Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12
Reactant: COC(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 58.7 %

Procedure:
A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0 mmol) and K2CO3 (12.1 g, 87.5 mmol) in Ph2O was heated at 180° C. for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from a mixture of ethyl acetate-hexanes to afford 38 (3.6 g, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4 and 10.0 Hz, 1H), 8.27 (s, 1H), 8.21 (m, 1H), 7.77 (dd, J=8.0 and 9.2 Hz, 1H), 7.06 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=4[O-:39])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc[n+]2[O-])cc1
Yield: 57.5 %

Procedure:
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino }benzamide (200 mg, 0.5 mmol) was dissolved in dichloromethane (50 mL) and stirred while adding 3-chloroperbenzoic acid (85%, 200 mg). The solution was stirred for one hour at 25° C., then washed twice with sodium bicarbonate solution and dried. The solvent was evaporated to give the title compound as a white solid (120 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.35 (s, 2H), 7.18 (d, 2H), 7.31(d, 1H), 7.42 (m, 2H), 7.60 (m, 2H), 7.78 (m, 1H), 7.99 (d, 2H), 8.36 (m, 2H), 9.84 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]([CH3:10])=O.CS(O)(=O)=O>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH2:5][O:6][C:8]([CH3:10])([CH3:7])[O:4]1
Reactant: CC(C)=O
Reactant: OCC(O)CO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)OCC(CO)O1
Yield: 83.1 %

Procedure:
Glycerin (250 g), acetone (522 g) and 800 mL of toluene were charged into a 2 L four-neck flask to which a thermometer, a nitrogen inlet tube, a stirrer and a dehydrating column with a condenser were attached, and then, methane sulfonic acid (26 g) was added thereto and refluxed for 30 hours while removing the distilled water. Next, a potassium hydroxide solution was added to neutralize the reaction mixture. The reaction product was washed with ion exchanged water five times, and after that, the toluene was distilled off under reduced pressure, and thus, 298 g of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolan was obtained.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C)C=O>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(OCc2ccccc2Cl)c1
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
To 1.31 g (9.22 mmol) of orcinol monohydrate in 20 mL anhydrous N,N-dimethylformamide under a nitrogen atmosphere was added 220 mg (9.17 mmol) of NaH (100%). After 5 min, 1.30 mL (10.0 mmol) of 2-chlorobenzyl bromide was added. The reaction mixture was stirred for 2 h and then quenched with 1 N HCl. The reaction mixture was extracted into ethyl acetate (200 mL). The organic phase was washed with water (4×100 mL), dried (MgSO4), and concentrated in vacuo. Purification by flash chormatography (diethyl ether/hexane (50:50 to 100:0) gave 656 mg of the title compound as a glass. 1H-NMR (300 MHz, CDCl3) δ 7.54 (dd, 1 H, J=3, 7 Hz), 7.39 (dd, 1 H, J=3, 7 Hz), 7.2-7.3 (m, 2 H), 6.41 (s, 1 H), 6.29-6.30 (m, 2 H), 5.29 (s, 2 H), and 2.28 (s, 3 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][OH:19]>>[CH3:18][O:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CO
Product: COc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and methanol to give (1-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 241(MH+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19]>C(#N)C>[F:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[N:3]1[CH2:4][C@@H:5]([CH3:8])[NH:6][CH2:7][C@@H:2]1[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Yield: 40.4 %

Procedure:
trans-2,5-Dimethylpiperazine (4.81 g, 42.1 mmol) and 1,2-difluoro-4-nitrobenzene (10.00 g, 62.9 mmol) are dissolved in 60 mL of dry acetonitrile and refluxed for 3 h, upon which a yellow precipitate forms on the bottom of the flask. The crude reaction mixture is concentrated in vacuo and the residue is chromatographed (silica gel, 10% MeOH in CH2Cl2) to give 4.32 g (17.0 mmol, 40%) of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.01 (d, J=6.0 Hz, 3H), 1.09 (d, J=6.3 Hz, 3H), 2.45 (dd, J=11.5, 9.0 Hz, 1H), 2.72 (dd, J=12.1, 9.0 Hz, 1H), 3.05-3.12 (m, 1H), 3.15 (dd, J=12.1, 3.3 Hz, 1H), 3.26 (dd, 2H), 7.12 (t, J=8.5 Hz, 1H), 7.91 (dd, J=11.2, 2.4 Hz, 1H), 7.95-8.01 (m, 1H). LCMS-ESI (m/z): calcd for C12H16FN3O2, 253.1; [M+H]+ found, 254.4.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C@H:18]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C:20](=[CH:21][CH2:22][C@@H:23]4[C@@H:39]3[CH2:38][CH2:37][C@@:36]3([CH3:44])[C@H:24]4[CH2:25][CH2:26][C@@H:27]3[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]2)(=O)=O)=CC=1.[I-:46].[Na+]>CC(C)=O>[I:46][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 48 h

Procedure:
A solution of cholest-5-en-3β-yl 6-(p-toluenesulfonyloxy)hexyl ether (33 g, 51 mmol) and sodium iodide (16 g, 0.106 mol) in acetone (250 ml) was refluxed for 4 hours. The solvent was removed under reduced pressure, filtered, and the collected salts washed well with ether. The filtrate was evaporated and residual yellow oil boiled in hexanes (400 ml). The solution was decanted, concentrated to 200 ml, and stored in the refrigerator for two days. The product was filtered and the mother liquors concentrated to give a total yield of 30 g (97%), m.p. 103.5°-104.5° C.
Reaction SMILES: [OH-].[K+].[N+:3]([CH3:6])([O-:5])=[O:4].[C:7]([C:11]1[CH:16]=[C:15]([CH2:17]OC)[CH:14]=[C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=1[OH:24])([CH3:10])([CH3:9])[CH3:8].[C:25]([OH:28])(=O)[CH3:26]>CO>[C:7]([C:11]1[CH:16]=[C:15]([CH2:17][CH:6]([N+:3]([O-:5])=[O:4])[CH2:17][C:15]2[CH:16]=[C:26]([C:7]([CH3:8])([CH3:9])[CH3:10])[C:25]([OH:28])=[C:13]([C:20]([CH3:23])([CH3:21])[CH3:22])[CH:14]=2)[CH:14]=[C:13]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:12]=1[OH:24])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(=O)O
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(CC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)[N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a solution of 14.5 g (0.22 mole) of 85% potassium hydroxide in 300 ml of methanol was added in a stream of nitrogen to exclude air 13.4 g (0.22 mole) of nitromethane and 50.0 g (0.2 mole) of 2,6-di-t-butyl-4-methoxymethylphenol. The magenta solution was stirred for one hour at reflux, with exclusion of air. After cooling somewhat, the solution was neutralized with 13 ml of acetic acid and chilled. A thick paste formed which was filtered, washed and dried. The resulting tan powder (48.1 g, mp 152°-154° C) was recrystallized from 500 ml of heptane, after filtering insoluble matter (10.4 g). The yield of tan crystals was 32.3 g, mp 161°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42]CO)[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:18][CH:17]=1
Reactant: OCCCN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCN4CCOCC4)cc3)c2cc1OC
Yield: 48.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-morpholino-1-propanol (38 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (38 mg, yield 41%).
Reaction SMILES: C[O:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.N>C(Cl)Cl.CO>[OH:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(=O)c3ccccc3oc12
Agent: BrB(Br)Br
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=c1c2ccccc2oc2c(O)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 4-methoxy-xanthen-9-one (12 g, 53 mmol) in methylene chloride (100 mL) at 0° C. was added a 1M solution of boron tribromide in methylene chloride (160 mL, 160 mmol) and the mixture was stirred at rt for 2 h. The reaction was slowly poured into a solution of ammonia in methanol (2M). The reaction was concentrated under reduced pressure and the resulting residue was partitioned between 1N HCl and methylene chloride. The organic phase was separated, dried over MgSO4, filtered, and evaporated to afford 7.5 g of Compound 3a, without further purification. MS m/z (M-H)− 243.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH2:11][NH:12][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=CCN)c2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CCNS(=O)(=O)c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 5 h
Yield: 88 %

Procedure:
2.69 g of 3,3-bis-(4-methoxyphenyl)allylamine was dissolved in 5 ml of pyridine. To the obtained solution, 1.9 g of benzenesulfonyl chloride was added under icecooling and the mixture was stirred for five hours. After the completion of the reaction, the reaction mixture was dissolved in ethyl acetate and washed with 5% hydrochloric acid and a saturated saline solution successively. The crude product thus obtained was purified by silica gel chromatography in a conventional manner. Thus 3.6 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1.[Br:25]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(#N)C>[Br:25][C:22]1[CH:23]=[C:18]([C:10]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[C:19]([NH2:24])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1-c1nc2cnccc2n1-c1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1-c1nc2cnccc2n1-c1cccc(F)c1F
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A solution of 3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (2.4 g, 7.43 mmol) in acetonitrile (70 mL) was treated with N-bromosuccinimide (1.45 g, 18.17 mmol) at 0° C. and the reaction mixture stirred for 30 min. reaction mixture was treated with saturated aq. NaHCO3 solution (150 mL), stirred for 30 min, and the resulting precipitate filtered and dissolved in CHCl3 (200 mL). The combined organics were washed with water (3×70 mL), brine (70 mL), and dried (Na2SO4). Filtration and evaporation of solvent in vacuo gave a solid, which was purified by silica gel chromatography (4% methanol/chloroform) to give 5-bromo-3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (2.2 g, 75% yield) as a light yellow solid; LC-MS: 402.0, 404.0 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]C(C)(C)C.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CCCCC>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cc(I)cc(OC)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Temperature: -20 °C
Yield: 70.9 %

Procedure:
To a solution of 5.28 g (20 mmol) of 1-iodo-3,5-dimethoxybenzene (W. Riedhl, F. Imhof, Justus Liebigs Ann. Chem., 1955;597:153–157) in 100 mL of THF at −78° C. is added 12.3 mL (21 mmol) of 1.7 M tert-BuLi in pentane, and after a further 5 minutes 4.4 g (30 mmol) of diethyl oxalate is added. After being allowed to warm to −20° C., the mixture is quenched with aqueous NH4Cl, and the THF is removed under vacuum. Work-up in EtOAc, followed by chromatography on silica, eluting with hexane/EtOAc (9:1) gives 3.38 g (71%) of the title compound as an oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[C:31]([C:35]([O:37][CH3:38])=[S:36])=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[CH2:39][CH2:40][CH3:41])=[CH:21][CH:20]=1)#[N:12].O1CCCC1>CS(C)=O>[OH:3][NH:2][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[C:31]([C:35]([O:37][CH3:38])=[S:36])=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[CH2:39][CH2:40][CH3:41])=[CH:21][CH:20]=1)=[NH:12]
Reactant: CCCc1nc2cccc(C(=S)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCc1nc2cccc(C(=S)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NO)cc1
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (20.85 g) in DMSO (200 ml) was added triethylamine (3.9 g) and the mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added the compound (16 g) obtained in Example (34c), and the mixture was stirred for 60 hours at 70° C. To the resultant mixture was added tetrahydrofuran (100 ml). After removal of crystalline precipitate by filtration, the filtrate was concentrated to dryness. The residue was partitioned between water (1.2 liter) and ethyl acetate (350 ml), and the upper layer was washed with water (70 ml×3). Ethyl acetate was evaporated under reduced pressure, and to the residue was added methanol (70 ml). Resulting crystalline precipitate was filtered off. The filtrate was concentrated to dryness under reduced pressure to give the title compound as a pale yellow syrup (13.0 g, 76%).
Reaction SMILES: [CH:1]([C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10](CNC(N)=S)[CH2:9][CH2:8]1)=[O:5])([CH3:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].[C:24]([NH:32][C:33]([NH:35]CC1CCC(NC(C(C)C)=O)CC1)=[S:34])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.CO>[C:24]([N:32]([CH3:18])[C:33]([NH:35][CH:10]1[CH2:9][CH2:8][CH:7]([NH:6][C:4]([CH:1]([CH3:2])[CH3:3])=[O:5])[CH2:12][CH2:11]1)=[S:34])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)C(=O)NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1
Reactant: CC(C)C(=O)NC1CCC(CNC(N)=S)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(=O)NC1CCC(NC(=S)N(C)C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Similarly, N-Benzoyl-N′-[4-(2-methoxyethylformyl-amino)-cyclohexyl]methylthiourea was obtained: 100% yield, 378 (ESMS, MH+); 1H NMR (CDCl3) δ 10.85 (broad, 1H), 9.03 (broad, 1H), 8.18 & 8.08 (two s, 1H), 7.84 (d, 2H, J=7.9 Hz), 7.64 (m, 1H), 7.52 (d, 2H, J=7.8 Hz), 3.63-3.24 (m, 7H), 3.34 & 3.33 (two m, 3H), 2.03-1.13 (m, 9H). N-[4-(Isopropylformylamino)cyclohexyl]methylthiourea: K2CO3 (2 equivalents) in water was added to a solution of N-benzoyl-N′-[4-(isopropylformylamino)-cyclohexyl]methyl-thiourea in MeOH and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOH. The solution was filtered to remove a white precipitate and the filtrate concentrated. The crude product was chromatographed to yield the desired product: 100% yield; 100% yield; 258 (ESMS, MH+); 1H NMR (CD3OD) δ 8.15 & 8.13 (two s, 1H), 4.15 & 3.73 (two m, 1H), 3.34 & 2.97 (two m, 1H), 3.29 (m, 2H), 1.26 (d, 3H, J=6.7 Hz), 1.23 (d, 3H, J=6.7 Hz), 1.91-1.03 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21]([S:22][CH2:23][CH2:24][CH3:25])=[CH:20][C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH3:29])[C:17]2=[O:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(Cl)Cl>[CH2:27]([N:18]1[C:19](=[O:26])[CH:20]=[C:21]([S:22][CH2:23][CH2:24][CH3:25])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:17]1=[O:30])[CH2:28][CH3:29]
Reactant: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Yield: 48.3 %

Procedure:
A mixture of 1-(2'-cyanobiphenyl-4-yl)methyl-3-propyl-6-propylthiopyrimidine-2,4(1H,3H)-dione (0.77 g), sodium azide (1.8 g) and ammonium chloride (1.48 g) in dimethylformamide (10 ml) was heated at 115° C. for 84 hours. The reaction mixture was diluted with methylene chloride and then the precipitate was filtered. The filtrate was concentrated to dryness in vacuo. The resulting residue was extracted with methylene chloride water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give yellow amorphous powders (0.41 g, 46%).
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.[P:11]([OH:14])([OH:13])[OH:12].C>O.ClC1C=CC=CC=1>[NH2:5][CH2:6][CH2:7][C:8]([OH:10])([P:11]([OH:14])(=[O:12])[OH:13])[P:11]([OH:14])(=[O:13])[OH:12]
Reactant: OP(O)O
Reactant: NCCC(=O)O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Solvent: O
Product: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Reaction time: 3 h

Procedure:
206 gm (1.5 mols) of phosphorus trichloride are slowly dropped while stirring into a mixture heated in a boiling water bath of 89.1 gm (1 mol) of β-alanine, 123 gm (1.5 mols) of phosphorous acid, and 500 ml of chlorobenzene, and heating on the boiling water bath is continued for a further 3 hours. During this time the contents of the flask become solid. After the reaction is finished, 600 ml of water are added and the product is heated for a short time, treated with animal charcoal and filtered while hot. The 3-amino-hydroxypropane-1,1-diphosphonic acid gradually crystallizes out from the aqueous phase in a cooling cabinet. The mother liquor is concentrated and treated with methanol, whereupon still further diphosphonic acid is precipitated. The 3-amino-1-hydroxypropane-1,1-diphosphonic acid is then recrystallized from water.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([I:7])[N:6]=1.S(=O)(=O)(O)O.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[NH:6][C:5]([I:7])=[C:4]([N+:13]([O-:15])=[O:14])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nc(I)c[nH]1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1nc(Cl)[nH]c1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
2-Chloro-4-iodoimidazole (431 mg) was suspensed in concentrated nitric acid (d. 1.38) (2.5 ml), under ice-cooling, concentrated sulfuric acid (2.5 ml) was added, and stirred at a room temperature for 6 hours. Then, the diposited matters were collected by filtration, and dried, there was obtained 2-chloro-5-iodo-4-nitroimidazole (348 mg, yield: 67.0%) as yellow solid product.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH3:5]>>[C:1]([CH2:2][CH2:3][NH:5][CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: C=CC#N
Reactant: N
Product: N#CCCNCCC#N

Procedure:
It is advantageous to introduce the acrylonitrile into the reactor at a space velocity of about 0.05 to 0.6 hr-1. Simultaneously, a gaseous ammonia charge is introduced into the reactor via a distribution device; e.g. a frit at the lower floor of the column, preferably in such an amount that the acrylonitrile and ammonia flow through the reaction chamber at a mole ratio of 2 : 1. According to the method of the present invention, the ammonia is completely absorbed as the gas bubbles rise. Furthermore, the ascending gas bubbles insure an intimate mixing of the reactants and thus an immediate reaction occurs resulting in the formation of bis-(2-cyanoethyl)-amine. The reaction product is removed at the lower end of the reactor above the distribution device. It is recovered as a clear liquid with a water content between 8 and 15% depending on the water concentration in the acrylonitrile. The yields obtained are greater than 90%.