (0.07 g). The reaction was heated at reflux, under nitrogen, overnight. The solvents were evaporated and the residue partitioned between water and 5% methanol/dichloromethane. The organic phase was separated, dried over magnesium sulphate and evaporated in vacuo. The residue was subjected to silica gel chromatography using 2% methanol/dichloromethane as eluant. The product was treated with hydrogen chloride in methanol and recrystallised from ethyl acetate/diethyl ether to afford1-methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-one hydrochloride(0.2 g; 32%) as yellow crystals. Found C, 70.50; H, 4.90; N, 11.20% C22H17N3O.HCl requires C, 70.30; H, 4.83; N, 11.18%.m/e (ES+) 340 (M+H)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[C:20]([Si:24]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:43][C:39]1[CH:38]=[C:37]([Si:24]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:36]=2)([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
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: Cc1ccccc1
Solvent: O
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture solution of dibenzo[b,d]thiophen-4-boronic acid (1.84 g, 8.04 mmol), bis(3-bromophenyl)diphenylsilane (9.97 g, 20.17 mmol), Pd(PPh3)4 (0.19 g, 0.16 mmol) and potassium carbonate (6.69 g, 48.4 mmol,) in toluene (60 mL) and water (20 mL) was heated at 100° C. under nitrogen overnight. After cooling to room temperature, the reaction mixture was quenched with water, extracted with DCM, washed with brine and water, and dried over Na2SO4. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5 to 9:1, v/v) as eluent. The crude product was dissolved in DCM, precipitated with methanol, and filtered to yield (3-bromophenyl)(3-(dibenzo[b,d]thiophen-4-yl)phenyl)diphenylsilane (3.0 g, 62%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[N+:19]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)([O-:21])=[O:20]>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[N+:19]([O-:21])=[O:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1ccccc1[N+](=O)[O-])C(=O)N2
Yield: 33 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and 2 nitro benzaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[N:11][C:12]([CH2:15]Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[N:18]([CH2:15][C:12]1[N:11]=[C:10]([CH3:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[N+:19]=[N-:20]
Reactant: Cc1nc(CCl)ccc1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CN=[N+]=[N-])ccc1OCc1ccccc1

Procedure:
A solution of 3-benzyloxy-6-chloromethyl-2-methylpyridine (8.02 g) and sodium azide (5.98 g) in 400 ml of ethanol is heated at 80° for 4 hours. The reaction mixture is cooled, filtered and evaporated to yield a residue which is partitioned between ice-cold 0.5N NaOH (150 ml) and ether (150 ml). The organic phase is dried over sodium sulfate and evaporated to yield 6-azidomethyl-3-benzyloxy-2-methylpyridine, NMR: δ(CDCl3) 2.47 (3H), 4.27 (2H), 4.95 (2H).
Reaction SMILES: [N+]([CH2:4][CH2:5][CH3:6])([O-])=O.[CH:7]1[CH:15]=[CH:14][C:13]2[C:9](=[N:10][O:11][N+:12]=2[O-:16])[CH:8]=1.C(NCC)C>O1CCCC1>[OH:11][N:10]1[C:9]2[CH:8]=[CH:7][CH:15]=[CH:14][C:13]=2[N+:12]([O-:16])=[C:4]1[CH2:5][CH3:6]
Reactant: [O-][n+]1onc2ccccc21
Reactant: CCC[N+](=O)[O-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCc1n(O)c2ccccc2[n+]1[O-]
Reaction time: 8 h

Procedure:
To a mixture containing 1-nitropropane (10.7 g., 0.12 moles), benzofuroxan (13.6 g., 0.10 moles) and tetrahydrofuran (50 ml.) is added dropwise diethylamine (8.7 g., 0.12 moles). The reaction temperature rises almost to reflux on addition of amine. Upon completion, the mixture is allowed to cool and then sit overnight.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C.Cl>C(OCC)C>[CH:1]([C:4]1[CH:5]=[C:6]([B:33]([OH:38])[OH:34])[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)c1cc(B(O)O)cc(C(C)C)c1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3,5-diisopropylbromobenzene (5.76 g, 23.9 mmol) and tetramethylethylenediamine (3.6 mL, 23.9 mmol) in diethyl ether (30 mL), solution of n-butyllithium in n-hexane (14.5 mL, 23.9 mmol) was dropped at −60° C. Reaction solution was stirred for 1.5 hours at −60° C., and further was stirred for 30 minutes at 0° C., then, solution of triisopropyl borate (6.6 mL) in diethyl ether (5 mL) was dropped at −60° C. Reaction solution was stirred for 30 minutes at −60° C., and further, was stirred overnight at room temperature, then, diluted hydrochloric acid (50 mL) was added. Resulting solid part was filtered to obtain the crude product of 3,5-diisopropylphenylboronic acid (5.9 g).
Reaction SMILES: [N:1]1[C:13]2[C:12](=[O:14])[N:11]3[C:6](=[N:7][CH2:8][CH2:9][CH2:10]3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:6]1[C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:13]=2[C:12](=[O:14])[NH:17][N:16]=1
Reactant: O=C1c2nccnc2C2=NCCCN12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NCCCNc1n[nH]c(=O)c2nccnc12

Procedure:
7,8-Dihydro-6H-1,4,5,8a-tetraaza-fluoren-9-one (0.53 mmol) was treated with hydrazine hydrate (3.0 mmol) in ethanol (3 mL) for 20 h at RT. Ethanol was removed under vacuum and the crude produce was purified by flash chromatography (MeOH/DCM/Et3N) to yield 8-(3-amino-propylamino)-6H-pyrazino[2,3-d]pyridazin-5-one.
Reaction SMILES: CO[C:3](=[S:18])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.[NH3:21]>O>[C:6]1([CH:5]([CH2:4][C:3]([NH2:21])=[S:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: COC(=S)CC(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A reactor equipped with an impeller stirrer and a gas introduction tube was charged with methyldiphenylmethylthioacetate (100 g; 1 equivalent) and methanol (300 mL; 3 volumes) at room temperature. The mixture was heated to 35° C. Ammonia (7 equivalents) was introduced within 3 hours, and the mixture contacted at 35° C. for 16 hours before adding 3 equivalents of ammonia. When the reaction was completed, the mixture was cooled to 25° C. and water (90 ml; 0.9 volume) added. The mixture was filtered and dried under vacuum.