Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].[CH:11](N)=O>O>[CH3:7][C:4]1[N:5]=[N:6][C:2]2[C:3]=1[C:8](=[O:9])[N:10]=[CH:11][N:1]=2
Reactant: Cc1n[nH]c(N)c1C(N)=O
Reactant: NC=O
Solvent: O
Product: CC1=C2C(=O)N=CN=C2N=N1
Temperature: 180 °C

Procedure:
A mixture of 5-amino-3-methyl-1H-pyrazole-4-carboxylic acid amide (11.06 g, 79.0 mmol, Example 1) and formamide (60 mL, Aldrich) was heated at 180° C. for 3.5 hours. After cooling to 80° C., icy water (100 g) was added and the mixture was vigorously stirred to give a white precipitate. The precipitate was filtered and washed with cold water and then dried in a vacuum desiccator to give 3-methyl-pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. (Yield 9.07 g). This material was used in the next step (described in Example 3) without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.N[C:11](N)=[O:12]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:11](=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Br)cnc1N
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)cnc2[nH]1
Temperature: 100 °C
Yield: 35.3 %

Procedure:
A mixture of 5-bromopyridine-2,3-diamine (2 g, 10.6 mmol) and urea (2.5 g, 41.6 mmol) was dissolved in DMF and heated to 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4 then concentrated to provide 6-bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.80 g, 36%) as an off white solid which was used without further purification. LCMS Method W: retention time 0.98 min; [M+2]=212, 214.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[CH:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-n2cncn2)c1
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4cncn4)c3)cnc2n1

Procedure:
1-(3-Bromophenyl)-1H-[1,2,4]triazole (1.7 g, 7.6 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (3.8 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (1-3%), then crystallisation from toluene/isohexane, gave 3-[3-([1,2,4]triazol-1-yl)-phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine as an off-white solid: δH (400 MHz, DMSO) 9.43 (1H, d, J 7), 9.41 (1H, s), 8.38 (1H, s), 8.30 (1H, s), 8.26-8.28 (1H, m), 7.97-8.00 (1H, m), 7.76-7.81 (2H, m), 7.56 (1H, d, J 7); m/z (ES+) 331 (M++H).
Reaction SMILES: O.[C:2]([S:6]([CH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Ca+2].[OH-]>CS(C)=O>[C:2]([S:6]([CH2:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)C(C)(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)S(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 56.9 %

Procedure:
550 ml of water are placed in a sulphonation flask having a mechanical stirrer, pH control as well as a dropping funnel and treated while stirring vigorously with 4.85 g (16.36 mmol) of ethyl (RS)-α-[[(RS)-t-butylsulphinyl]methyl]hydrocinnamate (see EPA 0 236 734) in 15 ml of dimethyl sulphoxide. The reaction solution is thereafter adjusted to pH 7.5, treated with 200 mg of α-chymotrypsin and the pH is held constant with 0.037N calcium hydroxide solution. After 220 ml of this calcium hydroxide solution have been consumed (about 45 hours) the unreacted ester is extracted with ethyl acetate, the aqueous phase is adjusted to pH 2 with 30% sulphuric acid and extracted with ethyl acetate. The extracts are washed in succession with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated, whereby there are obtained 2.50 g of (S)-α-[[(RS)-t-butylsulphinyl]methyl]hydrocinnamic acid, MS: 269 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:3])[CH3:2].[Br:12]Br.C(=O)([O-])O.[Na+]>ClCCl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:10]=1
Reactant: CC(C)Oc1ccccc1O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Oc1cc(Br)ccc1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To 200 ml of dichloromethane solution containing 27.2 g (0.179 mol) of 2-isopropoxyphenol was added dropwise 50 ml of dichloromethane solution containing 28.4 g (0.177 mol) of bromine at −70° C. or lower. After completion of the dropwise addition, the mixture was stirred at the same temperature 1 hour, and gradually raised to −10° C. After completion of the reaction, the reaction mixture was poured into ice-water, the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and then extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 38.8 g of the title compound as a colorless oil. (Yield: 94%)
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([O:25]C)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:27](=[O:29])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1
Yield: 72.9 %

Procedure:
A solution of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (10.1 mg, 0.025 mM) and 0.025 mL (0.025 mM) of 1 N NaOH in 3 mL of ethanol was stirred for 16 h at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 7.1 mg (70%) of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-7.05 (m, 11H), 6.55 (d, 1H, J=8 Hz), 5.75 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 3471, 1657, 1615, 1591, 1496, 1453, 1412, 1330, 1272, and 1151. MS (ES) m/e 373, 375, 397. Elemental Analyses for C22H17N2O4Na: C, 66.67; H, 4.29; N, 7.07. Found: C, 66.75; H, 4.55; N, 6.83.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].O.[C:26](OCC)(=O)C>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][C@@H:18]1[CH3:26])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C[C@H](C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.3 g (10 mmol) of 17β-acetoxy-5α-androst-1-en-3-one in 15 ml of ethyl acetate and 143 mg (0.1 mmol) of CuBr are added to solution a). It is stirred for 16 hours at 25° C. The reaction solution is hydrolyzed with 1 ml of water, stirred for 15 minutes more and the inorganic solid is filtered off. The solid is washed with ethyl acetate. After evaporation of the solvent, 3.5 g of substance is obtained that is recrystallized from acetone. After suctioning off of the crystals, 2.9 g of 17-acetoxy-1α-methyl-5α-androstan-3-one of a melting point of 179-180° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][CH2:21][CH2:22][N:23]=2)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+].CC(C)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:23]3[CH2:22][CH2:21][NH:20][C:19]=23)=[CH:16][CH:17]=1
Reactant: Clc1ccc(CC2=NCCN2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=c1c2cccnc2c(-c2ccc(Cl)cc2)c2n1CCN2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Add a solution of 2-chloro-3-pyridinylcarbonyl chloride (4.4 g) in tetrahydrofuran (55 ml) to a stirred, cooled mixture of 2-(4-chlorophenyl)methylimidazoline (4.9 g), potassium tert.-butoxide (2.8 g) and tetrahydrofuran (200 ml). Use a bath of ice and acetone for cooling. Keep the reaction mixture in the bath for 15 minutes, and then allow it to warm to 20° C. over another 15 minutes. To the warmed mixture, add a second portion (2.8 g) of potassium tert.-butoxide; allow the reaction mixture to stir at 20° C. overnight. Evaporate solvent, partition the residue between chloroform and water, and dry the chloroform solution Use sodium sulfate as a drying agent. Filter the dried solution, evaporate the solvent, and crystallize the residue from acetonitrile to obtain 10-(4-chlorophenyl)-2,3-dihydro-imidazo[1,2-g]-[1,6]naphthyridin-5(1H)-one, mp 260°-262° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13]OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[C@H](COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: C=CC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Yield: 63.7 %

Procedure:
4(S)-(3,4-Dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (8.25 g) (see Preparation 93) and imidazole (5.3 g) were dissolved in anhydrous acetonitrile (80 ml) and the mixture heated under reflux for 6 days. The solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether and aqueous saturated sodium hydrogen carbonate solution (pH of the aqueous phase was kept >7). The phases were separated and the aqueous phase extracted with diethyl ether. The combined organic extracts were then washed with water, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel, eluting with a solvent gradient of 98:2 changing to 95:5, by volume, dichloromethane:methanol to give 4(S)-(3,4-dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (4.78 g) as an oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>ClCCl>[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:10](=[Se:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: OC(=[Se])c1ccccc1Cc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc(NC(=[Se])c2ccccc2Cc2ccccc2)cc1

Procedure:
To a solution of 6 g (0.0206 mol) 2-benzylselenobenzoic acid and 2.1 g (0.0206 mol) triethylamine in 100 ml dichloromethane at 0°-5° C. is added in one portion 5.24 g (0.0206 mol) bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 30 minutes a solution of 2.63 g (0.0206 mol) 4-chloroaniline at 0° C. is added and after 15 minutes a solution of 2.1 g (0.0206 mol) triethylamine in 30 ml dichloromethane (within 21/2 hours). The reaction mixture is then immediately extracted with 100 ml 1N aqueous hydrochloroic acid solution, 100 ml 1N caustic soda solution and 100 ml distilled water. The organic phase is dried with sodium sulfate and the solvent removed under vacuum. The residue is purified by recrystallization from 80 ml 2-propanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH2:14][OH:15])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@@H](C=O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A solution of benzyl[(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (260 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (56.9 mL) and a solution of sulfur trioxide•pyridine complex (71.3 g) in dimethyl sulfoxide (260 mL) was successively added. The mixture was stirred at the same temperature for 1 hr, and at room temperature for 4 hr. A 1 mol/L aqueous citric acid solution (450 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a colorless oil (yield: 16.3 g, 55%).
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.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]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: C1COCCN1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCOCC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to morpholine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(morpholine-4-carbonyl)benzamide. MS (Q1) 456 (M)+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]([OH:24])([CH3:23])[CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]2=[O:22])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O1CCOCC1>O>[CH3:23][C:11]1([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]2=[O:22])[O:24][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1c(=O)oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(Cn2c(=O)oc3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Yield: 38 %

Procedure:
A mixture of 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-3H-benzoxazol-2-one prepared in Example 541 (615 mg, 1.74 mmol), sodium hydride (76.6 mg, 1.91 mmol), 1,4-dioxane (15 ml) was stirred under reflux for 1 hour. The reaction mixture was allowed to return to room temperature. To the solution, water was added and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-3H-benzoxazol-2-one (209 mg, yield 38%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:13])[C:5](=[O:12])[N:6]2[CH3:11].[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:14][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([CH3:13])[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CC1C(=O)N(C)c2cccc(O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cccc2c1C(C)C(=O)N2C
Yield: 86.2 %

Procedure:
A slurry of 1,3-dihydro-4-hydroxy-1,3-dimethyl-2H-indol-2-one (50 g), milled potassium carbonate (60.1 g) and HPLC grade acetone (400 ml) was mechanically stirred at room temperature as dimethylsulfate (41.4 ml) was added dropwise. The addition funnel was replaced with a condenser and the slurry was refluxed for 18 hours. The K2CO3 was filtered off and washed well with acetone. Acetone was evaporated and the residue was purified by column chromatography to yield 46.5 g of an oil. The oil was dissolved in ether and placed in the refrigerator where, upon standing overnight, the product crystallized, m.p. 73°-74° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22](Br)=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[CH:30][N:31]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].[Cu][C:43]#[N:44]>CN1C(=O)CCC1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:43]#[N:44])=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[CH:30][N:31]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Br)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 75.8 %

Procedure:
The bromide 58 (300 mg, 0.46 mmol) was added to a microwave reaction tube containing copper(I) cyanide (124 mg, 1.38 mmol) in NMP. The capped reaction tube was placed in a microwave reactor and the mixture irradiated at 230° C. for 30 min. After dilution with EtOAc, the organic layer was washed with 15% NH4OH solution prior to drying over anhydrous MgSO4. After filtration and concentration under reduced pressure, the residue was purified by silica column chromatography to provide the cyanide 59 (208 mg, 76%) as a white solid. MH+597.
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:26])[F:25])=[N:17]3)[CH2:8][C@@H:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.[CH2:36]([NH2:38])[CH3:37]>C1COCC1>[CH2:28]([C@H:7]1[CH2:8][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:26])([F:25])[F:27])=[N:17]3)[CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:38][CH2:36][CH3:37])=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN
Reactant: CCOC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Solvent: C1CCOC1
Product: CCNC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1

Procedure:
The title compound was prepared by the method outlined for Example 117 using [(S)-2-Benz yl-4-(8-methoxy-2-trifluoromethyl-quinolin-5-yl)-piperazin-1-yl]-acetic acid ethyl ester and a 2 M THF solution of ethylamine. The title compound was isolated as a yellow solid (68 mg, 63%). LC/MS (Method B) 2.82 min, [M+1]+ 486.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][O:15][C:14]([CH2:18]I)([CH3:17])[CH2:13][N:12]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([CH:11]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]1[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CI)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Yield: 85 %

Procedure:
To a solution of 4-benzyl-6-iodomethyl-6-methyl-morpholine-3-carboxylic acid benzyl ester (Intermediate 17, 1.23 g) and tributyltin hydride (1.8 ml, 2.5 eq.) in 11 ml of toluene under gentle reflux was added over 1.5 hr a solution of AIBN in toluene (25 mg/1 ml). The mixture was allowed to cool down and was concentrated to dryness. The residue was partitioned into 15% 1M HCl in acetonitrile and hexane. The separated hexane phase was extracted two times with the acetonitrile solution. The combined acetonitrile solutions were washed with hexane two times and concentrated. The residue was partitioned into ether and 1M K2CO3. The separated ether phase was washed successively with 0.4M Na2S2O3 and brine, dried over MgSO4 and concentrated. The residue was purified on silica (7.5% EtOAc/hexane) to give 760 mg (oil, 85% yield) of compound 4-benzyl-6,6-dimethyl-morpholine-3-carboxylic acid benzyl ester. 1H-NMR (300 MHz, CDCl3): δ 1.21 (s, 3H), 1.24 (s, 3H), 2.12 (d, 1H), 2.84 (d, 1H), 3.29 (t, 1H), 3.58 (d, 1H), 3.95-4.05 (m, 2H), 5.15 (d, 1H), 5.21 (d, 1H), 7.28-7.36 (m, 10H). MS (M+H+):340.