Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:20]=1N>>[Cl:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:20]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18]
Reactant: COc1cccc(Cl)c1
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Agent: CC(C)CCON=O
Product: COc1ccc(-c2cc(Cl)c(Cl)cc2Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
Isoamyl nitrite (18.8 mL, 0.140 mol) was added portionwise over the course of 1 hour to a mixture of 3-chloroanisole (100 g, 0.70 mol) and 2,4,5-trichloroaniline (13.75 g, 0.070 mol) at 120° C. under nitrogen and the reaction was allowed to stir an additional 18 hours, and then distilled (0.2 mmHg, 160°-185° C.) to yield 14.07 g (62%). A 300 mg portion of the distillate was further purified via flash chromatography (silica gel, hexane eluent). Fraction 1 (32.2 mg, Rf=0.33; GC RT=14.44 minutes) was identified as 2',4,4',5'-tetrachloro-2-methoxybiphenyl. Fraction 2 (75.2 mg, Rf=0.22) contained a mixture of two products in a 40:60 ratio. Through subsequent demethylation and separation, these were determined to be the 2,2',4',5'-tetrachloro-6-methoxy and 2,2',4',5'-tetrachloro-4-methoxybiphenyl derivatives (GC retention time=14.01, 14.69 minutes respectively).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH:24]1([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:38]([C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[N:29]([C:27]([CH:24]2[CH2:25][CH2:26]2)=[O:28])[CH2:30][CH2:31]3)(=[O:39])=[O:40])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(C1CC1)N1CCc2cc(S(=O)(=O)Cl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Diisopropylethylamine (0.33 ml, 2.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.2 g, 1.0 mmol) in DCM (5 ml) at room temperature. To this mixture was added 1-cyclopropanecarbonyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (0.29 g, 1.0 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, dried with diethyl ether and dried under vacuum give the title compound (0.36 g, 73% yield) as a pale yellow solid. Tr=2.02 min m/z (ES+) (M+Na+) 472.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18](Cl)[CH3:19].C(=O)=O>CN(C)C=O>[C:3]([C:2]1([C:1]([O:8][CH3:9])=[O:7])[CH2:17][CH:18]1[CH3:19])([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(Cl)CCl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CC1C
Temperature: 118 °C

Procedure:
The apparatus described in Example 1 was charged successively with 132.1 g dimethyl malonate (1.0 mol), 166 g (1.2 mols) finely comminuted potassium carbonate, 339 g 1,2-dichloropropane (3.0 mols) and 250 ml of dimethylformamide. While stirring vigorously, the reaction mixture was heated to 118° C., and the reaction temperature was increased to 125° C. over a period of 15 hours. While releasing carbon dioxide, the reaction mixture distilled off as an azeotrope which was separated into dichloropropane and water in the phase separator and was then drained. Flash distillation was used to separate the salts and high boiling components, and the distillate was separated by way of a column into the fractions 1,2-dichloropropane, dimethylformamide and 1,1-dicarbomethoxy-2-methylcyclopropane. The target product distilled over at 78° C./14 mbar and was identified by means of H-NMR as the desired target product.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH2:21][CH2:22][CH3:23])/[C:18]([OH:20])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1/C=C(\C)/C(O)=O>CC(C)=O>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH2:21][CH2:22][CH3:23])/[C:18]([OH:20])=[O:19]
Reactant: CCC/C(=C\c1c(Cl)c(OC)c2ccccc2c1OC)C(=O)O
Agent: C/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC(C)=O
Product: CCC/C(=C\C1=C(Cl)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 43b was prepared from 42b (0.053 g, 0.16 mmol) as described above for 39a to give 0.016 g (0.05 mmol, 33%) of the product as a yellow solid following flash chromatography (2:3 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine 1,1-dioxide (1.09 g, 8.0 mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.90 g, 74%). 1H NMR (CDCl3, 300 MHz): 7.50-7.44 (m, 2H), 7.22-7.16 (m, 2H), 3.60 (s, 2H), 3.09-3.02 (m, 4H), 3.00-2.94 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1(Br)[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:14]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(C#N)c(O)c1OC
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(OC2CCC2)c1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
2-Hydroxy-3,4-dimethoxybenzonitrile (6.65 g, 0.037 mol) was added to a suspension of cyclobutyl bromide (5.01 g, 0.037 mol) and potassium carbonate (5.11 g, 0.037 mol) in dimethylformamide (65 ml) and the reaction stirred at 80° C. for 4 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with further ethyl acetate (100 ml) and the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a brown oil (6.50 g, 75%). Rf 0.63 (dichloromethane). MS m/z 251 (MNH4)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:15]=O)[S:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12].C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8](/[CH:15]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[S:9][C:10]=1[Si:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1sc(C=O)cc1C1OCCO1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1cc(C2OCCO2)c([Si](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophene-2-carbaldehyde (12.82 g, 50.00 mmol) in chloroform (128 ml) was added methyl (triphenyl phosphanylidene)acetate (17.55 g, 52.50 mmol) at 0° C. by small portions. After stirring at 0° C. for 1 hr, the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, diethyl ether (200 ml) was added to the residue, and the mixture was stirred. The insoluble material (mainly triphenylphosphineoxide) was filtered, and washed 4 times with diethyl ether (50 ml). The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 450 g, ethyl acetate:hexane=1:6) to give methyl (2E)-3-[4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophen-2-yl]acrylate (13.76 g, 44.04 mmol, yield 88.1%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:18][NH:19][CH3:20].O1CCCC1>CN1C(=O)CCC1>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Yield: 100 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.2 g, 0.68 mmol) and 2.0 M dimethylamine in tetrahydrofuran (1.3 ml, 2.7 mmol) in 10 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. N1,N1-dimethyl-4-nitro-N3-phenylbenzene-1,3-diamine (0.17 g, 100%) was obtained by flash column chromatograph (30% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.02 (s, 6H), 6.21 (d, J=2.6 Hz, 1H), 6.23 (s, 1H), 7.22-7.45 (m, 5H), 8.17 (d, J=2.6 Hz, 1H), 9.96 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 40.5, 93.6, 104.8, 124.9, 125.4, 129.5, 130.0, 139.8, 145.9, 155.5.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][NH:32][NH2:33])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:32]([CH2:31][C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)[N:33]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNCc1ccc(Cl)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1Cc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with (4-chloro-benzyl)-hydrazine (CAS Reg. No. 25198-45-2) to give the title compound as orange oil. MS (ESI): m/z=508.0 [M+H]+.
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:10])[CH2:5][CH2:6][CH2:7][C:8]#[N:9].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:10][C:4]1([CH2:5][CH2:6][CH2:7][C:8]#[N:9])[O:13][CH2:12][CH2:11][O:3]1
Reactant: OCCO
Reactant: CC(=O)CCCC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC1(CCCC#N)OCCO1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus and under inert atmosphere (N2), 5-oxo-hexanenitrile (1.69 g, 15.2 mmol) was dissolved in dry toluene (10 mL). Ethylene glycol (4.24 mL, 76.0 mmol) and p-TsOH (289 mg, 1.5 mmol) were added and the reaction mixture stirred at 120° C. for 5 h. The reaction mixture was then cooled down to rt and sat. aq. NaHCO3 was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.94 min.
Reaction SMILES: C(C([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:9]=1)=O)(C)(C)C.Cl.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24])[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7])=[O:27]
Reactant: COc1cc(C(=O)c2cccc(NC(=O)C(C)(C)C)c2)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccc(N)c2)cc(OC)c1OC
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
N-tert-butylcarbonyl-3-(3,4,5-trimethoxybenzoyl)aniline (7.10 g, 18.92 mmol), prepared as described above, was dissolved in acetic acid (125 mL, 1.4N) at room temperature. A solution of hydrochloric acid/acetic acid (20 mL) was added and the mixture allowed to stand for 45 minutes. Diethylether (800 mL) was added and the resulting precipitate filtered and dried to yield 3-(3,4,5-trimethoxybenzoyl)aniline (5.24 g, 85.7%) as a tan solid.
Reaction SMILES: I[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.CCN(CCOC1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl.C(#N)C.[C:39]([O:43][CH3:44])(=[O:42])[CH:40]=[CH2:41]>[Zn].O>[CH3:13][O:12][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[O:10][CH3:11])[CH2:41][C:40]([C:39]([O:43][CH3:44])=[O:42])=[CH:4]2
Reactant: COc1cc(I)c(C=O)cc1OC
Reactant: C=CC(=O)OC
Agent: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Temperature: 80 °C
Yield: 21.3 %

Procedure:
2-Iodo-4,5-dimethoxybenzaldehyde (292 mg, 1.0 mmol), CoCl2 (dppe) complex (26.4 mg, 0.05 mmol), dppe (19.9 mg, 0.05 mmol) and zinc power (179.8 mg, 2.75 mmol) were placed in a vial, which was sealed with a septum and flushed several times with nitrogen. Acetonitrile (3 mL) and methyl acrylate (172 mg, 2.0 mmol) were then sequentially added and the mixture was heated at 80° C. overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic extracts were concentrated under reduced pressure and the residue was purified by flash chromatography using petroleum ether/ethyl acetate 8:1 (v:v) as eluent to give methyl 5,6-dimethoxy-1H-indene-2-carboxylate (50 mg, 21%). LC-MS (ES-API); rt 7.89 min; m/z calculated for C13H14O4 [M+H]+ 235.1, found 235.1.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[I-].C([N+](CC)(CC)CC)C.C1(C)C=CC=CC=1>[CH2:23]([N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Yield: 85.3 %

Procedure:
A mixture of Example 2C (650 mg, 2 mmol), 1-iodobutane (920 mg, 5 mmol), potassium carbonate (653 mg, 4 mmol), tetrabutylammonium iodide (20 mg, 0.05 mmol), tetrabutylammonium hydrogensulfate (20 mg, 0.06 mmol) and tetraethylammonium iodide (20 mg, 0.07 mmol) in anhydrous toluene (60 mL) was refluxed for 15 h. The mixture was then washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed over silica gel (EtOAc-Hexane 1:1) to afford 650 mg of the title compound. MS (DCI/NH3) m/z 381 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH3:24])[CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[O:30][C:29]([C@@H:31]2[C:5]3=[C:6]4[N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10](=[O:20])[C:11]4=[C:12]([C:13]4[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=4)[N:4]3[CH2:3][C@H:2]([CH3:24])[O:1]2)=[CH:28][CH:27]=1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2C[C@H](C)O)c1
Reactant: O=Cc1ccc(Cl)o1
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2C[C@H](C)O[C@@H]3c2ccc(Cl)o2)c1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxypropyl)-1,3-dimethyl-5-m-tolyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 5-chlorofuran-2-carbaldehyde by an analogous method to Example 12. Purification was carried out by chromatography on silica eluting with 0-55% EtOAc in iso-hexane;
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[CH:16]=[CH2:17])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])/[CH:16]=[CH:17]/[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
A mixture of (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester (20.0 g, 76.3 mmol), 4-bromobenzaldehyde (14.4 g, 77.8 mmol), Pd2(dba)3 (0.56 g, 0.61 mmol), tri-o-tolylphosphine (0.370 g, 1.22 mmol) and triethylamine (42.1 mL, 0.300 mol) in DMF (300 mL) was stirred at 100 degrees Celcius under N2 for 5 hours. The reaction mixture was allowed to cool down to room temperature and poured into a saturated aqueous solution of NH4Cl. The precipitate was filtered off and washed with water, dried in vacuo at 40° C. overnight. The crude product was purified by flash column chromatography to obtain a yellow solid (15.5 g, 56%). MS: calc'd 367 (MH+), exp 367 (MH+). 1H NMR (d6-DMSO, 400 MHz) δ 10.0 (s, 1H), 9.79 (s, 1H), 8.53 (s, 1H), 7.98 (d, 2H, J=8.0 Hz), 7.87 (d, 2H, J=8.0 Hz), 7.68 (d, 1H, J=16 Hz), 7.60 (m, 2H), 7.14 (m, 2H), 7.10 (d, 1H, J=16 Hz), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]1[C@@H:6]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@@:5]1([F:27])[C@@H:4]([OH:28])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3.Cl(O)(=O)(=O)=[O:30]>ClCCl>[CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]1[C@@H:6]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@@:5]1([F:27])[C@@H:4]([OH:28])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3.[C:10]([CH2:11][C:13]([OH:30])=[O:14])(=[O:15])[CH3:2]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: ClCCl
Product: CC(=O)CC(=O)O

Procedure:
(VI) or triamcinolone is reacted with an acetylalkanoic acid in a solution of dichloromethane in the presence of catalytic amount of perchloric acid to produce the corresponding 16α,17-carboxycyclic acetal pregnane derivatives, e.g., when triamcinolone and acetylacetic acid are used the product is (XVI) 9α-fluoro-11β,21-dihydroxy-3,20-dioxo-16α, 17-(methyl, carboxylicmethyl)methylenedioxy-1,4-pregnadiene; when triamcinolone and acetylbutyric acid are used the product is (XVII) 9α-fluoro-11β,21-dihydroxy-3,20-dioxo-16α,17-(methyl, carboxylic-n-propyl)methylenedioxy-1,4-pregnadiene; (XVII) is reacted with diazomethane to produce same (VIII);
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>CN(C=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(O)cc2o1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.5 %

Procedure:
To a solution of 6-hydroxybenzo[d]oxazol-2(3H)-one (3 g, 19.85 mmol) in dry DMF (30 mL), K2CO3 (5.54 g, 40.1 mmol) and SEM-Cl (4.79 mL, 27.0 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel using 10 to 50% ethyl acetate in hexane to give 6-hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as an white solid (1.2 g, 21%). 1HNMR 400 MHz, DMSO-d6: δ ppm −0.055 (s, 9H), 0.86 (t, J=8.00 Hz, 2H), 3.58 (t, J=8.00 Hz, 2H), 5.19 (s, 2H), 6.64 (dd, J=2.40, 8.40 Hz, 1H), 6.78 (d, J=2.00 Hz, 1H), 7.10 (d, J=8.40 Hz, 1H), 9.52 (s, 1H). LCMS: R.T. 1.845 min; 280.1 [M−H].
Reaction SMILES: CS[C:3]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH:7]=[N:6]1)=[NH:4].[Cl:12][C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(#N)C>[NH2:4][C:3]([N:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH:7]=[N:6]1)=[N:21][S:18]([C:16]1[S:17][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:20])=[O:19]
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Reactant: CSC(=N)N1CC(C)(C)C=N1
Solvent: CC#N
Product: CC1(C)C=NN(C(N)=NS(=O)(=O)c2ccc(Cl)s2)C1
Yield: 0.5 %

Procedure:
1.0 g (1 mol equiv.) 4,4-Dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 1.21 g (1.05 mol equiv.) 5-chloro-thiophene-2-sulfonic acid amide were added to 10 mL acetonitrile. The reaction mixture was refluxed overnight, and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=2:1) afforded 1.58 g (80%) 5-chloro-thiophene-2-sulfonic acid amino-(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 6H), 3.63 (s, 2H), 6.00-6.50 (br.s., 1H), 6.79 (s, 1H), 6.85 (d, J=4.0 Hz, 1H), 7.10-7.35 (br.s., 1H), 7.37 (d, J=4.0 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=5)[C:19]([CH3:30])=[C:18]([CH3:31])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)ccn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2cc[nH]c(=O)c2)c1C
Temperature: 55 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (96 mg, 0.23 mmol) in CH3CN (4.8 mL) was added TMSI (65.6 μL, 0.46 mmol) drop wise. The suspension became a clear solution on TMSI addition. The reaction was stirred at 55° C. for 5 hours. The reaction was allowed to cool down to room temperature. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (50 mg, 54%). ESI-MS m/z calc. 401.5. found 402.5 (M+1)+. Retention time 1.41 minutes.