Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:14])=O.O[CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[Cl:14][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reaction time: 0.17 h

Procedure:
24 ml (0.3 mole) of pyridine, 400 ul of dimethylformamide and 21.6 ml (0.3 mole) of thionyl chloride are added to a solution of 103 g (0.2 mole) of benzhydryl 3-hydroxymethyl-7β-phenylacetamido-3-cephem-4-carboxylate (prepared, for example, in accordance with Helv. Chim. Acta 57, 2044 (1974)) in 3.5 l of absolute tetrahydrofuran, while cooling with ice. After 10 minutes, the mixture is concentrated on a rotary evaporator, the residue is taken up in 2 l of ethyl acetate and the mixture is extracted by shaking twice with sodium bicarbonate solution and once with water. The organic phase is extracted by stirring with 50 g each of kieselguhr and active charcoal and the extract is filtered with suction over a frit covered with silica gel. The filtrate is then dried over magnesium sulphate and concentrated, the residue is taken up in 200 ml of methylene chloride and the product is precipitated with petroleum ether.
Reaction SMILES: [O:1]=[C:2]([CH2:24][CH3:25])[CH2:3][C:4]([NH:6][C@@H:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH2:12][S:13][C@H:8]12)=[O:5].C(O)(=O)C.[N:30]([O-])=[O:31].[Na+]>O>[OH:31][N:30]=[C:3]([C:2](=[O:1])[CH2:24][CH3:25])[C:4]([NH:6][C@@H:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH2:12][S:13][C@H:8]12)=[O:5]
Reactant: O=N[O-]
Reactant: CCC(=O)CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)C(=NO)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12

Procedure:
To a solution of 6 g. of benzhydryl ester of 7β-(3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid in 20 ml. of glacial acetic acid are added dropwise 1.54 g. of sodium nitrite dissolved in 15 ml. of water, and the mixture is stirred for 2 hours at ambient temperature. The mixture is then diluted with 500 ml. of ethyl acetate and washed 3 times with 100 ml. of an aqueous saturated sodium chloride solution. The organic phase is made anhydrous and evaporated to dryness and the residue is triturated with diethyl ether. 5.5 g. of benzhydryl ester of 7β-(2-hydroxyimino-3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid melting at 56°-62° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[NH:18]1[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[N:4]=[C:3]([CH2:2][N:18]3[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]3)[CH:8]=[N:7][C:6]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc[nH]n1
Reactant: COc1ncc(CBr)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine (Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was added methyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and potassium carbonate (264.44 mg, 1.91 mmol). The reaction was stirred at room temperature for 2 h. The LCMS showed two peaks with [M+H] values consistent with the two major regioproducts. The mixture was diluted with DCM (5 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 20-100% EtOAc/hexanes) afforded the title compound (100 mg; 44%). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, J=1.1, 2.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.45-7.36 (m, 2H), 5.64 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H). [M+H]=360.24.
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[NH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1)(=[O:18])=[O:17].C(N(C(C)C)CC)(C)C.[Cl:44]CCCl>CN(C=O)C>[ClH:44].[ClH:44].[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][NH:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1)(=[O:18])=[O:17]
Reactant: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Reactant: O[C@H](CCI)c1ccccc1
Reactant: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cl
Product: O=S(=O)(NCCNCC[C@@H](O)c1ccccc1)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 80 °C

Procedure:
Add sodium iodide (4.29 g, 29 mmol) to a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (0.5 g, 2.93 mmol) in acetone (9.75 mL), and heat to reflux overnight. Cool and filter the suspension, then remove the volatiles under reduced pressure. Resuspend the residue in ether, filter and evaporate to afford (R)-3-iodo-1-phenyl-1-propanol (0.71 g). Add (R)-3-iodo-1-phenyl-1-propanol (0.1 g, 0.4 mmol) to a solution of 7-phenyl-isoquinoline -5-sulfonic acid (2-amino-ethyl)-amide (0.087 g, 0.27 mmol) in DMF (0.5 mL) and DCE (0.27 mL) containing diisopropylethylamine (0.094 mL, 0.53 mmol), and warm to 80° C. for 30 minutes. Cool to ambient temperature, and apply to a cation exchange resin cartridge. Wash with methanol, and elute product from the resin with 2M methanolic ammonia. Evaporate and purify the residue by silica gel chromatography using a methanol-methylene chloride gradient, followed by treatment with aqueous hydrochloric acid and lyophylization to afford the title compound. 1H NMR (DMSO): δ9.71(s, 1H), 9.00-8.82 (m, 3H), 8.80-8.73(m, 2H), 8.69 (d, J=1.8 Hz, 1H), 8.59 (d, J=6.2 Hz, 1H), 7.95 (dd, J1=1.5 Hz, J2=8.5 Hz, 2H), 7.62 (t, J=6.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.38-7.29 (m, 4H), 7.28-7.21 (m, 1H), 5.50-4.67 (bs, 2H), 4.65 (dd, J1=4.5 Hz, J2=8.5 Hz, 1H), 3.23-3.10 (m, 2H), 3.06-2.86 (m, 4H), 2.00=−1.77(m, 2H). LCMS: m/z 462(M+H)+460(M−H)−.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH3:24][C:25]([CH3:32])([CH:30]=O)[C:26]([O:28]C)=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.IC1C=CC=CC=1>[CH3:24][C:25]([CH3:32])([CH2:30][N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[C:26]([OH:28])=[O:27]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)C(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: Ic1ccccc1
Product: CC(C)(CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (160 mg, 0.478 mmol) and sodium triacetoxyborohydride (118 mg, 0.558 mmol), and the reaction mixture was stirred for 18 h. Additional methyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (320 mg) and sodium triacetoxyborohydride (236 mg) were added and the mixture was stirred at rt for 2 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at rt for 18 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The resulting TFA salt was treated with ACN (1 mL) and 1N HCl aqueous solution and concentrated to give 64 mg of product as off-white solid (HCl salt). MS: (M+H)+=311.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 7H), 1.59-1.83 (m, 3H), 1.98 (br. s., 3H), 2.58-2.74 (m, 1H), 2.85-3.24 (m, 7H), 3.42 (br. s., 2H), 7.08-7.43 (m, 5H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:13][CH2:12]3)O1.[OH:26]OS([O-])=O.[K+]>CC(C)=O.O>[OH:26][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:13][CH2:12]2
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a stirred solution of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (1.5 g, 4.11 mmol) in acetone (15 mL) was added dropwise a solution of oxone (2.78 g, 4.52 mmol) in water (15 mL). The resulting mixture stirred for another 10 min before the reaction mixture quenched with Na2O5S2 solution and diluted with DCM. The organic layer was separated, washed with brine (2×) and dried on Na2SO4. Solvent evaporated in vacuo to afford the title compound as a white solid (1.05 g, 100%). MS (ESI): m/z [M−H]− 254.0
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].C(N(CC)CC)C.COC(O)C.[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[N:3]=1
Reactant: NCC(O)CO
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Nc1nc(NCC(O)CO)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.544, 2 mmol), 3-amino-1,2-propanediol (1.87 mg, 2 mmol), triethylamine (607 mg, 6 mmol) and methoxyethanol (6 ml) were refluxed overnight under nitrogen. 1 N NaOH (2 ml) was added and the solution was concentrated under vacuum and dried by evaporation of ethanol. The residual oil was chromatographed on silica gel. Title compound was eluted with 20% methanol-chloroform; white powder after crystallization from acetonitrile-methanol (0.300 g, 47%), m.p. 119-121° C. 1H-NMR: (DMSO-d6) δ 7.60 (s, 1, H-8), 6.90-6.80 (br m, 1, NH), 6.10 (m, 1, =CH), 5.85 (m, 3, =CH and NH2), 5.40 (br m, 1, CH--N), 4.90 (m, 1, OH), 4.72 (t, J=5.3,1, OH), 4.62 (t, J=5.9, 1, OH), CH), 2.70-2.50 (m, overlapping solvent, 0.5 CH2), 1.70-1.50 (m, 1, 0.5 CH2).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:15]=2)C(OC)=O)=[CH:4][N:3]=[CH:2]1.[CH2:27]1COCC1.C[Mg]Cl.C([O:38][CH2:39][CH3:40])(=O)C>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:39]([OH:38])([CH3:40])[CH3:27])[CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: C[Mg]Cl
Product: CC(C)(O)c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a flask containing the product of Step 3 (254 mg, 0.67 mmol) was added THF (6.7 mL). The solution was cooled to 0° C. and then methylmagnesium chloride (3.0M in Et2O, 1.1 mL, 3.3 mmol) was added and the reaction was stirred for one hour. After one hour, more methylmagnesium chloride (3.0M in Et2O, 1.1 mL, 3.3 mmol) was added and the reaction was stirred for 30 minutes. The reaction was then diluted with ethyl acetate and carefully quenched with water and then diluted with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 2-[3-(1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]propan-2-ol (188 mg, 0.49 mmol, 74% yield). MS ESI: [M+H]+ m/z 381. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.07 (s, 1H), 8.82 (d, J=4.8, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.79 (s, 1H), 7.45 (s, 1H), 7.28 (d, J=4.9, 1H), 5.12 (s, 1H), 1.46 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[N:8]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[C:7](=[O:18])[NH:6][C:5](=[O:19])[CH:4]=1)#[N:2].[OH-].[Na+].[Cl:22][C:23]([Cl:27])([Cl:26])[S:24]Cl>C(Cl)Cl>[C:1]([C:3]1[N:8]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[C:7](=[O:18])[N:6]([S:24][C:23]([Cl:27])([Cl:26])[Cl:22])[C:5](=[O:19])[CH:4]=1)#[N:2].[C:1]([C:3]1[N:8]([N:9]([S:24][C:23]([Cl:27])([Cl:26])[Cl:22])[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[C:7](=[O:18])[NH:6][C:5](=[O:19])[CH:4]=1)#[N:2]
Reactant: Cc1cccc(C)c1Nn1c(C#N)cc(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cccc(C)c1N(SC(Cl)(Cl)Cl)n1c(C#N)cc(=O)[nH]c1=O
Product: Cc1cccc(C)c1Nn1c(C#N)cc(=O)n(SC(Cl)(Cl)Cl)c1=O

Procedure:
To a mixture of 6-cyano-1-(2,6-dimethylanilino)-2,4-pyrimidinedione (50 mmol) and aqueous sodium hydroxide (50 mmol) is added 55 mmol of trichloromethylsulfenyl chloride in methylene chloride at 5° and with rapid stirring. When the pH of the mixture is 7-8, the reaction is complete. The layers are separated and the aqueous phase is discarded. The methylene chloride is removed, followed by washing with water and drying to yield a mixture of two crude products. Separation by chromatography on silica gel, eluting with acetone/hexane, gives the two final products, 6-cyano-1-(2,6-dimethylanilino)-3-trichloromethylthio-2,4-pyrimidinedione and 6-cyano-1-(2,6-dimethyl-N-trichloromethylthioanilino)-2,4-pyrimidinedione.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[N:24]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Reactant: COc1ccccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 250 °C
Yield: 142.1 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(272 mg, 1.0 mmol) was dissolved in diethylene glycol(10 ml), and 2-methoxyaniline(281 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eleunt to obtain 298 mg of desired compound as solid in 76% of yield.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][C:10]2[C:15]([CH:16]=[O:17])=[CH:14][C:13]([O:18][CH3:19])=[N:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:20][N:21](C=O)C>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>[CH:16]([C:15]1[CH:14]=[C:13]([O:18][CH3:19])[N:12]=[CH:11][C:10]=1[O:9][CH2:8][C:7]1[C:2]([C:20]#[N:21])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:17]
Reactant: CN(C)C=O
Reactant: COc1cc(C=O)c(OCc2cccnc2Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C=O)c(OCc2cccnc2C#N)cn1
Temperature: 125 °C
Yield: 84 %

Procedure:
To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), Zn (CN)2 (71 mg, 0.62 mmol, 2.0 equiv), Pd(PPh3)4 (72 mg, 0.06 mmol, 0.2 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 15 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (71 mg, 84%) as a white solid. 1H NMR (400 MHz; CDCl3) δ=10.54 (s, 1H), 8.86 (d, 1H), 8.22 (s, 1H), 8.20 (d, 1H), 7.74 (dd, 1H), 6.37 (s, 1H) 5.52 (s, 2H), 4.04 (s, 3H). LRMS (M+H+) m/z 270.1.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylate (199 mg, 0.506 mmol) in THF (2.84 mL) and water (1.42 mL) was added 1.0 M LiOH (0.658 mL, 0.658 mmol) and the resulting solution was stirred at room temperature overnight. The mixture was acidified to pH=4 with 1 N HCl. The precipitated solids were filtered, washed with water and dried to give 179 mg of the title compound as an a white solid. (96% yield). LC/MS (FA) ES+ 365, 367.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (1.62 g, 5 mmol), morpholine (2.18 mL, 25 mmol) in DMSO (10 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.83 g, 94%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([C:10]1[CH:25]=[CH:24][C:13]2[C:14](=[O:23])[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[CH:18][C:12]=2[CH:11]=1)[CH:8]=[CH2:9].C1C=CC=CC=1.[CH2:32](O)[CH2:33][OH:34]>C(#N)C.C(N(CC)CC)C>[CH2:32]1[CH2:33][O:34][C:14]2([C:13]3[CH:24]=[CH:25][C:10]([CH2:7][CH:8]=[CH2:9])=[CH:11][C:12]=3[CH:18]=[CH:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]2=3)[O:23]1
Reactant: OCCO
Reactant: C=CCc1ccc2c(=O)c3ccccc3ccc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCc1ccc2c(c1)C=Cc1ccccc1C21OCCO1

Procedure:
0.5 Gm. of phosphorus pentachloride is added to a solution of 0.5 gm. of 2-(2-propenyl)5H-dibenzo[a,d]cyclohepten-5-one in 20 ml. of benzene, and the mixture is stirred for one hour, and then added to a mixture of 1.0 ml. of ethylene glycol, 1.0 ml. of triethylamine and 20 ml. of acetonitrile. After 2 hours the mixture is washed with water, dried and evaporated to give a nearly quantitative yield of 5,5-ethylenedioxy-2-(2-propenyl)5H-dibenzo[a,d] cycloheptene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][N+]([O-])=O)=[CH:26][CH:25]=1>>[CH2:15]([N:22]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Cc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1

Procedure:
The title compound (89.7 mg) was prepared from 0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 272 μL of benzylamine, and 0.41 g of 1-methyl-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C21H22N2, 302.18. found, m/z 303.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.23-7.20 (m, 2H), 7.18-7.14 (m, 4H), 7.06 (s, 1H), 5.13 (s, 2H), 4.33 (s, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[C:5]([NH:15]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1)[CH3:2].ClC1C=C2C(C(CC(O)=O)=[C:32]([C:36]([C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=3)=[O:37])N2)=CC=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:14][CH:13]=2)[NH:15][C:32]=1[C:36]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=1)=[O:37]
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Reactant: CCc1ccc(/C=C/C(=O)OC)c(NS(=O)(=O)c2ccc(C)cc2)c1
Product: CCc1ccc2c(CC(=O)OC)c(C(=O)c3cc(C)ccn3)[nH]c2c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-ethyl-2-(p-toluenesulfonylamino)cinnamate (step 5) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C:16]1=[O:21])([CH3:14])[C@@H:12]([C:22]([OH:24])=[O:23])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.O.[CH2:31]([OH:33])[CH3:32]>>[CH2:31]([O:33][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([OH:24])=[O:23])[CH2:4][C@@H:3]1[OH:1])[CH3:32]
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A solution of 2α,3α-epoxy-5α-androstan-11-one-17β-carboxylic acid (940 mg.) and concentrated sulphuric acid (0.25 ml.) in dry ethanol (30 ml.) was stirred at room temperature for 30 minutes. Water (100 ml.) was added and the reaction mixture extracted with chloroform. The chloroform solution was washed with water, dried, filtered and evaporated to give a froth which solidified when triturated with chloroform/petrol. Filtration afforded the solid crude product (752 mg.) which, after recrystallisation from ethanol/water, afforded the pure title compound; m.p. 249°-260°; [α]D + 74°, (c 0.33).