Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[NH:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)C>[CH2:29]([O:28][C:26]([C:25]1[N:8]=[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]([C:10]2[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[CH:24]=1)=[O:27])[CH3:30]
Reactant: N=C(Nc1c(Cl)cccc1Cl)c1ccc(Br)s1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)s2)n1
Temperature: 95 °C
Reaction time: 17 h
Yield: 67.2 %

Procedure:
A stirred mixture of 5-bromo-N-(2,6-dichlorophenyl)-thiophene-2-carboxamidine (3.9 g, 11 mmol) and sodium bicarbonate (1.85 g, 22 mmol) in isopropanol (55 mL) was charged with ethyl bromopyruvate (2.5 mL, 20 mmol) and then heated at 95° C. After 17 h the reaction mixture was allowed to cool to ambient temperature, filtered and the solids rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 15:85 to 65:35) to give the title compound (3.3 g, 67%) as a tacky yellow solid, which was used in the next step without further purification. 1H-NMR (DCM-d2): δ 7.60 (s, 1H), 7.49-7.59 (m, 3H), 6.89 (d, 1H), 6.56 (d, 1H), 4.37 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: CC(N(C)C)=O.[Li+].[Cl-].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=C=O)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[NH2:17]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Nc1cc(Cl)cc(Cl)c1

Procedure:
The saccharide-bonded silica gel was dispersed into a mixture of 8 ml of anhydrous DMA-LiCl and 3 ml of pyridine, and 5 g of 3,5-dichlorophenyl isocyanate (this was formed from 3,5-dichloroaniline by an ordinary method) dissolved in 5 ml of DMA were added thereto and reacted at 80° C. in nitrogen for 12 hours. The presence of excess isocyanate groups in the reaction mixture was confirmed by the peak of C=N stretching vibration at 2,270 cm-1 in its IR spectrum. The saccharide-bonded, surface-treated silica gel was washed with tetrahydrofuran, methanol, acetone and hexane and dried in vacuum at 60° C. for 2 hours. The resultant compound was then subjected to IR spectrometry and elementary analysis. Results of elementary analysis are shown in Table 1.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4]>CC(O)=O.CC([O-])=O.CC([O-])=O.[Cu+2].O>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:2](=[O:1])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:4])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C(=O)C(O)c2cccc(OC)c2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A solution of 2-hydroxy-1,2-bis(3-methoxyphenyl)ethanone (3.5 g, 12.87 mmol, 1.00 equiv), NH4NO3 (1.04 g, 13.00 mmol, 1.00 equiv), and Cu(OAc)2.H2O (260 mg, 1.30 mmol, 0.10 equiv) in 80% aqueous HOAc (30 mL) was allowed to react, with stirring, for 2 hrs while the temperature was maintained at reflux in an oil bath. Upon cooling to 0° C., the solid was filtered and washed with H2O (3×30 ml), affording 2.5 g (72%) of 1,2-bis(3-methoxyphenyl)-1,2-ethandione as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:38][CH2:37][C:36]1=[O:40]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:36](=[O:40])[CH2:37][CH3:38])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: CN1CCCC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 65 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (65% yield). HPLC: 92%, RT=4.234 min. MS: m/z=411 [M+H]+, RT=3.35 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[S:24]([C:18]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])(=[O:26])=[O:25])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)ccc1OC)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (23.00 g, 0.12 mol) in dichloromethane (0.70 L) and pyridine (0.10 L) was treated with 2-methoxy-5-methyl-benzenesulfonyl chloride (31.78 g, 0.14 mol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was then washed with 0.5 N HCl (0.40 L), water (2 times 0.40 L) and brine (0.25 L) and the organic phase dried over sodium sulphate and evaporated. The residue was sonicated in ether/dichloromethane 95:5 and the precipitate filtered and dried under vacuum. 1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester was obtained as an off-white solid, 42.05 g (93%), MS (ISP): m/e=376.4 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:14].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:35])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CCOc1ccc(-c2ccc(C#N)cc2)cc1)CC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
To a -78° C. solution in THF (100 mL) of diisopropylamine (0.94 mL, 7.15 mmol) was added n-butyllithium (25M in hexanes, 2.86 mL, 7. 15 mmol) and the mixture was stirred for 15 minutes. A solution in THF (25 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid ethyl ester (2.01 g, 6.5 mmol), prepared as in step 1, was added dropwise and the reaction mixture was stirred for 15 minutes. Neat t-butyl bromoacetate (1.03 mL, 6.8 mmol) was added rapidly and the reaction mixture was stirred at -78° C. for 2 hours, then for 0.5 hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted twice with ethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Successive chromatographies on silica gel (dichloromethane, then 1:3 ethyl acetate-hexanes) gave 3-carboethoxy-5-[4(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.91 g, 33%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:27][C:28]#[N:29]>CN(C=O)C>[O:22]=[C:20]1[N:19]([CH2:27][C:28]#[N:29])[C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[S:21]1
Reactant: N#CCCl
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCc3ccccc3)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)SC(=Cc2ccc(OCCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-[4-(2-phenylethoxy)phenylmethylene]-2,4-thiazolidinedione Example 4 (1.0 g, 3.07 mmol) in 25 ml dry DMF was treated with NaH (0.1 g, 4.2 mmol) and stirred at room temperature for 10 min. The mixture was treated with chloroacetonitrile (0.3 g, 4 mmol) and stirred at room temperature for 24 h. The mixture was poured into 500 ml ice water, and the resulting tan solid was collected by filtration, washed with water, and dried to give the desired product in 75% (1.0 g) yield; mp 155-157° C.; NMR(CDCl3TMS): δ3.13 (t, 2H, ArCH2), 4.25 (t, 2H, OCH2), 4.60 (s, 2H, CH2CN), [7.00 (d, 2H), 7.45 (d, 2H) OPh], 7.26 (m, 5H, Ph), 7.94 (s, 1H, C=CH); Anal calcd for C20H16N2O2S, MW 364.42: C, 65.92; H, 4.43; N, 7.69; S, 8.80. Found: C, 66.15; H, 4.24; N, 7.93; S, 8.69. Mass spec m/e 365(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:26].[I-].N.CCO>>[NH2:26][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 38.3 %

Procedure:
A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (59 mg, 0.142 mmol), NH4I (41.5 mg, 0.286 mmol) in a solution of NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (21 mg, 38%). 1H-NMR (MeOD): 2.04 (d, 1H), 2.15 (dd, 1H), 4.51 (m, 1H), 5.75 (d, 1H), 6.78 (m, 1H), 6.99 (d, 1H), 7.20-7.26 (m, 2H), 7.26-7.35 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[N+:34]([O-:36])=[O:35])[N:19]=[CH:18][N:17]=1>CN(C=O)C>[N+:34]([C:23]1[CH:24]=[CH:25][C:26]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:27][C:22]=1[C:20]1[CH:21]=[C:16]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[N:17]=[CH:18][N:19]=1)([O-:36])=[O:35]
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(OCc2cccc(C(F)(F)F)c2)ncn1

Procedure:
To a solution of 99 mg of 3-(trifluoromethyl)benzyl alcohol in 2 mL of DMF was added 27 mg of a 50% dispersion of sodium hydride in oil. After 15 min the solution was treated with 150 mg of intermediate 3.1b. After an additional 2 h the reaction mixture was partitioned between water and ethyl acetate. The organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated to give a yellow syrup that was used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[CH2:3]([N:2]([CH3:1])[C:24](=[O:25])[CH2:23][Br:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCCCNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCN(C)C(=O)CBr
Reaction time: 16 h

Procedure:
To a solution of N-methyl-N-dodecylamine (2.5 ml) and triethylamine (1.4 ml) in dichloromethane (10 ml) was added with stirring and ice cooling a solution of bromoacetyl bromide (0.87 ml) in dichloromethane (10 ml). The cooling bath was removed after 30 min and the reaction stood for 16 h at ambient temperature. The mixture was washed with water and saturated sodium hydrogen carbonate, dried (K2CO3) and the solution purified by flash chromatography (silica, methanol-dichloromethane). Appropriate fractions were combined and evaporated to a pale yellow oil, yield 1.53 g (48%). 1H-NMR (CDCl3) δ0.8 (3H,t), 1.2 (18H,m), 1.5 (2H,m,), 2.88 and 2.99 (3H,2xs), 3.27 (2H,m), 3.77 and 3.79 (2H,s)); MS (APCI+) found (M+1)=320, 322, C15H30BrNO requires 319,321.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6].[C:17](C1C=C(C=C(OC(C)C)C=1)C(OC)=O)#[N:18]>>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: COC(=O)c1cc(C#N)cc(OC(C)C)c1
Reactant: COC(=O)c1ccc(OCC2CC2)c(Br)c1
Product: COC(=O)c1ccc(OCC2CC2)c(C#N)c1

Procedure:
Prepared from methyl 3-bromo-4-(cyclopropylmethoxy)benzoate according to the procedure for methyl 3-cyano-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C13H13NO3: 231.3; no m/z observed, tR=3.97 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.N1C=CC=CC=1.[CH2:20]([S:29](Cl)(=[O:31])=[O:30])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][S:29]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])(=[O:31])=[O:30])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: O=C(CS(=O)(=O)Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)CC(=O)c2ccccc2)c2c(c1)OC(C)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To a solution of 15.5 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 10.5 grams of anhydrous pyridine in 100 cc of methylene chloride cooled to 0°-5° C., a solution of 24.5 grams of phenacylsulfonyl chloride in 80 cc of methylene chloride is added. When the dripping is terminated the reaction mixture is warmed to room temperature and stirred for 5 hours. At the end of this time the solution is washed with water, dried over sodium sulfate and concentrated to dryness. Crystallization of the resulting thick oil from ethyl alcohol-ethyl ether gives 16 grams of the compound of the title which melts at 143°-145° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13]O.O=S(Cl)[Cl:17]>>[Cl:17][CH2:13][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(-c2ccccc2)nc1CO
Product: Cn1cc(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-Methyl-4-phenyl-1H-imidazol-2-yl)-methanol 5 (0.2 g, 0.097 mmol) was added SOCl2 (0.14 g, 0.121 mmol), and the mixture was stirred at room temperature overnight. The mixture was evaporated to afford 2-Chloromethyl-1-methyl-4-phenyl-1H-imidazole 6, which was used without purification. 1H NMR (400 MHz, DMSO-d6): δ8.24 (s, 1H), 7.87 (d, J=6.8 Hz, 2H), 7.54-7.49 (m, 2H), 7.43-7.41 (m, 1H), 5.24 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: C(O)(C)C.[C:5]([O:9][C:10](=[O:23])[NH:11][CH2:12][CH2:13][N:14]1[CH2:21][CH:20]2[O:22][CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)([CH3:8])([CH3:7])[CH3:6].[O:24]1[CH2:26][C@H:25]1[CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>O>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH2:27][C@@H:25]([OH:24])[CH2:26][N:18]2[CH2:17][CH:16]3[O:22][CH:20]([CH2:21][N:14]([CH2:13][CH2:12][NH:11][C:10](=[O:23])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:15]3)[CH2:19]2)=[CH:30][CH:31]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Temperature: 66 °C
Yield: 99.4 %

Procedure:
iso-Propanol (5 mL) and water (0.5 mL) were added to [2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester (see Example 3 (Alternative I) above; 0.43 g, 1.6 mmol) and 0.4-[(2S)-oxiranylmethoxy]benzonitrile(0.280 g, 1.6 mmol; see Preparation D above) was added. The mixture was heated at 66° C. for 19 hours (reaction was complete in 2 hours). The solvent was evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.71 g, 100%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[O:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2o1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2o1

Procedure:
This material was prepared according to the method described in Example 66 using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzooxazol-2-ylamine, (Example 70(c)), (0.27 g, 0.72 mmol) and acetic anhydride (82 uL, 0.87 mmol) in pyridine (3 mL). Purification by silica gel chromatography (1:1.5 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 415 (M+1). Mp: 205.1-205.2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[N:35]1[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:41]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[O:42])[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccncc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 3.0 ml (21.6 mmol) of triethylamine in 15 ml of CH2Cl2 cooled to 0° C. was added 1.7 g (9.5 mmol) ml of 4-pyridinecarbonyl chloride (isonicotinoyl chloride). The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was washed with H2O, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to give 1.8 g of a light tan solid; Anal. for C24H23N3O6S: Calc'd: C,59.9; H,4.8; N,8.7; S,6.6; Found: C,59.0; H,4.8; N,8.5; S,6.9; Mass spectrum (ES) 482.6(M+H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]>O.C(#N)C>[N:1]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=NCCc1ccccc1[N+](=O)[O-]

Procedure:
Sodium azide (22.8, 0.351 mol) in water (60 mL) was added to a solution of 2-(2-bromoethyl)-nitrobenzene (27.9 g, 0.121 mol) in acetonitrile (120 mL). The reaction was refluxed for 4 h, cooled, and partitioned between methylene chloride and water. The organic phase was washed with saturated brine, and dried over magnesium sulfate. The title compound was obtained as an oil (22.8 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:9]([CH3:11])[CH3:10])([CH2:7]O)[CH2:5][OH:6].[CH3:12][O:13][CH2:14][CH:15]=[O:16].C1CCCCC1>O>[CH3:12][O:13][CH2:14][CH:15]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH:9]([CH3:11])[CH3:10])[CH2:7][O:16]1
Reactant: COCC(CO)(CO)C(C)C
Reactant: COCC=O
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCC(COC)(C(C)C)CO1
Yield: 83 %

Procedure:
A mixture of 486 g (3 moles) of 2-methoxymethyl-2-isopropyl-1,3-propanediol, 287 g (3.3 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb AC 10 under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 543 g (83% yield) of 2,5-dimethoxymethyl-5-isopropyl-1,3-dioxane of boiling point 95° C./1 mbar obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][O:14][CH2:13]2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:19]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: C1CC2COCC1N2
Product: CC(Cc1ccc(Br)cc1)N1C2CCC1COC2
Yield: 28.5 %

Procedure:
The title compound (54 mg, colorless oil) was prepared from 1-(4-bromophenyl)propan-2-one (130 mg) and 3-oxa-8-azabicyclo[3.2.1]octane (100 mg), as in Reference Example P-R5-1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:34]=[CH:33][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([OH:32])=[CH:26][C:27](=[O:31])[O:28]4)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([OH:32])=[C:26]([N+:1]([O-:4])=[O:2])[C:27](=[O:31])[O:28]4)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:34]=1
Reactant: O=c1cc(O)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1oc2cc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)ccc2c(O)c1[N+](=O)[O-]

Procedure:
Fuming nitric acid (10 ml; d 1.52) was added dropwise over 15 mins to a cold (0° C.) stirred suspension of 1-(4-chlorobenzyl)-4-[3-(4-hydroxycoumarin-7-yloxy)propyl]piperazine (2.0 g) in chloroform (200 ml) and the mixture stirred for a further 1 hour at 0°. The solution which formed precipitated a yellow solid on addition of water which after filtration was washed with ethanol to give 2.62; (95%) of the dinitric acid salt of the title compound of m.p. 142°-144° (dec). νmax (mull) 2700 (br), 1740, 1615, 1525 cm-1. (Found; C, 45.87; H. 4.52; Cl, 5.66; N, 11.36; C23H24ClN3O6 2HNO3 requires; C, 46.05; H, 4.37; Cl, 5.91; N, 11.67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1sc(C(=O)O)cc1-c1ccnn1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (203 mg, 0.805 mmol) in Tetrahydrofuran (TH F) (4 mL). 6N NaOH (4 mL, 24.0 mmol) was added slowly, the reaction mixture stirred overnight at 70° C. The mixture was neutralized by addition of 6N HCl and partitioned between CHCl3 and H2O. The layers were separated, the organic layer dried over Na2SO4 and concentrated affording the title compound (152 mg, 0.64 mmol, 79%), which was used in the next step without further purification: LC-MS (ES) m/z=239 (M+H)+.