Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[C:6]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:35][CH:34]=1>C1C=CC=CC=1>[CH2:6]([O:14][C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:18]([C:19]([N:46]2[CH2:47][CH2:48][N:43]([C:36]3[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:33]=[CH:34][N:35]=3)[CH2:44][CH2:45]2)=[O:21])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(c3ncnc4ccccc34)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h
Yield: 84 %

Procedure:
DMF was added to a stirred suspension of 4-benzoyloxy-5-methoxy-2-nitro benzoic acid (6) (0:500 mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6 h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added dropwise over a period of 1 h to a stirred suspension of (4-quinazolinyl)piperazine (350 mg, 1.65 mmol) triethyl amine (5 ml). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCl and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of (7d), (700 mg in 84% yield). 1H NMR (CDCl3) δ 3.15-3.30 (m, 4H), 3.65-3.75 (m, 4H), 3.95 (s, 3H), 5.20 (s, 2H), 6.45-6.55 (t, 1H) 6.70 (s, 1H), 7.30-7.50 (m, 5H), 7.55-7.65 (t, 1H), 7.65 (s, 1H), 7.70-7.90 (m, 2H), 7.85-7.95 (m, 2H); FABMS: 500 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H][H].[ClH:23]>CC(C)=O.[Pt]=O.C(O)C>[ClH:23].[CH:14]1([NH:20][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: NC1CCCCC1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCC(NC1CCCCC1)C2

Procedure:
A mixture of 5.3 g of 6-methoxy-2-tetralone, 3 g of cyclohexylamine and 70 ml of absolute ethanol was heated for 7 hours at reflux. To the mixture was added 0.3 g of platinum oxide, and a catalytic reduction was conducted in the presence of hydrogen. After absorption of hydrogen gas was completed, the platinum oxide catalyst in the reaction solution was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. Then, an ethanol solution saturated with hydrogen chloride was added to the residue and the solution was concentrated under reduced pressure. The residue obtained was dissolved in acetone and the solution was stirred to form crystals. After collecting the crystals by filtration and recrystallizing from a mixed solvent of ethanol and diethyl ether, 5.0 g of N-cyclohexyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride was obtained as colorless needles having a melting point of 252°-254° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]#[N:46])=[CH:47][CH:48]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (86.0 mg, 0.369 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (108.0 mg, 0.442 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (193 ul, 1.1 mmol). To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (76 mg, 0.406 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (29.7 mg, 20.0%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.94-7.04 (m, 3H), 4.44-4.55 (m, 1H), 3.79-3.88 (m, 1H), 3.35 (br. s., 2H), 3.30 (br. s., 4H), 2.54-2.69 (m, 1H), 2.45 (br. s., 4H), 1.97-2.09 (m, 1H), 1.80-1.90 (m, 1H), 1.57-1.69 (m, 1H), 1.32-1.56 (m, 3H). [M+H] calc'd for C23H26N6O, 403; found, 403. MP: 212.2° C.
Reaction SMILES: NC1C2=C3N(C(C)CC2)C=C(C(O)=O)C(=O)C3=CC=1.[CH3:20][CH:21]1[N:30]2[C:25]3[C:26](=[CH:35][CH:36]=[C:37]([N:38]4[CH:42]=[CH:41][CH:40]=[CH:39]4)[C:24]=3[CH2:23][CH2:22]1)[C:27](=[O:34])[C:28]([C:31]([OH:33])=[O:32])=[CH:29]2.[H][H]>FC(F)(F)C(O)=O.[Rh]>[CH3:20][CH:21]1[N:30]2[C:25]3[C:26](=[CH:35][CH:36]=[C:37]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[C:24]=3[CH2:23][CH2:22]1)[C:27](=[O:34])[C:28]([C:31]([OH:33])=[O:32])=[CH:29]2
Reactant: [H][H]
Reactant: CC1CCc2c(-n3cccc3)ccc3c(=O)c(C(=O)O)cn1c23
Agent: [Rh]
Agent: CC1CCc2c(N)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: O=C(O)C(F)(F)F
Product: CC1CCc2c(N3CCCC3)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
Using the method of Example 5, 3.0 g of 8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was converted to 6,7-dihydro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The crude product was dissolved in 50 ml of trifluoroacetic acid and 2 g of rhodium on alumina was added. The mixture was hydrogenated at 20° C. for 18 hours at 50 psi of hydrogen gas. The mixture was filtered, evaporated to dryness and dissolved in 10 percent sodium hydroxide solution. The solution was acidified with glacial acetic acid. The product was recrystallized from N,N-dimethyformamide to provide tan crystals of 6,7-dihydro-5-methyl-1-oxo-8-(1-pyrrolidyl)-1H,5H-benzo[ij]quinolizine-2-carboxylicacid, m.p. 170°-174° C. Nuclear magnetic resonance analysis showed water and N,N-dimethyl formamide present in the solid. Analysis: Calculated for C18H20N2O3.1/10(CH3)2NCHO.1/2H2O: %C, 66.8; %H, 6.6; %N, 9.2; Found: %C, 66.7; %H, 6.2; %N, 9.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:36]=1[C:37]([NH:39][CH2:40][C:41]1([CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1)=[O:38].[C:57](O)(=[S:59])[CH3:58].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:49]1([CH2:48][C:41]2([CH2:40][NH:39][C:37](=[O:38])[C:36]3[CH:52]=[CH:53][C:54]([Cl:56])=[CH:55][C:35]=3[Cl:34])[CH2:42][CH2:43][CH:44]([O:47][C:57](=[S:59])[CH3:58])[CH2:45][CH2:46]2)[CH2:51][CH2:50]1
Reactant: O=C(NCC1(CC2CC2)CCC(O)CC1)c1ccc(Cl)cc1Cl
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OC1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(CC2CC2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
To a stirred solution of triphenylphosphine (0.44 g; 1.68 mmol) in THF (20 ml) at 0° C. was added diisopropylazodicarboxylate (0.34 g; 1.68 mmol) and the solution stirred at 0° C. for 90 minutes. To a stirred solution of 2,4-dichloro-N-{[1-(cyclopropylmethyl)-4-hydroxycyclohexyl]methyl}benzamide (0.30 g; 0.84 mmol; less polar alcohol isomer) in THF (10 ml) was added thioacetic acid (0.12 ml; 1.68 mmol). The resulting solution was added dropwise to the triphenylphosphine solution at 0° C. On complete addition, the solution was stirred at 0° C. for 1 hour then allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was partitioned between EtOAc (200 ml) and water (100 ml). The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow oily solid. The crude product was chromatographed on silica eluted with 10-30% EtOAc in isohexane to give the product contaminated with triphenylphosphine oxide. The contaminated product was chromatographed on silica eluted with 1% EtOAc in dichloromethane to give the desired product as an oil (220 mg). 1H NMR δ (ppm) (CDCl3): 7.66 (1H, d, J=8.4 Hz), 7.43 (1H, d, J=2.1 Hz), 7.34 (1H, dd, J=2.1, 8.4 Hz), 6.26 (1H, s), 3.58 (2H, d, J=6.0 Hz), 3.45-3.52 (1H, m), 2.30 (3H, s), 1.83-1.88 (2H, m), 1.65-1.74 (4H, m), 1.44-1.52 (2H, m), 1.26 (2H, d, J=7.0 Hz), 0.64-0.71 (1H, m), 0.47-0.52 (2H, m), 0.00-0.06 (2H, m).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:12]([NH:14][C:15](=[O:17])[O-:16])[CH3:13].[OH:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:23]([CH3:31])[CH:24]3[CH2:28][NH:27][CH2:26][CH:25]3[C:29]=2[CH:30]=1>CC#N.O.C(Cl)Cl>[CH2:12]([NH:14][C:15](=[O:16])[O-:17])[CH3:13].[CH:5]1([CH2:4][O:18][C:19]2[CH:20]=[CH:21][C:22]3[CH:23]([CH3:31])[CH:24]4[CH2:28][NH:27][CH2:26][CH:25]4[C:29]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC1c2ccc(OCC3CC3)cc2C2CNCC12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(Bromomethyl)cyclopropane (13 mg, 0.09 mmol) and K2CO3 (24 mg, 0.17 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (23 mg, 0.09 mmol) in CH3CN, and stirred overnight at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C19H25NO3+H: 316, observed: 316.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)(Cl)Cl>[N:30]1([CH2:1][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(C)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CN2CCCC2)nc1

Procedure:
A solution of methyl 6-methyl-3-pyridinecarboxylate (0.43 g) N-bromosuccinimide (0.59 g) and benzoylperoxide (50 mg) in dry carbon tetrachloride (10 ml) was stirred at 22° and irradiated with a 200 w light bulb for 2 days. Pyrrolidine (2.4 ml) was added and after 15 min the solution was partitioned between dichloromethane (20 ml) and 2N sodium carbonate solution (20 ml). The organic phase was washed with water, saturated brine, dried and evaporated to leave an oil (0.68 g). The oil was purified by flash chromatography eluting with a mixture of dichloromethane, ethanol and ammonia (300:8:1) to give the title compound as an oil (0.22 g). T.l.c. silica (Dichloromethane:methanol: 0.88 ammonia 300:8:1) Rf 0.5.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].C(N(CC)CC)C.[CH3:19][N:20]([S:24][C:25]1([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]1=[O:30])[C:21](Cl)=[O:22]>O1CCOCC1>[CH3:19][N:20]([S:24][C:25]1([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]1=[O:30])[C:21]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:22]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SC1(C)CCCC1=O)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SC1(C)CCCC1=O)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a solution of 3.93 g (0.0225 m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one and 2.28 g (0.0225 m) of triethylamine in 75 ml of dioxane was added dropwise with stirring 5.0 g (0.0225 m) of N-methyl-N-(2-methyl-1-oxo-2-cyclopentanesulfenyl)carbamoyl chloride whilst maintaining the temperature between 10°-15° C. The reaction mixture was left standing for 16 hours at 5° C., and then diluted with ice water. The product was extracted in ethylacetate, dried and concentrated to yield 0.66 g of white solid, m.p. 119°-121° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C@H:15]([CH3:16])[O:14]1.C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O>C(OCC)(=O)C>[N:18]1([CH2:17][C@@:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:14])[C@H:15]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH3:16])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1cncn1)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 110 °C
Reaction time: 24 h
Yield: 50.9 %

Procedure:
A mixture of 1H-1,2,4-triazole (1.17 g), (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (2 g), lithium carbonate (6.32 g) and dimethylformamide (40 ml) was stirred for 24 hours at 110° C. After cooling, to the mixture was added ethyl acetate (50 ml). The mixture was filtered to remove insoluble substances. The filtrate was distilled under reduced pressure. The residue was dissolved in ethyl acetate (100 ml). The mixture was washed with saturated saline (30 ml×2). The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel chromatography (silica gel 50 g, eluent: ethyl acetate/acetone=4:1) to give (2R,3R)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-butanol (1.32 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)=O>ClCCCl>[C:21]([O:20][C:18](=[O:19])[C@H:17]([NH:16][CH2:27][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)[CH2:25][CH3:26])([CH3:22])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC[C@@H](N)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Sodium triacetoxyborohydride (9.86 mmol) and (R)-tert-butyl 2-aminobutanoate hydrochloride (5.59 mmol) were added to a 100 mL round bottom flask, followed by DCE (20 mL). The reaction mixture was stirred at room temperature for 30 min and cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (3.29 mmol) in DCE (20 mL) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (1.4 g, 95%). [M+H] calc'd for C23H33N3O6, 448; found, 448.6.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>CC1C=CC=CC=1>[Br:15][CH2:16][C:17]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[O:9][CH:6]([CH2:5][O:4][C:3]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH2:7][O:8]1
Reactant: Cc1cccc(C)c1OCC(O)CO
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Cc1cccc(C)c1OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1

Procedure:
A mixture of 11.8 parts of 3-(2,6-dimethylphenoxy)-1,2-propanediol, 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred for 30 minutes with silica gel. The latter is filtered off and the filtrate is evaporated, yielding A+B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[S:22][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:25]=2)O1.Br[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:43][C:40]1[CH:41]=[CH:42][C:37]([C:23]2[S:22][C:21]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=3)=[CH:25][CH:24]=2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)s2)OC1(C)C
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])c(-c2ccc(-c3ccc(F)cc3)s2)n1
Yield: 12.1 %

Procedure:
A suspension of 2-chloro-6-methoxy-3-nitropyridine (94 mg, 0.5 mmol), 2,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene (168 mg, 0.5 mmol), 1-bromo-4-fluorobenzene (105 mg, 0.6 mmol), 1.5 mL of dioxane, 1.5 mL of 1 M Na2CO3, and tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol) was heated in a microwave reactor at 95 C for 10 min. It was concentrated under reduced pressure and the residue was chromatographed (EtOAc/hexane) to afford 2-(5-(4-fluorophenyl)thiophen-2-yl)-6-methoxy-3-nitropyridine (WZ02103) as a yellow solid (20 mg, 12%). MS (ESI) m/z 330 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](C(O)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:24]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)O)C3)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tent-butyl ester (0.5 g, 1.1 mmol) in DCM (6.5 mL) was treated with TFA (6.5 mL). The reaction mixture was stirred at RT for 4 hours then concentrated in vacuo. The residue was azeotroped with DCM then dissolved in DCM and washed with an aqueous saturated sodium bicarbonate solution (×2) followed by brine. The mixture was passed through a phase separator cartridge and concentrated in vacuo to give 235 as a pale orange gum (397 mg, quant.). LCMS: RT=3.13 min, [M+H]+=368. 1H NMR δ (ppm) (DMSO-d6): 9.34 (1 H, s), 9.05 (1 H, s), 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, d, J=0.58 Hz), 7.23 (1 H, dd, J=8.24, 1.89 Hz), 7.13 (1 H, d, J=1.84 Hz), 5.82-5.72 (1 H, m), 4.36-4.30 (2 H, m), 4.25-4.17 (2 H, m), 4.13-3.97 (3 H, m), 3.43-3.37 (2 H, m), 1.50 (6 H, d, J=6.59 Hz).
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=O)=[CH:16][N:15]=2)=[CH:10][CH:9]=1>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][C:17]([CH2:18][NH2:20])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(-c2ccc(F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NCc1ccc(-c2ccc(F)cc2)nc1
Yield: 8.7 %

Procedure:
To an ice-bath cooled solution of sodium borohydride (5.47 g, 144.5 mmol) in anhydrous 1,4-dioxane (100 ml) was added slowly a solution of glacial acetic acid (8.27 ml, 144.5 mmol) in 1,4-dioxane (50 ml). To this mixture was added 6-(4-fluorophenyl)nicotinamide (Description 24; 6.25 g, 28.9 mmol) and the resulting mixture heated at reflux for 4 hours. The cooled reaction mixture was evaporated and water (60 ml) added slowly. This mixture was extracted with dichloromethane, and the solid which appeared between the layers was removed by filtration. This solid was triturated with a mixture of dichloromethane and iso-hexanes, filtered and dried to give the title compound (510 mg, 8%) as a pale green solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:32])[CH:24]=[CH:25]1)[CH2:20][CH2:19]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
17β,19-Dihydroxy-4-androsten-3-one dipropionate and dichlordicyanobenzoquinone are refluxed in anhydrous dioxane for about 48 hours. The mixture is cooled and filtered and the filtrate concentrated under vacuum. Methylenechloride is added and the mixture filtered. The filtrate is washed well with water, dried over sodium sulfate and the solvent removed. Chromatography on silica gel and elution with methylenechloride results in a solid which is crystallized from acetone-hexane to yield the desired 17β,19-dihydroxy-1,4-androstadien-3-one dipropionate.