Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccc(C2CC(=O)c3c(C)ccnc3C2)s1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)s1
Yield: 78.1 %

Procedure:
A mixture of 4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (257 mg), aminoguanidine hydrochloride (117 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (5 ml) was refluxed for 30 minutes. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 71) (273 mg) as pale yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is added under an argon atmosphere to a suspension of 0.06 g (2.3 mmol) of NaH in 20 ml of dry THF. After agitation for one hour at 23° C., a solution of 0.29 g (2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is maintained for another 2 hours at 23° C. and the whole is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, the organic phase is then washed twice with 25 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified on a silica column (eluant: 12% of ethyl acetate in heptane). The pure fractions are evaporated in order to produce a colourless oil with a yield of 40%.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CO>[C:14]1([CH:11]2[NH:10][C:9]3=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=[C:8]3[O:13][CH2:12]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc2c1N=C(c1ccccc1)CO2
Solvent: CO
Product: Nc1cccc2c1NC(c1ccccc1)CO2
Reaction time: 2 h

Procedure:
The 5-nitro-3-phenyl-2H-1,4-benzoxazine oil was taken up in MeOH (50 mL) in a Parr shaker bottle, deoxygenated with nitrogen, the catalyst 10% Pd on carbon (0.25 g) was added, the reaction vessel was charged to 55 psi with hydrogen and shaken. After 2 h the reaction was complete by LC/MS. The reaction was filtered to remove the catalyst and concentrated under reduced pressure to give 3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine as a dark oil. (3.5 g, 97%). LCMS calc. for C14H15N2O (M+H)+: m/z=227.1. found: 227.1. 1H NMR (500 MHz, DMSO-d6) δ 7.44 (d, J=7.4 Hz, 2H), 7.37 (dd, J=7.5 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 6.35 (dd, J=7.9 Hz, 1H), 6.21 (dd, J=7.8, 1.0 Hz, 1H), 6.07 (d, J=7.9 Hz, 1H), 5.00 (s, 1H), 4.62 (s, 2H), 4.44 (dd, J=4.9, 2.6 Hz, 1H), 4.21-4.13 (m, 1H), 3.87 (dd, J=10.4, 7.7 Hz, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[NH:48][CH:49]=[CH:50][N:51]=3)=[CH:43][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:48]1[CH:49]=[CH:50][N:51]=[C:47]1[C:44]1[CH:45]=[CH:46][C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[CH:9]=3)[NH:4][CH:3]=2)=[CH:42][CH:43]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc[nH]3)cc2)OC1(C)C
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(-c5ncc[nH]5)cc4)c3c2)cc(OC)c1OC
Yield: 22.1 %

Procedure:
3-Iodo-1-(toluene-4-sulfonyl)-5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate CJ, 30 mg, 0.053 mmol), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole (Intermediate CG, 18 mg, 0.064 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.003 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (1 ml) and stirred at 60° C. for 2 d. Additional Intermediate CG (18 mg, 0.064 mmol) was added and stirring was continued for another day. EtOAc was added and the mixture was washed with water, dried, evaporated and purified by silica gel chromatography using 0-5% MeOH:DCM to yield 5 mg (22%) of the title compound. MS ESI (m/z): 427.2 (M+1)+, calc. 426.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20]
Reactant: Oc1cccc2ccoc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc2ccoc12
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 7-hydroxybenzofuran (2.60 g) in DMF (30 ml) was added potassium carbonate (3.75 g) and then was added dropwise bromopropane (2.87 g) under nitrogen atmosphere, and the mixture was stirred overnight. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give brown oil of 7-propoxybenzofuran (2.73 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[CH:57](OC)=[O:58]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:57]=[O:58])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: COC=O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (30 mg) was mixed with methyl formate (0.5 ml) and stirred at 0° C. for 1 hr. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The excess methylformate was removed with nitrogen flow and the crude mixture was purified by preparative tlc on silica gel (1000 microns, 5% i-PrOH/CH2Cl2) to give 25 mg of the title compound. (Mass, 1H and 13C data were consistent with the proposed structure).
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.O.O.P([O-])(O)(O)=[O:17].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].[Cl-].[NH4+]>C(O)(C)(C)C.O>[F:1][CH:2]([F:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([OH:17])=[O:10])=[CH:7][CH:6]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc(OCC(F)F)cc1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(OCC(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
4-(2,2-Difluoroethoxy)benzaldehyde (2.50 g, 13.4 mmol) prepared in Example 13 (13a) was dissolved in a solution mixture of tert-butanol:water (28 mL, 22:6, V/V). Then, to the resulting mixture were added sodium dihydrogen phosphate dihydrate (2.10 g, 13.4 mmol), 2-methyl-2-butene (6.26 mL, 59.1 mmol), and sodium chlorite (4.25 g, 37.6 mmol). The mixture was stirred at room temperature for 4 hours, and then 2-methyl-2-butene (2.85 mL, 26.9 mmol) and sodium chlorite (1.52 g, 13.4 mmol) were further added thereto. The resulting mixture was further stirred at room temperature for 20 hours, and then a saturated ammonium chloride aqueous solution was added to the reaction solution to terminate the reaction. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2.71 g of the title compound (white solid, yield: quantitative).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9](=[CH:11][CH2:12][CH2:13]/[C:14](=[CH:16]/[CH2:17]O)/[CH3:15])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:6][C:5]([CH2:7][CH2:17][CH:16]=[C:14]([CH3:15])[CH2:13][CH2:12][CH:11]=[C:9]([CH3:10])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(=O)C=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(=O)C=C(C)CCC=C(C)CCC=C(C)C
Temperature: 200 °C
Yield: 78 %

Procedure:
A mixture of 200 parts of mesityl oxide, 200 parts of geraniol and 400 parts of tetrahydrofuran has 0.01 part of p-toluenesulfonic acid added to it and the whole is heated for 3 hours at 200°C at 50 atmospheres pressure. The reaction mixture is distilled and 133 parts of 4,8,12-trimethyl-3,7,11-tridecatrien-2-one is obtained. At a conversion of 52% the yield is 78% of theory based on geraniol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]([NH:12][C:13](=O)[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:11])[NH:12][C:13](=[S:27])[CH2:14][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@]1(c2cc(Br)ccc2F)COCC(=S)N1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A pressure tube was charged with a solution of N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (2.00 g, 6.9 mmol) in tetrahydrofuran (50 ml). The colorless solution was treated with Lawesson's reagent (2.81 g, 6.9 mmol) to give a yellow suspension. The tube was sealed and the mixture stirred at 70° C. overnight. For the workup, the reaction mixture was diluted with ethyl acetate (300 ml) and extracted with a saturated solution of sodium hydrogen carbonate (75 ml). The organic layer was washed with brine (2×80 ml). The combined aqueous layers were extracted with ethyl acetate (300 ml). The combined organic layers were dried over sodium sulphate and concentrated at reduced pressure. The (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholine-3-thione was obtained as a light yellow gum (1.93 g, 92% of theory) sufficiently pure to be engaged in the next step without further purification. MS (ISP): m/z=302.0 [M+H]+, 304.0 [M+2+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:16])[C:10]([CH2:12][C:13]([OH:15])=[O:14])=[CH2:11]>C1(C)C=CC=CC=1.O1CCOCC1>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[C:9](=[O:16])[O:5]2)=[CH:7][CH:8]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Oc1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)CC1Cc2ccc(O)cc2OC1=O
Temperature: 100 °C
Yield: 50 %

Procedure:
In a round-bottomed flask equipped with a Dean-Stark apparatus, 10 g of resorcinol and 11.8 g of itaconic acid were dissolved in 150 ml of a toluene/dioxane mixture (volume ratio 1/1) in the presence of Amberlyst 15 resin from Aldrich. The reaction mixture was heated at 100° C. for 3 hours. After cooling, the crude reaction product was filtered and the filtrate was concentrated under vacuum. The crude product was recrystallized hot from ethyl acetate. This gave 10 g of a white powder, which corresponds to the expected product (50% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C[C@H]2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 187 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=149-150° C.; 400 MHz 1H NMR (CDCl3) δ: 8.04 (dd, J=7.8, 1.2 Hz, 1H), 7.73 (dd, J=7.8, 0.8 Hz, 1H), 7.64 (td, J=7.6, 1.2 Hz, 1H), 7.48 (td, J=7.4, 1.2 Hz, 1H), 7.34-7.20 (m, 5H), 4.02-3.94 (m, 1H), 2.93 (s, 2H), 2.87 (dd, J=13.3, 6.8 Hz, 2H), 2.78-2.66 (m, 3H), 2.50-2.38 (m, 3H), 2.18-2.08 (m, 2H), 1.94-1.78 (m, 2H); LCMS: 436 [M+H]; enantiomeric excess determined by chiral HPLC: >99%; Chiral HPLC Rt=63.08 min.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=2[O:2]1.CN(C)C=O.[CH3:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33]Cl)=[O:31]>C(N(CC)CC)C>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:19]([O:21][CH2:33][O:32][C:30](=[O:31])[C:29]([CH3:36])([CH3:35])[CH3:28])=[O:20])=[CH:8][N:9]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Reaction time: 0.5 h

Procedure:
To a mixture of 2.6 g. 6,7-methylenedioxy-1-(2,2,2-trifluoroethyl)-4(1H)-quinolone-3-carboxylic acid and 35 ml. of dimethyl formamide was added 1.4 g. of triethylamine. The mixture was warmed to 55° and kept there for 1/2 hour. 2.8 g. of chloromethyl trimethylacetate was then added and the resulting mixture was stirred at 55° for 5 hours. The cooled solution was diluted with 150 ml. of ethyl acetate and washed with water. The ethyl acetate solution was dried over magnesium sulfate and concentrated. The solid residue, 6,7-methylenedioxy-1-(2,2,2-trifluoroethyl)-4(1H)-quinolone-3-carboxylic acid, trimethylacetoxymethyl ester, was recrystallized from CH2C12 -ether mixture; m.p. 190°-1° .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1)=[O:12].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1ccccc1F)c1ccc(Cl)nn1
Product: O=C(NCCc1ccccc1F)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(2-fluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (70.7% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.95, 7.75-7.72, 7.63, 7.55, 7.36, 7.22-7.15, 7.05-6.97, 4.07-4.02, 3.89-3.83, 3.79-3.67, 3.35-3.32, 2.96.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[N:14]1(CCO)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:3]1([CH2:8][C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCN1CCCC1
Reactant: CCOC(=O)CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: O=C(CN1CCCC1)OCCN1CCCC1
Temperature: 225 °C

Procedure:
To a mixture of 1.3 g of sodium hydride (in the form of a 60% by weight suspension in mineral oil) and 100 g (0.64 mol) of ethyl 1-pyrrolidineacetate was added 91 g of 2-(1-pyrrolidinyl)ethanol. The mixture was heated slowly to about 225° C., and the ethanol by-product was collected in a Dean-Stark trap. The reaction mixture was cooled to about 25° C., then 12 g of 1-bromopropane was added to react any alkoxide present. The sodium bromide by-product was removed by filtration. The desired product 2-(1-pyrrolidinyl)ethyl 1-pyrrolidineacetate was purified by distillation at 95° C. at a pressure of 250 μmHg. The structural assignment was confirmed by mass spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N[C:12]([C:14]([NH:16][C:17](=O)[CH3:18])=[O:15])=[O:13])(=O)C>>[C:2]1([NH:1][C:12]([C:14]([NH:16][C:17]2[CH:18]=[CH:4][CH:3]=[CH:2][CH:7]=2)=[O:15])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(=O)C(=O)NC(C)=O
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 2 h

Procedure:
Aniline (50 ml, 0.549 mol) and N,N'-diacetyloxamide (5 g, 0.029 mol) are charged into a three-necked flask equipped with a condenser, a magnetic stirrer, an inlet tube for nitrogen and a thermometer. The temperature is brought to 50° C. while vigorously stirring and after 2 hours the reaction is stopped by removing the heating bath.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[Cl-].[K+].[Cl-].[Na+:9].[CH2:10]([S:16][S:17][CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=[O:21])[C@H:11]([NH2:15])[C:12]([OH:14])=[O:13]>>[C:20](=[O:21])([O-:2])[O-:22].[Na+:9].[Na+:9].[CH2:10]([S:16][S:17][CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=[O:21])[C@H:11]([NH2:15])[C:12]([OH:14])=[O:13]
Reactant: O=P([O-])([O-])[O-]
Agent: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Agent: [Cl-]
Agent: [K+]
Product: O=C([O-])[O-]
Reaction time: 48 h

Procedure:
To 25 ml aliquots of incubation buffer (0.01 M phosphate, 0.0027 M potassium chloride, 0.137 M sodium chloride, pH 7.4, Sigma Aldrich Corp, Catalog # P-4417), increasing amounts of solid phase cystine (Sigma Aldrich Corp, St Louis, Mo., Catalog # C-6195) were added and incubated for 48 hours at 37° C. with stirring. Residual solid phase was then separated to form a supernatant and a pellet, and the pellet was dissolved in 25 ml of a cystine-dissolving agent, an alkalinizing buffer of 0.1 M sodium carbonate, pH 9.9, (Sigma Aldrich Corp, Catalog # S-7795), to form a final cystine solution. Cystine concentration was determined in both the supernatant and the final cystine solution according to the procedure given in Example 3. Various separation techniques were used for removing the pellet: (1) in one experiment, centrifugation was performed at 4000 rpm at 37° C. for 20 minutes; (2) in two experiments, separation was performed by filtration using a Metricel filter (Gelman Sciences, Ann Arbor, Mich.); and (3) in four experiments, centrifugation was performed at room temperature at 3800 rpm for 20 minutes. As all methods were equivalent in outcome, the latter was employed in all subsequent experiments.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(N(CC)CC)C.O>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]([C:23]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:5]4[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:10][C:11]2=3)=[O:24])[CH:26]=[C:27]([Br:31])[C:28]=1[O:29][CH3:30]
Reactant: COc1cncc(-c2cnc3c(c2)NCCO3)c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cncc(-c2cnc3c(c2)N(C(=O)c2cc(Br)c(OC)c(Br)c2)CCO3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
In a 10 ml flask, 7-(5-methoxy-pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (72 mg, 0.30 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (146 mg, 0.45 mmol) were dissolved in dichloromethane. Triethylamine (0.21 ml, 1.50 mmol) was added thereto and then stirred at room temperature for 3 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(5-methoxy-pyridin-3-yl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (116 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:14]([CH:15]([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:18]([CH3:20])[CH3:19])=[O:7])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH:18]([CH3:19])[CH3:20])=[CH:11][CH:12]=[CH:13][C:14]=1[CH:15]([CH3:16])[CH3:17])=[O:7]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Step 2): Zinc powder (7.81 g, 119 mmol) was added slowly to a solution of 2-nitro-N-(2,6-diisopropylphenyl)benzamide (2.0 g, 6.3 mmol) in acetic acid (38.3 ml) below 10° C. The mixture was stirred for 2 hours at room temperature. The excess reagent was filtered off and the filtrate was neutralized with 10% NaOH solution. The mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated. The residue was recrystallized (ethyl acetate/hexane) to give 2-amino-N-(2,6-diisopropylphenyl)benzamide (77.1%): mp 207°-209° C.