Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([CH:9]2[CH2:11][CH2:10]2)[C:3]=1Br.C1(C)C=CC=CC=1.C[O:21]CCO[AlH2-]OCCOC.[Na+]>C1C=CC=CC=1>[CH:9]1([C:4]2[CH:5]=[CH:6][C:7]([OH:21])=[CH:2][CH:3]=2)[CH2:11][CH2:10]1
Reactant: COCCO[AlH2-]OCCOC
Reactant: Oc1ccc(Br)c(Br)c1C1CC1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 ml flask equipped with a reflux condenser, and magnetic stirring bar under a nitrogen atmosphere were placed 11 g (37.6 moles) of dibromocyclopropylphenol, 100 ml of toluene, and 50 g of 70% solution of "Red-Al" [sodium bis(2-methoxyethoxy aluminum hydride)] in benzene. The solution was then heated to reflux for 6 hours and allowed to stir overnight at room temperature. The reaction was then quenched with water and acidified with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with 100 ml of ether. The organic layers were combined and washed with dilute base. The water layer was then acidified with concentrated hydrochloric acid and extracted with methylene dichloride. The methylene dichloride extract was dried over anhydrous magnesium sulfate and the solvent evaporated. A yield of 3 g of 4-cyclopropylphenol, an amber oil, was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)(=[O:10])=[O:9])[CH:2]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[S:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:10])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Product: CCCCNC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reaction time: 48 h
Yield: 82 %

Procedure:
The title compound was prepared according to procedures described above, using methyl 2-[(pyridin-3-ylamino)sulfonyl]benzoate and n-butylamine. The title compound was further purified by dissolving 2.0 g in ethyl acetate (10 mL). Hexane was then added dropwise to the solution until it became cloudy. A few drops of ethyl acetate were then added to obtain a clear solution. The resulting solution was left at rt for approximately 48 h. The resulting solids were collected, washed with 20% ethyl acetate/hexane (3×150 mL), and dried under high vacuum overnight at rt to afford the title compound as a crystalline solid (1.64 g, 82%). 1H NMR (400 MHz, DMSO-D6) δ 9.90-10.00 (m, 1H) 8.73 (t, 1H) 8.28-8.37 (m, 2H) 7.71-7.76 (m, 1H) 7.61-7.70 (m, 2H) 7.49-7.57 (m, 2H) 7.35-7.44 (m, 1H) 3.25 (q, 2H) 1.51-1.54 (m, 2H) 1.29-1.40 (m, 2H) 0.90 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(O)C>[NH2:8][C:9]1[N:18]=[C:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:16]2[C:11](=[CH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc2c(Cl)nc(N)nc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 110 °C
Yield: 63.1 %

Procedure:
1-Methyl-piperazine (210 uL, 1.9 mmol) was added to a mixture of methyl 2-amino-4-chloroquinazoline-7-carboxylate (300 mg, 1 mmol) in ethanol (3 mL) and triethylamine (350 μL, 2.5 mmol). The mixture was heated in an oil bath at 110° C. for 1 h. The reaction mixture was concentrated to remove the ethanol and was partitioned between water and EtOAc. The organic phase was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated to give the crude product, (190 mg, 50%) as an off white amorphous solid. 1H NMR (300 MHz, DMSO) δ 2.23 (s, 3H), 3.56 (m, 4H), 3.86 (s, 3H), 3.90 (m, 4H), 6.53 (b, 2H), 7.50 (d, 1H), 7.80 (m, 2H); Analytic LCMS (M+H)+: m/z=302.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C=O.[C:17](O)(=O)[CH2:18][C:19]([OH:21])=[O:20].N1C=CC=CC=1>>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:17]=[CH:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)CCCCCCCCCCCC=O
Solvent: c1ccncc1
Product: CC(C)CCCCCCCCCCCC=CC(=O)O
Reaction time: 3 h

Procedure:
13-methyl-tetradecanaldehyde (56.5 g, 0.25 mole), malonic acid (26.5 g, 0.51 mole), and pyridine (30.8 ml, 0.374 mole) were added to a flask and refluxed with heating for 3 hours. After cooling down 30% sulfuic acid was added and the reaction mixture was stirred for 3 hours under ice bath and then extracted by diethyl ether. Diethyl ether was removed by evaporation and product was subject to vacuum fractional distillation and 170–172° C./1.0 mmHg fraction was collected as 15-methyl-2-hexadecenoic acid (50.9 g, yield rate 76%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3]/[CH:4]=[CH:5]/[C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[S:15]1[C:19]2=[CH:20][CH:21]=[CH:22][C:23]([S:24]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)(=[O:26])=[O:25])=[C:18]2[N:17]=[CH:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:12][C:6]1(/[CH:5]=[CH:4]/[CH2:3][C:2]([F:1])([F:13])[F:14])[CH2:7][CH2:8][N:9]([C:32]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][S:24]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[S:15][CH:16]=[N:17][C:18]=34)(=[O:26])=[O:25])=[CH:36][CH:35]=2)=[O:33])[CH2:10][CH2:11]1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Reactant: OC1(/C=C/CC(F)(F)F)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1)N1CCC(O)(/C=C/CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with (E)-4-(4,4,4-trifluorobut-1-enyl)piperidin-4-ol (50 mg 0.24 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (80 mg, 0.24 mmol), DIPEA (155 mg, 1.2 mmol), HATU (110 mg, 0.29 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.99 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.17-7.24 (m, J=8.3 Hz, 2H), 7.08-7.15 (m, J=8.1 Hz, 2H), 5.78-5.94 (m, 1H), 5.64-5.76 (m, 1H), 4.28-4.47 (m, 1H), 3.51 (s, 1H), 3.32-3.48 (m, 1H), 3.27 (br. s., 1H), 2.84 (dd, J=10.5, 7.0 Hz, 1H), 1.66 (br. s., 4H), 1.46 (d, J=9.7 Hz, 2H). LC-MS: m/z 526.7 (M+H)+
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>C1CCCCC1>[O:15]([C:22]1[CH:23]=[C:24]([NH:25][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][C:2]([F:14])([F:13])[F:1])[CH:6]=2)[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: FC(F)(F)COc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
EX-659B) The 3-(2,2,2-trifluoroethoxy)benzaldehyde (0.360 g, 1.76 mmol) product from EX-659A and 3-phenoxyaniline (0.326 g, 1.76 mmol) were combined in 50 mL of cyclohexane with 3A molecular sieves (1 g) and stirred overnight at 80° C. The mixture was cooled, filtered, and evaporated, then dissolved in 50 mL of methanol and cooled to 0° C. Solid sodium borohydride (0.030 g, 0.79 mmol) was added in portions, and the mixture was stirred overnight. The reaction was quenched with 5% aq. NaHCO3 and extracted with ether (3×). The combined ether layers were washed with water and brine, dried over MgSO4, filtered, and evaporated to give 0.50 g (76%) of the desired N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine product as an amber oil, >95% pure by normal phase HPLC analysis. MS m/z=373 [M+].
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].C([O-])(O)=O.[Na+]>ClC(Cl)C>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:2]([C:28]([O:30][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:29])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(C)c2c1OC(C)(C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A] A slurry of 6.9 g (12 mmoles) of Z-Arg(Pmc)-OH in 60 ml of dichloroethane was added with 8.64 ml (36 mmoles) of N,N-dimethylformamide-di-tert.-butylacetale, in 60 minutes at 50° C. At the end of the addition, the reaction mixture was kept under stirring for 40 minutes at 50° C., then it was added with 20 ml of an aqueous solution of 5% sodium hydrocarbonate. The dichloroethane was evaporated under vacuum and the aqueous phase was diluted with 100 ml of ethyl acetate. The organic phase was separated and washed with an aqueous solution of 5% sodium hydrocarbonate and with a saturated aqueous solution of sodium chloride till neutrality. The organic phase was then anhydrified and evaporated under vacuum, and the resulting crude was purified on a silica gel column (eluent: ethyl acetate/n-hexane 6:4). There were obtained 3.4 g of Z-Arg(Pmc)-OtBu (HPLC, gradient (I): R.t. 32 min.; purity 99%).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH:17]([CH3:19])[CH3:18].[OH-].[K+]>C(O)C.O>[CH:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1)([CH3:19])[CH3:18]
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(O)cc2)cc1
Yield: 44 %

Procedure:
4,4′-Oxydiphenol (3.68 g, 0.018 mmoL) and 2-iodopropane (1.82 mL, 0.018 mmoL) were dissolved in ethanol (3 mL) and heated at reflux. It was then treated with a solution of potassium hydroxide (0.0012 g, 0.019 mmoL) dissolved in H2O (3 mL) by addition over 10 min. The reaction was refluxed for 1 hr then it was concentrated in vacuo. The residue was dissolved in diethyl ether (50 mL) and washed with brine (1×50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, ethyl acetate:hexanes (25:75)) to afford 1.97 g (44%) of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 6.74-6.92 (m, 8H) 4.57 (s, 1H) 4.40-4.51 (m, 1H) 1.32 (d, J=5.88 Hz, 6H). MS m/z (DCI) 266 (M+NH4)+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11](C4C=CC5OCCNC=5N=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:33]1[N:34]=[N:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([CH:45]3[CH2:48][O:47][CH2:46]3)[CH2:41][CH2:40]2)=[CH:37][CH:38]=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11]([C:33]4[N:34]=[N:35][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:41][CH2:40]5)=[CH:37][CH:38]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Brc1ccc(N2CCN(C3COC3)CC2)nn1
Reactant: C[C@@H](Oc1cc(-c2ccc3c(n2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C4COC4)CC3)nn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 61 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 3-bromo-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazine as a starting material to afford 52.7 mg (61%) of (R)-4-((R)-1-((1-cyclopropyl-5-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.12 (s, 1H), 8.04 (d, J=9.9 Hz, 1H), 7.80 (d, J=1.1 Hz, 1H), 7.62 (m, 2H), 7.35 (d, J=9.9 Hz, 1H), 4.81 (m, 1H), 4.52 (m, 4H), 3.69 (m, 5H), 3.41 (m, 2H), 3.20 (m, 1H), 2.54 (m, 1H), 2.37 (m, 6H), 1.34 (d, J=6.3 Hz, 3H), 1.09 (m, 4H). MS (ESI+) m/z 504.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13]>[Cl-].[Zn+2].[Cl-]>[C:12]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:11]
Reactant: C=C(C)CC(C)(C)C
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C)CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
In a 2-liter reaction flask fitted with a condenser, nitrogen inlet, stirrer, thermometer and addition funnel is placed 272 grams (2.0 moles) of anhydrous zinc chloride. The flask is placed under a nitrogen atmosphere and 166 ml (2.0 moles) of concentrated (12 N) hydrochloric acid is added over a 10-minute period with the temperature rising from 22° to 40° C. To this is then added 276 grams (2.0 moles) of o-nitroaniline over a 15-minute period to avoid the formation of lumps. The resulting thick red slurry is heated to 60° C. and then 474 grams (3.0 moles) of diisobutylene is added gradually over a 110-minute period with the temperature rising during this period from 60° to 90° C. The deep red fluid reaction mixture is heated for another 18 hours at reflux till only a trace of o-nitroaniline is observed by thin layer chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COC(=O)C=CC=CCBr
Reactant: COc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCSc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.50 g, 7.3 mmol) and 4-methoxythiophenol (0.93 mL, 7.3 mmol) in tetrahydrofuran (40 mL) was added dropwise triethylamine (1.1 mL, 8.0 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for one hour, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (50 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography ((9:1 to 8:2 40-60° C. petroleum ether:diethyl ether) to give the title compound as a colourless oil (1.6 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:19][CH2:20][O:21][C:22](Cl)=[O:23]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:22](=[O:23])[O:21][CH2:20][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cccc(OC)c1
Reaction time: 1 h
Yield: 108.3 %

Procedure:
To a solution of {2-[3-(methyloxy)phenyl]ethyl}amine (20 g, 132.3 mmol) and triethylamine (20 g, 198 mmol) in dichloromethane (150 mL) was added ethyl chloridocarbonate (17.7 g, 163 mmol) dropwise at 0° C. After being stirred for 1 h the solvent was removed under vacuum and the residue was washed with ethyl acetate. Following filtration, the filtrate was concentrated to afford ethyl {2-[3-(methyloxy)phenyl]ethyl}carbamate (32 g, crude, 100%). 1H NMR(CDCl3) δ: 7.15-7.25 (1H), 6.7-6.8 (3H), 4.72 (1H), 3.75 (3H), 3.4 (2H), 2.75 (2H), 2.0 (3H), 1.15-1.3(2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:5]=1[C:6]#[N:7])([O-])=O.C(O)(=O)C.C>[Fe].CC(O)C>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:5]=1[C:6]#[N:7]
Reactant: COc1ccc([N+](=O)[O-])c(C#N)c1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(N)c(C#N)c1OC
Yield: 88.3 %

Procedure:
Iron powder (8.70 g, 156 mmol) was added to a suspension of 2-nitro-5,6-dimethoxybenzonitrile (9.30 g, 44.5 mmol) in an acetic acid (30 ml) and 2-propanol (30 ml) mixture. The mildly exothermic reaction which resulted was allowed to reach 100° and a gentle reflux was maintained for 1 hour with application of heat. Charcoal (10 g) was added, the reaction mixture filtered, and the solid residue obtained was washed with hot 2-propanol (100 ml). The combined filtrates were evaporated to an oily residue which was redissolved in CHCl3 and washed with 5% aqueous NaHCO3 and saturated aqueous NaCl solution. The CHCl3 phase was dried with Na2SO4 and evaporated in vacuo to yield 7.0 g (88.4%) of the target compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(SC(F)(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidin-2-one (1.30 g, 3.50 mmol) in ethanol (3 ml) was added 8N aqueous sodium hydroxide solution (1.31 ml,10.5 mmol), and the mixture was stirred at 80° C. for 4 hrs. To the reaction solution was added water (20 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (0.8 g, 77%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)=[O:33])[CH:27]=1>C1COCC1>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)([OH:33])[CH:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:27]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: O=C(c1cccnc1)c1ccncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1cccnc1)(c1ccncn1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, diisopropylamine (0.079 mL, 0.56 mmol) was dissolved in THF (1 mL). The solution was cooled to 0° C. n-Butyl-lithium (2.5 M solution in hexanes, 0.215 mL, 0.54 mmol) was slowly added and the reaction was stirred at 0° C. for 15 min. A solution of 3-(pyridin-3-ylmethyl)pyridine (0.087 g, 0.51 mmol) in THF (1mL) was slowly added drop-wise. The reaction became dark red. After 10 min. a solution of pyridin-3-yl(pyrimidin-4-yl)methanone (0.099 g, 0.54 mmol, J. Heterocyclic Chem., 34, 17 (1997)) in THF (1 mL) was slowly added drop-wise. The reaction was stirred at 0° C. for 3 hr then removed from the ice bath. Sat. aq. NH4Cl (20 mL) was added and the reaction was stirred vigorously. The product was extracted with EtOAc (4×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford an oil which was purified by reverse phase HPLC (5-95% CH3CN/H2O+0.05% NH4OH). The fractions were combined and concentrated in vacuo to afford the title compound as a white solid. 1H NMR (CDCl3) δ 9.01 (d, 1H, J=1.22 Hz), 8.85 (d, 1H, J=1.95 Hz), 8.70 (d, 1H, J=5.37 Hz), 8.58 (d, 1H, J=2.19 Hz), 8.42 (dd, 1H, J=1.46 Hz), 8.38-8.33 (m, 3H), 7.94-7.87 (m, 2H), 7.70-7.67 (m, 1H), 7.07 (dd, 1H, J=1.22 Hz), 7.19-7.14 (m, 1H), 7.13-7.08 (m, 2H), 5.98 (s, 1H), 5.12 (s, 1H). HRMS m/z (M+H) Calculated: 356.1506, found: 356.1519.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]#[N:19])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:20][NH:21][CH3:22]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([N:21]([CH3:22])[CH3:20])=[NH:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2NC#N)c1
Reactant: CNC
Product: CN(C)C(=N)Nc1ccccc1-c1cccc(S(C)(=O)=O)c1

Procedure:
A mixture of N-(3'-methanesulphonyl-2-biphenylyl)-cyanamide (2.7 g) and 33% ethanolic dimethylamine solution (25 ml) was heated under reflux for 3 hours to give N-(3'-methanesulphonyl-2-biphenylyl)-N',N'-dimethylguanidine (m.p. 113°-114° C.) which was recrystallised from ethylacetate.
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])=[O:17])([CH3:3])[CH3:2].[NH3:34].CO.C(Cl)Cl>CO>[CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([NH2:34])=[O:26])=[O:17])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCCSC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)SCCCCCCCCCCCC(=O)Nc1ccccc1OCCCC(N)=O

Procedure:
To a stirred solution of (7) (20 mg, 0.041 mM) in methanol (10 mL) is added methanol saturated with ammonia (5 mL) and the stoppered mixture allowed to stir at ambient temperatures until TLC analysis shows little or no (D) remains. Concentration of the reaction mixture followed by preparative thin layer chromatography (silica gel; 3% methanol/methylene chloride as eluant) yields product 9 (11 mg) as a waxy solid.