Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[CH:14][N:13]=2)=[O:10])=[C:4]([F:22])[CH:3]=1.[CH3:23][C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][N:33]3[CH:36]=[CH:37][N:38]=[C:32]3[CH:31]=2)[CH:27]=[CH:26][CH:25]=1.CC([O-])=O.[K+].N#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.CS(C)=O>[C:18]([C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:36]3[N:33]4[CH:34]=[CH:35][C:30]([C:28]5[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=5)=[CH:31][C:32]4=[N:38][CH:37]=3)=[CH:3][C:4]=2[F:22])[CH:17]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccnc(NC(=O)Cc2ccc(Br)cc2F)c1
Reactant: Cc1cccc(-c2ccn3ccnc3c2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CS(C)=O
Product: Cc1cccc(-c2ccn3c(-c4ccc(CC(=O)Nc5cc(C(C)(C)C)ccn5)c(F)c4)cnc3c2)n1

Procedure:
In a stirred septum capped vial, charge 2-(4-bromo-2-fluoro-phenyl)-N-(4-tert-butyl-pyridin-2-yl)-acetamide (400 mg, 1.09 mmol), 7-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine (228 mg, 1.09 mmol), KOAc (213 mg, 2.18 mmol), PdCl2(PPh3)2 and flushes with N2 needle for 15 minutes then one adds DMSO (5 mL) and de-oxygenate with N2 needle and places vial in oil bath at 80 to 90° C. for 24 hours. Cool the reaction then purify by passing through Varian SCX® (10 g) column that is pre-washed with water and methanol, the product being eluted with (20%) 2 N NH3 in methanol/(80%) DCM. Evaporate solvent from the product containing fractions under reduced pressure. Chromatograph using (40 g ISCO®) SiO2 eluting with a gradient of 0% to 10% 2 M NH3 in MeOH with the balance DCM. Evaporate solvents and purify by reverse phase chromatography (C-18 acetonitrile/H2O with 0.1% TFA) Neutralize, extract, and strip off solvents. Dry in vacuum oven to afford 118.4 mg (21.9%) MS(ES), m/z 494 (M+1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:39][C:40]1[S:41][S:42][C:43](=[S:45])[N:44]=1>O1CCCC1.O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:39][C:40]2[S:41][S:42][C:43](=[S:45])[N:44]=2)=[O:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(CC(=O)O)cc1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOc1ccc(CC(=O)Nc2nc(=S)ss2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
2-[4-(Octyloxy)phenyl]acetic acid (0.900 g, 3.40 mmol) was dissolved in tetrahydrofuran (11 ml), and 1,1′-carbonyldiimidazole (0.622 g, 4.09 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at 0° C. Sodium hydride (60% oil suspension 0.136 g, 3.40 mmol) was suspended in tetrahydrofuran (11 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.511 g, 3.40 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 3 hours at 0° C. The mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-[4-(octyloxy)phenyl]-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 6) (0.290 g, 21%).
Reaction SMILES: CC(O)C.O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][CH:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]>CO>[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][C@@H:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL three neck flask IPA (5 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-90.5%) dissolved in methanol (6 mL) was added into the reaction mixture at 60-65° C. It was stirred for 30 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2-3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1, 10 mL). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-1.72 g, % Y-45%, Purity by HPLC-99.3%, % Chiral purity by HPLC of R-isomer 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH2:30])[CH3:29].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[CH:28]([NH:30][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:29]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)c1ccc(F)cc1-c1ccc(F)cc1F
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2ccc(F)cc2F)c1
Yield: 83.2 %

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (146 mg, 0.7 mmol), 1-(-2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethylamine (169 mg, 0.67 mmol), and triethylamine (187 μL, 1.3 mmol) according to the procedure and in the same manner as described in Example 105, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (235 mg, 83%) as a white solid;
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:8].[CH:20]1([C:23]2[C:27]([CH:28]=O)=[CH:26][N:25]([CH3:30])[N:24]=2)[CH2:22][CH2:21]1.CO>COCCOC>[CH:20]1([C:23]2[C:27]([CH2:28][C:8]#[N:7])=[CH:26][N:25]([CH3:30])[N:24]=2)[CH2:22][CH2:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cn1cc(C=O)c(C2CC2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cn1cc(CC#N)c(C2CC2)n1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a suspension of potassium tert-butoxide (8.95 g, 79.9 mmol) in DME (250 mL)-78° C. under nitrogen was added a solution of 1-(isocyanomethyl sulfonyl)-4-methyl benzene (9.36 g, 47.94 mmol) in DME (50 ml). After stirring for 10 minutes, a solution of 3-cyclopropyl-1-methyl-1H-pyrazole-4-carbaldehyde (6 g, 39.95 mmol) in DME (100 mL) was added. The resulting mixture was allowed to stir at −78° C. for 1 hour and then at room temperature for 1 hour. Methanol (50 mL) was added and the resulting mixture refluxed for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with hexane:EtOAc 90:10 to afford the title compound an off-white solid in 67% yield, 4.3 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[C:7](/[CH2:24][CH3:25])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:22][CH3:23])([CH2:20][CH3:21])[O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[S:5][CH:6]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>C1COCC1>[CH2:24](/[C:7](/[C:4]1[S:5][CH:6]=[C:2]([CH:33]=[O:34])[CH:3]=1)=[CH:8]\[CH2:9][CH2:10][C:11]([CH2:22][CH3:23])([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:20][CH3:21])[CH3:25]
Reactant: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(Br)cs1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(C=O)cs1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
11 g (24.7 mmol) of [(E)-5-(4-bromo-2-thienyl)-1,1-diethylhept-4-enyloxy]triethylsilane are dissolved in 100 mL of anhydrous THF and the mixture is cooled to −78° C. 10.9 mL (27 mmol) of 2.5 M butyllithium are added slowly and the mixture is stirred for 15 minutes. 2.1 mL (27 mmol) of dimethylformamide are then added and the medium is stirred for 30 minutes and then poured into aqueous ammonium chloride solution. After extraction with ethyl acetate and chromatography on silica gel (eluent: 9 heptane/1 ethyl acetate), the product is obtained in the form of a colourless oil (m=4 g; Y=41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([N+:16]([O-])=O)[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:16][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(N)ccc(OC)c1OC

Procedure:
Ethyl 2,3-dimethoxy-6-nitrobenzoate (200 g, 0.979 mole) was dissolved in ethanol (2 L) containing 5% palladium on carbon and hydrogenated until the theoretical amount of hydrogen was absorbed. Filtration and removal of the solvent in vacuo provided the product as a yellow oil, 220.6 g (98.0%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][NH:15][CH3:16])[C:4]1=O.B.Cl>O1CCCC1>[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14][NH:15][CH3:16])[CH2:4]1
Reactant: CNCC[C@H](c1ccccc1)N1C(=O)C(C)(C)c2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCC[C@H](c1ccccc1)N1CC(C)(C)c2ccccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 3,3-dimethyl-1-[(1R)-3-(methylamino)-1-phenylpropyl]-1,3-dihydro-2H-indol-2-one (Example 9, Step 2, 150 mg, 0.486 mmol) in dry tetrahydrofuran (3 mL) under nitrogen was added dropwise a solution of borane (1.0 M in tetrahydrofuran, 1.0 mL, 1.0 mmol, 2 equiv.) via a syringe. The resulting solution was heated at 70° C. with stirring for 2 h. Upon cooling, the reaction mixture was treated dropwise with a 2N aqueous solution of hydrochloric acid (2 mL), and was again heated at 60° C. for 20 minutes Upon cooling, solvent was removed under reduced pressure. To the residue was slowly added aqueous potassium carbonate (5 mL), and the mixture was extracted with dichloromethane (20 mL). The organic layer was washed with brine, dried (anhydrous sodium sulfate), and concentrated. Purification by Isco CombiFlash Companion chromatography (RediSep 4-g silica column, 0-15% methanol/dichloromethane/0.5% triethylamine) gave 100 mg (70%) of (3R)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-N-methyl-3-phenylpropan-1-amine as a viscous brown liquid, which was dissolved dichloromethane (3 mL) and treated with an ethereal solution of hydrochloric acid (1 M, 0.37 mL, 0.37 mmol). To the resulting solution was added hexane until white powder formed, which was collected, washed with hexane, and dried in vacuo to yield (3R)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-N-methyl-3-phenylpropan-1-amine hydrochloride as a yellow powder. MS (ES) m/z 295.3 ([M+H]+); HRMS: calculated for C20H26N2+H+, 295.2169; found (ESI, [M+H]+), 295.2160.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18][CH3:19])=[N:16][N:17]=[C:10]1[C:9](Cl)=[N:8]2)=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([O:18][CH3:19])=[N:16][N:17]=[C:10]1[C:9]([NH:24][CH:21]([CH3:23])[CH3:22])=[N:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(OC)n12
Reactant: CC(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)nc(NC(C)C)c1nnc(OC)n12
Temperature: 23 °C
Reaction time: 17 h

Procedure:
A mixture of 4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester (80 mg), isopropylamine (24 mg) and sodium bicarbonate (45 mg) in DMF (2 mL) was stirred at 23° C. for 17 hrs. The mixture was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. Trituration with EtOAc/hexanes afforded 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid methyl ester as a light yellow solid. MS (M+H)+=316.3.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.NO.[OH-].[K+].CO>C1COCC1>[CH3:18][N:16]([CH3:17])[C:13]1[CH:12]=[CH:11][C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCCSc1ccc(N(C)C)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(SCCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexanoic acid methyl ester (722 mg, 2.6 mmol) in distilled THF (20 mL) containing 50% aqueous hydroxylamine (1.7 mL, 25.7 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 4.4 mL, 4.4 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (20 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×40 mL) and the combined extracts were washed with brine (80 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The title compound was obtained as a colourless oil (377 mg, 52%).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH:46]([CH3:63])[CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH:46]([CH3:63])[CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.83 h
Yield: 93.9 %

Procedure:
20 ml of trifluoroacetic acid and subsequently 0.50 ml of trifluoromethanesulfonic acid were added dropwise, whilst ice-cooling, to a solution of 2.0 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[3-methyl-4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 3.08 ml of anisole, and the resulting mixture was stirred at the same temperature for 50 minutes. At the end of this time, the reaction mixture was worked up by the same procedure as described in Preparation 4(ii), to give 1.56 g of the title compound as an amorphous solid.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[N:23]=[CH:22][NH:21][N:20]=1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Reactant: Nc1nc[nH]n1
Solvent: O
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3nc[nH]n3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (4.84 g) was dissolved in a mixture of methanol (100 ml) and water (100 ml). To the solution was added 3-amino-1H-1,2,4-triazole (1.68 g). The mixture was stirred at ambient temperature for five hours and evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,2,4-triazol-3-yl)morpholin-2-yl]uracil (6.25 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH2:35])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:35][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32][CH2:33][CH3:34])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:43])[CH2:40][F:41])[C@@H:16]1[CH3:44])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCOc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add acetic anhydride (43 μL, 0.44 mmol) to a solution of (2R,3S,5R)-5-[(1S,2S)-1-Hydroxy-2-amino-3-(3-propoxy-5-fluorophenyl)-propyl]-2-(3-fluoro-2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (231 mg, 0.44 mmol) and triethylamine (92 μL, 0.65 mmol) in dichloromethane (4.6 mL) and stir at room temperature for 30 minutes. Concentrate reaction mixture under a stream of nitrogen and subject residue to silica gel chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][O:8][C:5]2=[N:6][CH:7]=1.BrC1C=C2C=CNC2=NC=1.[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]([CH2:25][CH:26]=[CH2:27])[CH3:24]>[Pd]>[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:23]([CH2:25]/[CH:26]=[CH:27]/[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][O:8][C:5]2=[N:6][CH:7]=1)[CH3:24]
Reactant: Brc1cnc2occc2c1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Brc1cnc2[nH]ccc2c1
Product: CC(C/C=C/c1cnc2occc2c1)N(C)C(=O)OC(C)(C)C

Procedure:
Other polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction. Thus both 5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine can undergo palladium catalyzed coupling with the previously described olefinic amine side chain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, to give (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-furo[2,3-b]pyridinyl)-4-penten-2-amine and (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-1H1H-pyrrolo[2,3-b]pyridinyl)-4-penten-2-amine respectively. Subsequent removal of the tert-butoxycarbonyl group with trifluoroacetic acid will provide (4E)-N-methyl-5-(5-furo[2,3-b]pyridinyl)-4-penten-2-amine and (4E)-N-methyl-5-(5-1H-pyrrolo[2,3-b]pyridinyl)-4-penten-2-amine. The requisite 5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine can be made from 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine respectively, by bromination (bromine and sodium bicarbonate in methanol) and dehydrogenation (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), using chemistry described by E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987). 2,3-Dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are, in turn, made from 2-chloropyrimidine (Aldrich Chemical Company), as described by A. E. Frissen et al., Tetrahedron 45: 803-812 (1989), by nucleophilic displacement of the chloride (with the sodium salt of 3-butyn-1-ol or with 4-amino-1-butyne) and subsequent intramolecular Diels-Alder reaction. Using similar chemistry, 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are also produced from 3-methylthio-1,2,4-triazene (E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987)), which in turn is made from glyoxal and S-methylthiosemicarbazide (W. Paudler et al., J. Heterocyclic Chem. 7: 767-771 (1970)).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][N:22]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:23][N:22]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1ccc(Br)cn1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cn1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 5-bromo-pyridine-2-carboxylic acid ethyl ester (22) as a gum. MS (ESI) 351.1 (M•)+.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([CH2:10][C:11]([OH:13])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:9])[CH2:10][C:11]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CC(=O)N(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC(=O)N(c1ccccc1)c1ccccc1)NCCN1CCOCC1

Procedure:
A solution of 13 g (0.05 mol) of N,N-diphenylcarbamoylacetic acid and 7.1 g (0.055 mol) of N-(2-aminoethyl)morpholine in 120 ml of methylene chloride is refluxed with agitation. A solution of 11 g (0.055 mol) of dicyclohexylcarbodiimide in 30 ml of CH2Cl2 is slowly added and the mixture is maintained under reflux for 3 hours.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]([CH:10]([OH:12])[CH3:11])[CH2:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[CH:5]([CH:10]([O:12][C:13](=[O:15])[CH3:14])[CH3:11])[CH2:4][CH:3]=1
Reactant: CC1=CCC(C(C)O)C(C)(C)C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC(C)C1CC=C(C)CC1(C)C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A 1 liter flask, provided with a mechanical stirrer, a heater and a reflux condenser fitted with a calcium chloride drying tube, is charged with 190.8 g of 1,5,5-trimethyl-4-(1-hydroxyethyl)-cyclohex-1-ene and 173.8 g of acetic anhydride. The mixture is brought to 100° for 4 hours. After cooling, the mixture is immersed in 250 ml of water and extracted with 3 times 100 ml of benzene. The extract is then washed once with 100 ml of water, twice with 100 ml of a 9% solution of sodium bicarbonate and twice more with 100 ml of water. The solvent is distilled off on a water bath, finally, under a pressure of 30 mm of mercury; the crude ester is distilled in a 500 ml three-necked flask fitted with a 1 meter adiabatic column filled with unoxidisable 4×4 mm particles, under a vacuum of 0.5 mm of mercury. 197 g of 1,5,5-trimethyl-4-(1 -acetoxyethyl)-cyclohex-1-ene (81.3%) are obtained having the following physical properties: