Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>ClCCl.CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2ccccc2cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reaction time: 0.5 h

Procedure:
3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10° C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15° C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutralized by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dichloromethane (2×150 ml), then dried (Na2SO4) and evaporated to give the crude product (2.69 g) as a yellow solid. Flash column chromatography using as eluant 5% methanol in dichloromethane gave a pure sample of the title compound (660 mg) and a sample (1.95 g) containing ca. 10% of the 8-nitro isomer.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[NH:19]1[CH2:22][CH:21]([C:23]2[C:24]([O:43][CH3:44])=[C:25]([CH:31]([NH:33][C:34]3[N:42]=[CH:41][N:40]=[C:39]4[C:35]=3[N:36]=[CH:37][NH:38]4)[CH3:32])[CH:26]=[C:27]([Cl:30])[C:28]=2[CH3:29])[CH2:20]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[Cl:30][C:27]1[C:28]([CH3:29])=[C:23]([CH:21]2[CH2:22][N:19]([C:3]([NH:2][CH3:1])=[O:4])[CH2:20]2)[C:24]([O:43][CH3:44])=[C:25]([CH:31]([NH:33][C:34]2[N:42]=[CH:41][N:40]=[C:39]3[C:35]=2[N:36]=[CH:37][NH:38]3)[CH3:32])[CH:26]=1.[C:14]([OH:16])([C:13]([F:18])([F:17])[F:12])=[O:15]
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reactant: CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)N1CC(c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl isocyanate (1.3 μL, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H25ClN7O2 (M+H)+: m/z=430.2. found: 430.2. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (1H, br s), 8.18 (2H, m), 7.44 (1H, s), 6.31 (1H, m), 5.68 (1H, m), 4.20 (3H, m), 3.96 (1H, m), 3.82 (1H, m), 3.75 (3H, s), 2.52 (3H, s), 2.15 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.CCN(CC)CC.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:18]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCCc1ccc(Br)cc1)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a mixture of 2-(4-bromophenyl)ethanol (1.00 g, 4.97 mmol, 1.00 equiv) and Et3N (0.763 ml, 0.554 g, 5.47 mmol, 1.10 equiv) in a round-bottom flask in THF (20 ml) was added benzoyl chloride (0.589 mL, 0.713 g, 5.07 mmol, 1.02 equiv). The reaction mixture was stirring for 4 h at 23 ° C. and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 1:1 (v/v) to afford 1.50 g of the title compound as a colorless solid (99%). Rf=0.7 (hexanes/EtOAc 1:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.00 (d, J=7.2 Hz, 1H), 7.58-7.54 (m, 1H), 7.45-7.42 (m, 4H), 7.16 (d, J=8.4 Hz, 2H), 4.51 (t, J=6.4 Hz, 2H), 3.04 (t, J=6.4 Hz, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 166.6, 137.1, 133.1, 131.8, 130.8, 130.3, 129.7, 128.5, 120.6, 65.2, 34.8.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([Pb+3])=[C:31]([CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH3:37])[CH:30]=1
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: Cc1cc(Br)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 7.6 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6 g, 0.039 mol) and 4-dimethylaminopyridine (24 g, 0.196 mol) are added to a mixture of chloroform (120 ml) and toluene (30 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2,6-dimethylphenyllead triacetate (24 g, 0.042 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×100 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2,6-dimethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (1 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CC(N(C)C)=O>[CH:25]1([NH:28][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:22])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NC1CC1
Solvent: CC(=O)N(C)C
Product: O=C(NC1CC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 5 and using dimethylacetamide as the reaction solvent. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.86 (1H, s), 10.87 (1H, s), 10.14 (1H, s), 8.20 (1H, s), 7.38-7.25 (6H, m), 4.01 (2H, br s), 2.79 (1H, m), 0.70 (2H, m), 0.45 (2H, m); HRMS calcd for C19H17N3O3+H+: 336.1348. Found: 336.1347.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:20]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])(=[O:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:27])(=[O:22])[CH3:21]
Reactant: CC(=O)NCCC(=O)O
Reactant: COC(=O)CC(CSCCN)C(=O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CC(CSCCNC(=O)CCNC(C)=O)C(=O)c1cccnc1
Yield: 75 %

Procedure:
A solution of methyl 3-[(2-aminoethylthio)methyl]-4-oxo-4-(3-pyridyl)butanoate (747 mg), 3-(acetylamino)propanoic acid (302 mg), dicyclohexylcarbodiimide (433 mg), 1-hydroxybenzotriazole (567 mg) and N-methylmorpholine (402 mg) in dichloromethane (10 mL) were stirred at room temperature overnight. The solution was concentrated and purified by flash chromatography (SiO2, chloroform:methanol=9:1) to give the title compound in 75% yield; ESMS (M+1)+353.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]1[C:9]([O:11]CC)=[O:10])[CH3:2].CO.C1COCC1.[OH-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]1[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: CCOC(=O)c1cc(C)cn1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCn1cc(C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 204 h
Yield: 78.9 %

Procedure:
To a mixture of ethyl 1-ethyl-4-methyl-1H-pyrrole-2-carboxylate (0.66 g), methanol (5.0 ml), and THF (5.0 ml) was added a 1 M aqueous sodium hydroxide solution (5.0 ml) under ice-cooling, followed by stirring at room temperature for 8.5 days. Water was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The residue was washed with diethyl ether, and citric acid was added to the aqueous layer under ice-cooling. The solid precipitated was collected by filtration, washed with water, and dried to obtain 1-ethyl-4-methyl-1H-pyrrole-2-carboxylic acid (0.44 g).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:29].Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>C(O)C.O.C(OCC)(=O)C>[OH:32]/[N:31]=[C:8](/[C:6]1[CH:5]=[CH:4][C:3](=[O:29])[N:2]([CH3:1])[CH:7]=1)\[CH2:9][C@@H:10]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 120 °C
Yield: 97.1 %

Procedure:
To a microwave vial was added (R)-1-methyl-5-(3-(4-(methylsulfonyl)phenyl)-3-o-tolylpropanoyl)pyridin-2(1H)-one (168 mg, 410 μmol), hydroxylamine hydrochloride (85.5 mg, 1.23 mmol) and sodium hydrogencarbonate (103 mg, 1.23 mmol) in ethanol (3 mL) and water (0.2 mL). The vial was capped and heated at 120° C. for 15 min. The reaction mixture was diluted with ethyl acetate and poured onto water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afforded the title compound (169 mg, 97%) as a mixture of the E and Z isomers (ratio ca. 85:15). Light yellow foam, MS (ESI+): m/z=425.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1ccncc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccncc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4-aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-4-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[Na+].[Na+]>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:21])([F:20])[F:10])[CH:13]=2)[C@@H:4]([C:7]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)=[O:8])[CH2:3]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D8) (1.02 g) was prepared according to the general procedure for substituted benzyl amines preparation starting from cis-4-Hydroxy-D-proline (4.0 g; available from Aldrich#H5877) and 3-(Trifluoromethyl)benzyl bromide (9.37 ml). (Na2CO3: 2.5 eq; Reaction time: 24 hrs; 60° C.).
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[CH:10][C:11]=1[Br:12].[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Br:12][C:11]1[CH:10]=[CH:9][O:8][C:7]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: Brc1ccoc1Br
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1NC(=O)C(c2occc2Br)C(=O)N1
Temperature: -20 °C

Procedure:
n-Butyl lithium is reacted with 2,3-dibromofuran in ether at -70° C. according to the procedure of Zaluski et al. [Bull. soc. chim. Fr., p. 1843 (1970)] and Sornay et al. [loc. cit., p. 990 (1971)]. The reaction mixture is warmed to -20° C. and an equivalent of anhydrous alloxan in tetrahydrofuran is added dropwise. Reaction is allowed to proceed to completion by warming to room temperature for 2 hours. The product, 5-(3-bromo-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione is isolated according to the method of Example 5.
Reaction SMILES: [C:1]1([C:7]2([N:13]=[N+]=[N-])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[C:1]1([C:7]2([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NC1(c2ccccc2)CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: NC1(c2ccccc2)CCCCC1
Temperature: 0 °C

Procedure:
The crude azide (18.0 g, ≤96 mmol) was dissolved in dioxane (300 mL) with triphenylphosphine (40 g, 152 mmol) and the stirred solution was refluxed for 4 h. under N2 (g) before adding H2O (9 mL, 0.5 mol). After about 46 h. further reflux, solvent was removed in vacuo at about 45-50° C. and residual moisture was removed by azeotropic distillations in vacuo with CH3CN and Et2O, respectively. The syrupy residue was dissolved in boiling Et2O and chilled to about 0° C. for about 16 h. Precipitated Ph3PO was removed by filtration, and 1M HCl in Et2O (90 mL) was added dropwise at about 5° C. to the etherol filtrate to precipitate the desired 1-phenyl-cyclohexylamine as its HCl salt (12.7 g, LC-MS m/z 162 (MH+)) which was recrystallized from CHCl3 /i-Pr2O before use.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=[CH2:28])[CH2:19][CH2:18][O:17][C:16]=3[CH:29]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:41]CC1.[OH2:45]>CC(O)(C)C.O=[Os](=O)(=O)=O>[OH:45][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:29]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2)[CH2:28][OH:41]
Reactant: C=Cc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(O)CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.5 %

Procedure:
To a solution of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-4-(2-vinylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (750 mg, 1.445 mmol) in t-BuOH (10 mL) and water (5 mL) was added NMO (338 mg, 2.890 mmol, Aldrich) followed by OsO4 (4% in water) (0.7 mL, 0.144 mmol, Aldrich) at 0° C. The reaction mixture was stirred at ambient temperature for 12 h. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated reduced pressure to obtain crude 4-(2-(1,2-dihydroxyethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 37.5%) which was used in the next step without purification. m/z (ESI) 553.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH3:9])[C:4](=O)[N:5]([CH3:7])[CH3:6])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:3]([CH3:9])[C:4]([N:5]([CH3:7])[CH3:6])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:2]
Reactant: CCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-ethyl-1,1,3-trimethylurea (6.57 g) in benzene (70 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 65°-70° C. gave 1-ethyl-2-(2-morpholinophenyl)-1,3,3-trimethylguanidine (bp. 140° C. at 0.2 mm Hg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 2 L two-necked round bottom flask was charged methyl 4-hydroxybenzoate (100 g, 0.657 mol) and 500 mL of DMF. Potassium carbonate (180 g, 1.3 mol) was added and the mixture was cooled to 0° C. Benzylbromide (77 mL, 0.66 mol) was added dropwise to the reaction mixture with vigorous stirring for 30 min. After the addition was complete, the reaction mixture was stirred for 8 h at RT, then diluted with 500 ml water. The solid precipitated was collected by filtration and washed with water. Drying in a vacuum oven overnight provided the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][C:21]#[N:22])SC)[N:11]=1.[CH3:26][NH:27][NH2:28].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]>CN(C)C=O.CC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[NH2:22][C:21]1[N:20]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH2:23])=[N:4][CH2:3][C:2]([F:25])([F:24])[F:1])[S:8][CH:9]=2)[N:27]([CH3:26])[N:28]=1
Reactant: CNN
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: CSC(=NC#N)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Product: O=C(O)/C=C\C(=O)O

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-cyano-2-methylisothioureido)butyl]thiazole (0.23 g.) and N-methylhydrazine (0.6 g.) in dimethylformamide (15 ml.) was heated at 40°-45° for 40 hours. The solvent was removed and the residue applied to 2 t.l.c. plates which were developed with chloroform/methanol/ammonia 9:1:0.1 v/v/v. The oil obtained was converted to a maleate in acetone to give 3-amino-1-methyl-5-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]-1H-1,2,4-triazole dimaleate (56.8 mg.), m.p. 181°-183°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:10]([C:5]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[C:3]([OH:9])[CH:4]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: OCC=Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: Cc1cc(O)c(O)cc1CC=Cc1ccccc1
Yield: 49.6 %

Procedure:
A mixture of 1,2-dihydroxy-5-methylbenzene (124 g.) and cinnamyl alcohol (134 g.) in 2% aqueous citric acid (1.5 l.) containing ascorbic acid (10.0 g.) was boiled at reflux for 20 hours. After cooling, an oily layer separated and was collected and distilled to give 4-cinnamyl-5-methyl-1,2-dihydroxybenzene (119 g.) as a colorless oil, b.p. 205°-230° at 1.0 mm Hg. The oil was crystallized from a benzene/low-boiling petroleum ether (1/1) mixture to give colorless needles, m.p. 85°. Found: C, 79.9; H, 6.68. Calculated for C16H16O2 : C, 80.0; H, 6.71. The 100 MHz nuclear magnetic resonance (nmr) spectrum of this compound in deuterated chloroform exhibited a singlet (3 protons) at δ 2.07, a doublet (2 protons) at δ 3.37 (J = coupling constant = 5.0 Hz), a singlet (2 protons) at δ 5.02, a multiplet (2 protons) at δ 6.23-6.31, a singlet (1 proton) at δ 6.65, a singlet (1 proton) at δ 6.68, and a multiplet (5 protons) at δ 7.10-7.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:35].Cl[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:46]3[CH2:47][CH2:48][C:43]([C:38]4[CH:39]=[CH:40][C:41]([Cl:35])=[CH:42][CH:37]=4)([C:49]([NH2:51])=[O:50])[CH2:44][CH2:45]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cl
Reactant: NC(=O)C1(c2ccccc2Cl)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccc(Cl)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.75 g, 1.4 mmol) and 4-(chloro-phenyl)-piperidine-4-carboxylic acid amide hydrochloride (1.85 mmol) to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][C:10](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH:9]=[C:8]1[CH3:19]>N1C=CC=CC=1.O>[Cl-:1].[C:15]([C:14]([C:17]#[N:18])=[C:10]1[CH:11]=[C:12]([CH3:13])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][N+:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:8]([CH3:19])=[CH:9]1)#[N:16]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)N1CCOCCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1=CC(=C(C#N)C#N)C=C(C)N1CCOCC[n+]1ccccc1
Product: [Cl-]

Procedure:
A 50 ml reaction flask, equipped with a reflux condenser, a heating bath and a magnetic stirrer was charged under Argon with 1.4 g (5 mmol) of the above 2-{1-[2-(2-chloro-ethoxy)-ethyl]-2,6-dimethyl-1H-pyridin-4-ylidene}-malononitrile in 25 ml of pyridine and heated to reflux for 5 hours. A heavy suspension was formed, which was filtered off and washed with a small amount of cold pyridine followed by THF. After drying 1.69 g of fine crystals were obtained, m.p. 248-251° C./decomp. UV (water) 352 nm (E=1149). Solubility in water>>200 g/l.