Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.C(C1C=C(C(C)(C)C)C=C[C:8]=1[OH:17])(C)(C)C.[C:18]([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([OH:32])=[C:24]([Br:33])[CH:23]=1)([CH3:21])([CH3:20])[CH3:19].[H-].[Na+].[CH2:36](Cl)[O:37][CH3:38]>C(Cl)Cl.C1COCC1.O>[CH3:36][O:37][CH2:38][O:32][CH2:25][O:17][CH3:8].[C:28]([C:26]1[CH:27]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:23]=[C:24]([Br:33])[CH:25]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Product: COCOCOC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Bromine (3.7 mL, 11.6 g, 72.5 mmol, 1 equiv) was added via syringe to a solution of 2,4-di-t-butyl-phenol (15 g, 72.8 mmol, 1 equiv) in CH2Cl2 (200 ml). The brown color of Br2 disappeared upon addition. GC-MS analysis after 5 min shows only the presence of the desired brominated product (M+=286). The organic mixture was washed with water, then dried over MgSO4, and filtered. Upon removal of volatile material by rotary evaporation, a golden oil was obtained which solidified after placing under high vacuum (<1 mTorr). This material (4,6-di-t-butyl-2-bromophenol) was dissolved in dry THF (200 mL), under argon, and was deprotonated with NaH (1.92 g, 80 mmol, 1.1 equiv). After the addition of NaH the reaction mixture was stirred for 1 h at room temperature then MOMCl (6.1 mL, 6.5 g, 80.3 mmol, 1.1 equiv) was added via syringe. The reaction mixture was stirred at room temperature for 9 h. Water was added and the mixture was concentrated under vacuum to remove the THF. The desired product was extracted with CH2Cl2 (three times). The combined organic fractions were dried over MgSO4, filtered, and concentrated to ˜50 mL. CaH2 was added and stirred at room temperature for 6 h then at 100° C., under vacuum, for 1 h. The reaction vessel was sealed with a needle valve and brought inside an inert atmosphere glove box. The mixture was filtered through a pad of activated alumina with the aid of some Et2O. Volatiles were removed under vacuum to give 23.5 g (98% yield over two steps) of desired product 1-methoxymethylether-2,4-di-t-butyl-6-bromobenzene, as a golden oil. 1H NMR (300 MHz, CDCl3) δ: 1.30 (s, 9H, C(CH3)3), 1.44 (s, 9H, C(CH3)3), 3.70 (s, 3H, OCH3), 5.23 (s, 2H, OCH2O), 7.32 (d, 2H, aryl-H, 4J=2.4 Hz), 7.41 (d, 2H, aryl-H, 4J=2.4 Hz). 13C NMR (75 MHz, CDCl3) δ: 31.0 (C(CH3)3), 31.5 (C(CH3)3), 34.8 (C(CH3)3), 36.1 (C(CH3)3), 57.9 (OCH3), 99.5 (OCH2O), 117.7, 124.1, 128.9, 144.6, 147.8, 150.7 (aryl). GC-MS: M+=328.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].N[C:24]1CN=C(C2C=CC=CC=2)C2C=C([N+]([O-])=O)C=CC=2N=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])([O-])OCC.C(Cl)(Cl)Cl>[N+:20]([C:17]1[CH:18]=[CH:19][C:5]2[N:4]3[CH:24]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 1 h

Procedure:
2-Hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine prepared from 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine in a similar manner to Example 7, is dissolved in a mixture of 20 parts by volume of ethyl orthoformate and 100 parts by volume of chloroform, followed by the addition of 10 parts of p-toluenesulfonic acid. The whole mixture is left standing at room temperature for 1 hour with occasional shaking. After completion of the reaction, the solution is washed with a saturated aqueous solution of sodium bicarbonate, then with water, and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with ethyl acetate, whereby 8-nitro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded as crystals. Recrystallization from tetrahydrofuran yields pale yellow needles melting at 271° C to 272° C.
Reaction SMILES: Cl/[C:2](=C/N(C)C)/[C:3](C1N(C(C)C)C(C)=NC=1)=[O:4].S([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:50]=[CH:49][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:46])[CH3:45])[C:42]([CH3:47])=[N:41][CH:40]=4)[C:36]([Cl:48])=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(C)(=O)=O>COCCO>[C:3]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:50]=[CH:49][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:45])[CH3:46])[C:42]([CH3:47])=[N:41][CH:40]=4)[C:36]([Cl:48])=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(=[O:4])[CH3:2]
Reactant: Cc1ncc(C(=O)/C(Cl)=C\N(C)C)n1C(C)C
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)ncc2Cl)n1C(C)C
Solvent: COCCO
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(Cl)c(-c4cnc(C)n4C(C)C)n3)cc2)CC1

Procedure:
(2E)-2-Chloro-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (1.68 g from Method 3-assumed 5 mmol) and N-[4-(4-acetylpiperazin-1-yl)phenyl]guanidine bicarbonate salt (Method 2) (1.94 g 6 mmol) in 2-methoxyethanol (25 ml) were heated under nitrogen at 110° C. for 3.5 hours before evaporation under reduced pressure. The residue was purified by chromatography on silica gel with MeOH:DCM (3:97 to 5:95) to give the title compound, after trituration with ether, as a foam. NMR: 1.36 (d, 6H), 2.02 (s, 3H), 2.48 (s, 3H), 3.00 (b t, 2H), 3.08 (b t, 2H), 3.56 (b q, 4H), 4.80 (septuplet, 1H), 6.90 (d, 2H), 7.21 (s, 1H), 7.47 (d, 2H), 8.50 (s, 1H), 9.48 (s, 1H); m/z 454.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8].S(OC)(OC)(=O)=O.O>CC(C)=O>[C:7]([C:10](=[N:16][O:17][CH3:1])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
234 g of potassium carbonate were added at 10° C. under a nitrogen atmosphere to a mixture of 180 g of raw ethyl 2-acetyl-2-hydroxyiminoacetate in 900 ml of pure acetone and then 103 ml of dimethyl sulfate were added thereto. The mixture was stirred at room temperature for 3 hours and was then poured into ice and 4 liters of water were added. The mixture was extracted with methylene chloride and the extracts were washed with water, dried and distilled to dryness to obtain 185 g of ethyl 2-acetyl-2-methoxyiminoacetate.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:18]([OH:20])=[O:19].S(Cl)([Cl:23])=O.[CH2:25]([N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32]O)[CH2:26][CH2:27][CH3:28]>N1C=CC=CC=1.C1C=CC=CC=1.C(Cl)Cl>[ClH:23].[ClH:23].[CH2:25]([N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][O:16][C:15]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][C:2]([C:18]([O:20][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:17])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)CCCO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)Cc1cc(C(=O)O)ccc1O2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)Cc1cc(C(=O)OCCCN(CCCC)CCCC)ccc1O2
Product: Cl
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To 17.4 g (0.06 mole) of xanthene-2,7-dicarboxylic acid was added 100 ml (1.4 moles) of thionyl chloride and 4 drops of pyridine. The resulting solution was refluxed for four hours and solvent and excess thionyl chloride were removed. The intermediate diacid chloride in benzene-methylene chloride was reacted with 24 g (0.13 mole) of 3-di-n-butylamino-1-propanol by refluxing for three hours. Most of the solvent was removed and the residue allowed to stand for two days. The residue was diluted with methylene chloride and 10% hydrochloric acid. The organic layer and two methylene chloride washings of the aqueous layer were combined and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated at reduced pressure to a solid residue. This was purified from isopropanol to give 12.9 g (29.6%) of bis(3-di-n-butylaminopropyl)xanthene-2,7-dicarboxylate dihydrochloride. M.P. 187.5°-190°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([NH:26][CH2:27][C:28](O)=[O:29])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)[Cl:47]>>[ClH:47].[ClH:47].[NH2:26][CH2:27][C:28]([NH:15][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:29]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NC(Cc1ccccc1)c1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cl
Product: NCC(=O)NC(Cc1ccccc1)c1ccccn1
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(2-pyridinyl)-2-phenylethylamine (8.55 g, 0.043 mol) in chloroform (200 ml) was added N-CBZ-glycine (9.50 g, 0.045 mol) and then a solution of dicyclohexylcarbodiimide (9.79 g, 0.047 mol) in chloroform (80 ml) and the mixture stirred for 64 hours at ambient temperature. The mixture was filtered, the solvent evaporated, the residue dissolved in ethyl acetate (300 ml) and filtered again. The filtrate was washed with a pH 11 sodium carbonate solution, the aqueous phase back extracted with ethyl acetate (3×200 ml), and the organic phases combined, dried and evaporated to an oil, 19.6 g. This was dissolved in methanol (225 ml) and 10% HCl (50 ml) and hydrogenated at 40 psi in a Parr apparatus over 2.6 g of 10% Pd/C catalyst for 16 hours. The catalyst was removed by filtration, the solvent evaporated and the residue dissolved in water (300 ml) and chloroform (300 ml). The mixture was basified to pH 10 with 2N sodium carbonate, saturated with NaCl, shaken and separated. The aqueous layer was extracted with chloroform (3×250 ml) and ethyl acetate (2×250 ml), and the combined organic phases and dried and evaporated to a yellow oily solid, 10.3 g. This was dissolved in 100 ml of methanol and 100 ml isopropanol, acidified with HCl gas. The solid was collected by filtration, recrystallized from absolute ethanol (100 ml), and vacuum dried at 80° C. for 3 days to provide 6.13 g of 2-amino-N-[1-(2-pyridinyl)-2-phenylethyl]acetamide dihydrochloride, mp 148°-151° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][C:13](=O)[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH:25][C:26]([NH2:28])=[NH:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[C:21]([O:20][C:18]([N:25]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])[N:27]=[C:26]1[NH2:28])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: O=C(CBr)CCCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)OCc2ccccc2)nc1N
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-bromo-5-oxo-hexanoic acid benzyl ester (3.42 g, 11.99 mmol) and Boc-guanidine (5.73 g, 35.97 mmol) were dissolved in DMF (35 mL) and allowed to stir at room temperature. After 48 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (30-100% EtOAc/Hexanes) to obtain the title compound (2.79 g, 66%) as a colorless oil which solidified upon prolonged standing. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 6.51 (s, 1H), 5.91 (s, 2H), 5.12 (s, 2H), 2.41 (m, 4H), 1.94 (quint., 2H, J=7.2 Hz), 1.57 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.45, 150.31, 149.59, 138.27, 136.36, 128.67, 128.29, 128.27, 107.05, 84.73, 66.23, 33.82, 28.16, 27.62, 23.79; HRMS (ESI) calcd for C19H26N3O4 (MH)+360.1917, found 360.1919.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:28]1([S:34]([Cl:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C(Cl)Cl.C(OCC)C>[C:28]1([S:34]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[ClH:37]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CCCN1CCC(NS(=O)(=O)c2ccccc2)CC1)c1ccccc1
Reaction time: 24 h

Procedure:
To a stirred solution of 4-amino-1-(4-phenyl-4-oxobutyl)-piperidine dihydrochloride (1.752 g. 0.005 mole) and triethylamine (2 ml.) in CH2Cl2 (10 ml.) was added dropwise a solution of benzenesulphonyl chloride (0.883 g. 0.005 mole) in CH2Cl2 (5 ml.). The mixture was stirred for 24 hours and extracted with water (3× 10 ml.). The organic phase was separated, dried (MgSO4) and evaporated to give a crystalline residue. Treatment of this with ethanolic HCl followed by diethyl ether afforded the title compound as the monohydrochloride, buff solid (1.961 g.), m.p. 195.2° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[S:17](Cl)([OH:20])(=O)=[O:18].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:17]([N:14]2[CH2:15][CH2:16][C:3]3[C:4](=[N:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[CH3:1])[CH2:12][CH2:13]2)(=[O:20])=[O:18])=[CH:25][CH:24]=1
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: Clc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Product: Cc1c2c(nc3ccccc13)CCN(S(=O)(=O)c1ccc(Cl)cc1)CC2
Yield: 75 %

Procedure:
3-(p-Chloro-benzene sulfonyl)-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with 4-chlorobenzene sulfochloride in pyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:16][CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CC3CC(C2)CN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CN2CC3CNCC(C3)C2)cc1

Procedure:
A solution of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane (from step (ii) above; 97 g; 6.4 mmol) in aqueous ethanol (95%) was hydrogenated over 5% Pd/C at 1 atm. until tic indicated that the reaction was complete. The catalyst was removed by filtration through a pad of Celite®, and the filtrate concentrated under reduced pressure to give the sub-title compound in quantitative yield.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:27])[C:7](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])#[N:2].[NH2:28][C:29]([CH3:34])=[CH:30][C:31](=[O:33])[CH3:32]>CCO>[C:31]([C:30]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:27])=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])[NH:28][C:29]=1[CH3:34])(=[O:33])[CH3:32]
Reactant: CC(=O)C=C(C)N
Reactant: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCN=[N+]=[N-]
Solvent: CCO
Product: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 7-azido-2-[(4-nitrophenyl)methylene]-3-oxoheptanoic acid 2-cyanoethyl ester (1.12 g, 3.00 mmol) and 4-amino-3-penten-2-one (330 mg, 3.30 mmol) in 20 ml of EtOH was refluxed for 48 hrs. After the EtOH was removed in vacuo, the residue was dissolved in 150 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3 :MeOH=5:95). 5-Acetyl-2-(4-azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-6-methyl-4-(4-nitrophenyl)pyridine was obtain as a yellow oil (1.05 g, 77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(O)CCC>CCOC(C)=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: Brc1cccc(Br)n1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2,6-dibromopyridine 16-1 (15 g, 70 mmol), 4-methoxybenzylamine (25 mL, 191 mmol) and butanol (25 mL) was heated at 100° C. for 6 days. After cooling, EtOAc was added, the solids removed by filtration and the solution concentrated in vacuo. Purification of the residue by silica gel chromatography (Hexane:EtOAc 4:1) afforded the title compound 16-2 as a white solid.
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH:23][OH:24])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1.C(O[C:32]([N:34]=[C:35]=[O:36])=[O:33])CCC.[OH-:37].[Na+].Cl>O1CCCC1>[O:37]=[C:35]1[NH:34][C:32](=[O:33])[O:24][N:23]1[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]3[CH:25]=[CH:26][C:4]([CH2:3][N:2]4[C:35](=[O:36])[NH:34][C:32](=[O:33])[O:1]4)=[CH:5][CH:6]=3)[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CCCCOC(=O)N=C=O
Reactant: [OH-]
Reactant: ONCc1ccc(Oc2cccc(Oc3ccc(CNO)cc3)c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(Cc2ccc(Oc3cccc(Oc4ccc(Cn5oc(=O)[nH]c5=O)cc4)c3)cc2)o1
Reaction time: 0.5 h

Procedure:
1,3-bis[4-(N-hydroxyaminomethyl)phenoxy]benzene (1.76 g) was dissolved in 35 ml of tetrahydrofuran to which, with ice-cooling and in an atmosphere of argon, was subsequently added dropwise 1.65 g of n-butoxycarbonyl isocyanate. After 30 minutes of stirring at the same temperature, 1N sodium hydroxide aqueous solution was added dropwise thereto and the stirring was continued for 30 minutes at room temperature. After adding 1N hydrochloric acid, the solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography to obtain 1.0 g of 1,3-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]benzene from fractions of chloroform-methanol (30:1) elution.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[N:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:14]([Mg]Br)[CH3:15]>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][CH3:15]
Reactant: C(=N/c1ncc[nH]1)\c1ccccc1
Reactant: CC[Mg]Br
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Product: CCC(Nc1ncc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To a solution of (1H-imidazol-2-yl)-[1-phenyl-meth-(E)-ylidene]-amine (0.19 ml, 1.63 mmol) in toluene (6 ml) was added scandium triflate (59 mg, 0.12 mmol). An ethereal solution of ethylmagnesium bromide (0.97 ml, 3 M, 2.91 mmol) was then added dropwise and the reaction mixture was stirred at room temperature for 2 hours and then quenched by the addition of saturated aqueous ammonium chloride solution. The mixture was extracted twice with ether and the organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant:methanol/dichloromethane 0:100 to 10:90) to yield the title compound as a brown gum (67 mg, 29%); MS (ISP): 202.4 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].[N:12]#[C:13][Br:14]>C(O)C.C(Cl)Cl>[BrH:14].[CH3:3][CH:2]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=[C:13]1[NH2:12])[CH3:1]
Reactant: N#CBr
Reactant: CC(C)Nc1ccccc1N
Solvent: CCO
Solvent: ClCCl
Product: Br
Product: CC(C)n1c(N)nc2ccccc21
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of N-(propan-2-yl)benzene-1,2-diamine (552 mg, 3.4 mmol) in ethanol (10 mL) is added a 3M solution of cyanogen bromide (1.35 mL, 4.04 mmol) in CH2Cl2. The reaction is stirred overnight and then concentrated. The crude residue is triturated with diethyl ether and the suspension is filtered to afford the title compound (870 mg, 92%) as a purple solid.
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].[C:14]1([CH:21]=CC=[C:17](O)[CH:16]=1)[OH:15]>>[OH:15][C:14]1[CH:21]=[C:4]2[C:5]([C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:1](=[O:2])[O:3]2)=[CH:17][CH:16]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C1CCCCCC1=O
Product: O=c1oc2cc(O)ccc2c2c1CCCCC2

Procedure:
The Applicant has now found that this compound can be synthesized in two chemical stages. The first stage consists of condensing in a strong acid (such as sulphuric acid, trifluoroacetic acid or methanesuiphonic acid) 2-carbetoxycycloheptanone with resorcinol, intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one is isolated by precipitation using an alcohol/water mixture (for example by adding ethanol then water). In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride, by the action of formic acid, then condensed with the previous intermediate dissolved in a solvent such as DMA. The reaction medium is treated with water and extracted by an organic solvent (preferably 2-methyltetrahydrofurane: MeTHF), and crude compound 1 is then precipitated from the organic phase by adding an antisolvent (preferably methylcyclohexane). Finally pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone or ethyl acetate while hot and precipitation by adding an antisolvent (preferably methylcyclohexane).
Reaction SMILES: [F:1][CH:2]([F:11])[P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6].C([N-]C(C)C)(C)C.[Li+].Br[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]1[CH3:27]>O1CCCC1>[CH3:28][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:2]([P:3](=[O:7])([O:8][CH2:9][CH3:10])[O:4][CH2:5][CH3:6])([F:1])[F:11]
Reactant: CC1C=CC=CC1(C)Br
Reactant: CCOP(=O)(OCC)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)Cc1ccccc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
30 mmol (5.64 g) of diethyl difluoromethane phosphonate dissolved in 30 ml of anhydrous tetrahydrofuran (THF) are slowly added to a stirred solution of (LDA) lithium diisopropylamide (prepared at 0° C. from 31 mmol of n-butyllithium and 30 mmol of diisopropylamine in 30 ml of anhydrous THF) at -78° C. under argon. After 30 minutes, 45 mmol (8.33 g) of 2-bromo-o-xylene are added to the reaction mixture which is stirred at -78° C. for 15 hours and quenched by adding 20 ml of an aqueous saturated solution of ammonium chloride. The crude mixture is evaporated to dryness; the residue is suspended in 50 ml of water and extracted 3 times with 100 ml of ethylacetate. The organic layers are dried over sodium sulfate, filtered and evaporated to give approximately 8 g of crude product which is purified by flash chromotography on silica gel affording 3.6 g of 1A (41% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cc(F)ccc2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cc(F)ccc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-fluorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about 1 hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-fluorobenzothiazol-2-yl isocyanate dimer.