Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([OH:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:27]([O-])([O-])=O.[K+].[K+]>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([O:23][CH3:27])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(/C=C/c2ccccc2)nc2n(c1=O)C1CC1(C(=O)O)C=C2
Agent: [K+]
Solvent: CI
Product: COC(=O)C12C=Cc3nc(/C=C/c4ccccc4)c(C)c(=O)n3C1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.8 g) was reacted with methyl iodide (0.55 g) and anhydrous K2CO3 (0.65 g) in dmethylformamide (7 ml) under stirring at room temperature for 4 hours. After dilution with ice water the precipitate was filtered off: crystallization from acetone gave 0.5 g of 2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 164°-165° C. By proceeding analogously the following compound were prepared:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([S:12][CH2:13][CH2:14]O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:5]1([S:12][CH2:13][CH2:14][Cl:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: OCCSC1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: ClCCSC1CCCCCC1
Reaction time: 0.25 h

Procedure:
5.11 cm3 of thionyl chloride were added dropwise, with stirring and under an inert atmosphere, at a temperature in the region of 20° C. to a solution of 1.74 g of 2-hydroxyethyl cycloheptyl sulfide in 30 cm3 of chloroform. After the addition, the reaction mixture was first stirred for 15 minutes at the same temperature and then for 1 hour at a temperature in the region of 600° C. The mixture was evaporated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C., then the residue obtained was taken up with 2 times 50 cm3 of water and then 1 times 50 cm3 of a saturated sodium hydrogencarbonate solution. The ethereal solution, separated by settling, was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 400° C. 1.89 g of 2-chloroethyl cycloheptyl sulfide were obtained in the form of an oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H+].[B-:24]([F:28])([F:27])([F:26])[F:25]>C(Cl)Cl.C(OCC)C>[F:25][B-:24]([F:28])([F:27])[F:26].[CH2:1]([S+:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CSc2ccccc2)cc1
Reactant: OCc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C[S+](Cc2ccccc2)c2ccccc2)cc1
Yield: 87 %

Procedure:
A solution of 75.0 g (0.374 mol) of benzylphenyl sulfide, 60.73 g (0.561 mol) of benzyl alcohol in 350 ml of methylene chloride is introduced into a reaction vessel provided with a stirrer and thermometer. 182.45 g (1.12 mol) of 54% by weight HBF4 in diethyl ether are added dropwise at an internal temperature of 20°-30° C. in the course of 35 min, while stirring. The reaction mixture is then stirred at RT for 2 h. The reaction mixture is diluted with 300-400 ml of methylene chloride and extracted 4 times with water (pH ~6). The organic phase is then dried over MgSO4 and the solvent is removed on a rotary evaporator. The yellow-brown oil which remains is stirred in 400 ml of toluene and the mixture is left to crystallize at 0°-5° C. for about 1 h. The suspension is filtered and the residue is washed with a little cooled toluene (0°-5° C.). The pure product is dried under a high vacuum at RT overnight. 123.8 g (87% of theory) of dibenzylphenylsulfonium tetrafluoroborate are obtained as white crystals of melting point 110°-115° C.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.ON1C2C=CC=CC=2N=N1.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:42][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 9.9 grams of Z-D-Glu-OBzl and 3.6 grams of 1-hydroxybenzotriazole in 50 ml of absolute tetrahydrofurane are added 1.96 grams of tert.-butylamine and at 0° C. 5.86 grams of DCC. The mixture is stirred for 2 hours at 0° C. and overnight at room temperature. The next day the precipitate is filtered off with suction and the filtrate is concentrated. The residue is dissolved in ethyl acetate and the solution is washed in succession with a saturated solution of sodium bicarbonate, 2n-HCl, a saturated solution of sodium bicarbonate and water, dried with sodium sulphate and concentrated. Yield: 4.6 gams of an oil.
Reaction SMILES: [C:1]([C:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:13]=3)[NH:8][C:7]=2[N:6]=[CH:5][CH:4]=1)#[CH:2].[N:29]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)=[N+:30]=[N-:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I>[CH3:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:29]2[CH:2]=[C:1]([C:3]3[C:15]4[C:14]5[C:9](=[CH:10][CH:11]=[C:12]([C:16]6[CH:17]=[CH:18][C:19]([N:22]7[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]7)=[CH:20][CH:21]=6)[CH:13]=5)[NH:8][C:7]=4[N:6]=[CH:5][CH:4]=3)[N:31]=[N:30]2)=[CH:38][CH:37]=1
Reactant: Cc1ccc(CN=[N+]=[N-])cc1
Reactant: C#Cc1ccnc2[nH]c3ccc(-c4ccc(N5CCN(C)CC5)cc4)cc3c12
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2cc(-c3ccnc4[nH]c5ccc(-c6ccc(N7CCN(C)CC7)cc6)cc5c34)nn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
To a solution of 4-ethynyl-6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole (example 44, 26.1 mg, 0.071 mmol) in 1.4 mL of anhydrous DMF (C=0.05M), was added CuI (2 mg, 0.15 eq) and 185 μL of a 0.5M solution of 1-(azidomethyl)-4-methylbenzene (1.3 eq). Then, diisopropylethylamine (82 μL, 7 eq) was introduced. The reaction mixture was stirred at room temperature for 15 h. The mixture was then hydrolysed with water (30 mL) The aqueous layer was extracted with AcOEt (4×15 mL). The combined organic layers were washed twice with brine, dried over MgSO4, filtered and concentrated under reduced pressure. A light brown solid was obtained in 66% yield (24.2 mg) after trituration of the crude product in MeOH and filtration. 1H NMR (500 MHz, DMSO) δ 11.99 (s, 1H), 9.01-8.92 (m, 2H), 8.47 (s, 1H), 7.70 (dd, J=8.4, 1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.41 (d, J=3.6 Hz, 1H), 7.34 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 5.73 (s, 2H), 3.19 (s, 4H), 2.29 (s, 3H), 2.25 (s, 3H); 13C NMR (126 MHz, DMSO) δ 153.1 (s), 149.5 (s), 145.5 (CH), 144.9 (s), 137.9 (s), 137.3 (s), 132.8 (s), 132.6 (s), 131.6 (s), 131.5 (s), 129.1 (CH), 127.7 (CH), 126.7 (CH), 125.0 (CH), 124.4 (CH), 121.5 (CH), 120.5 (s), 115.5 (CH), 110.9 (CH), 54.4 (2CH2), 52.8 (CH2), 47.9 (2CH2), 45.4 (NCH3), 20.4 (CH3); HRMS calcd for C32H32N7 [M+H]+ 514.2714 found 514.2699.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][CH2:10][CH3:11])[C:5]=1[CH2:12][OH:13].Cl[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.O>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:13][CH2:12][C:5]2[C:6]([CH2:9][CH2:10][CH3:11])=[N:7][O:8][C:4]=2[CH3:3])=[N:16][CH:17]=1
Reactant: CCCc1noc(C)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a stirred suspension of sodium hydride (2.78 g of a 60% dispersion in mineral oil, 64 mmol) in THF (40 mL) at 0° C. and under argon was added solution of (5-methyl-3-propyl-isoxazol-4-yl)-methanol (7.60 g, 49 mmol) in tetrahydrofuran (40 mL) dropwise. The mixture was warmed to ambient temperature, stirred for 30 min, then cooled to 0° C. and a solution of methyl 6-chloronicotinate (8.40 g, 49 mmol) in THF (40 mL) was added dropwise. The reaction mixture was warmed to room temperature. After 2 h, water was added then the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 20% ethyl acetate in heptane) gave the title compound (8.4 g, 50%) as a light yellow oil. MS: m/e=413.2 [M+H]+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[NH2:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])(C)C)=[O:39])[CH2:34]1>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([NH:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:44]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:39])[CH2:34]2)=[O:29])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 18.2 %

Procedure:
Following a procedure similar to that described in Preparation 19, but using 6.4 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 2.40 g of N,N'-carbonyldiimidazole and 2.7 g of (3R)-3-amino-1-t-butoxycarbonylpyrrolidine, 750 mg of the title compound were obtained as a powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: CON
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Product: CON=Cc1ccc(F)cc1F
Yield: 80 %

Procedure:
Reaction of 2,4-difluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (80% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.98 (3H, s, OCH3), 6.79–6.91 (2H, m, aromatics), 7.79–7.85 (1H, m, aromatic), 8.24 (1H, s, CH).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][OH:9])[N:3]=1.[H-].[Na+].[C:12]([C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[S:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][O:9][C:22](=[S:23])[NH:21][CH2:20][C:19]2[CH:24]=[CH:25][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:17][CH:18]=2)[N:3]=1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: Cc1cc(C)n(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)n(COC(=S)NCc2ccc(C(C)(C)C)cc2)n1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
3,5-dimethylpyrazol-1-methanol 33-3 (200 mg) and sodium hydride (42 mg) were dissolved in anhydrous tetrahydrofuran (20 ml) and the solution was stirred for 1 hour. To the solution was added 4-t-butylbenzylisothiocyanate (330 mg) and the mixture was stirred at room temperature for 12 hours. The resulting mixture was filtered under reduced pressure and the solvent was removed therefrom. The residue was purified by column-chromatography (ethyl acetate/hexane=1/2) to yield the compound 33-4 (253 mg, 48%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].Cl[C:21]1[N:26]=[C:25]2[CH2:27][N:28]([CH3:31])[C:29](=[O:30])[C:24]2=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)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]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:21]3[N:26]=[C:25]4[CH2:27][N:28]([CH3:31])[C:29](=[O:30])[C:24]4=[CH:23][CH:22]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Reactant: CN1Cc2nc(Cl)ccc2C1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CN1Cc2nc(Nc3sc(-c4ccc(C(C)(C)O)cc4)nc3C(N)=O)ccc2C1=O

Procedure:
The title compound was prepared as described in Example 8, Step 6 using 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (150 mg, 0.54 mmol), 2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (123 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.032 mmol), X-PHOS (77 mg, 0.16 mmol), potassium carbonate (82 mg, 0.60 mmol), and tert-amyl alcohol (1.2 ml) as starting materials. 1H NMR (600 MHz, d6-DMSO) δ 11.63 (s, 1H), 7.87 (m, 3H), 7.82 (s, 1H), 7.71 (s, 1H), 7.55 (d, 2H), 7.22 (d, 1H), 5.10 (s, 1H), 4.50 (s, 2H), 3.04 (s, 3H), 1.42 (s, 6H). LRMS (APCI) calc'd for C21H22N5O3S [M+H]+ 424.1, found 424.0.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:15]([CH3:25])[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
A solution of (S)-4-benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one (1.00 g, 3.07 mmol) in dry THF (10 ml) was added to lithium diisopropyl amide (400 mg, 3.69 mmol, 0.1 M) at −78° C. The reaction mixture was stirred for 2 h. Iodomethane (2.00 g, 14.1 mmol) was added to the reaction mixture and warmed to −20° C. and stirred for another 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (10%) in petroleum ether as eluent to afford 350 mg (33.8%) of (S)-3-((R)-2-(4-methoxyphenyl)propanoyl)-4-benzyloxazolidin-2-one as light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:19][CH:20]=[C:21]([NH2:23])[CH:22]=2)=[CH:13][C:12]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:32][C:33]1[CH:34]=[C:35]([C:39](O)=[O:40])[CH:36]=[N:37][CH:38]=1>>[CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:19][CH:20]=[C:21]([NH:23][C:39]([C:35]3[CH:36]=[N:37][CH:38]=[C:33]([I:32])[CH:34]=3)=[O:40])[CH:22]=2)=[CH:13][C:12]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)c1
Reactant: O=C(O)c1cncc(I)c1
Product: O=C(Nc1ccc(-c2cc(NC(=O)c3cncc(I)c3)cnc2OCC(F)(F)F)cc1Cl)OCc1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using {4-[5-amino-2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-chloro-phenyl}-carbamic acid benzyl ester (example 73 a) and 5-iodo-3-pyridinecarboxylic acid (CAN 15366-65-1) as starting materials; LC-MS (UV peak area/ESI) 68.6%, 683.4 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([O:27][CH:28]([CH3:30])[CH3:29])[CH:11]=2)[C:6](=[O:31])[CH2:5]1.O.[Cl-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:31][CH:6]1[CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:12]([O:27][CH:28]([CH3:29])[CH3:30])[CH:11]=2)[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]1
Reactant: CC(C)Oc1cc(C2CCN(C)CC2=O)ccc1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc(C2CCN(C)CC2O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 26 %

Procedure:
486 mg of NaBH4 are added, in portions, to a suspension of 700 mg of benzyl [4-(1-methyl-3-oxopiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate in 35 ml of ethanol brought to 5° C. The reaction medium is stirred at ambient temperature for 50 minutes. 4 ml of water, 15 ml of a saturated aqueous sodium chloride solution and 40 ml of ethyl acetate are added. The two phases are separated, and the aqueous phase is washed with twice 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and (MeOH+10% NH4OH) (99/1 to 90/10). 183 mg of benzyl [4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate (trans diastereoisomers) and 183 mg of benzyl [4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate (cis diastereoisomers) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrCc1ccc(Br)cc1
Product: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 1b using 3-oxopentanoic acid ethyl ester and 1-bromo-4-bromomethylbenzene.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]2)[O:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.CCOCC>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]3)[O:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1CCC2(C1)OCC(CO)O2
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)CC1CCC2(C1)OCC(COS(=O)(=O)c1ccc(C)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (00) stirred solution of the alcohol of Example K (2.44 g, 10 mmol) in pyridine (30 ml) is added p-toluenesulfonyl chloride (1.91 g, 10 mmol) in portions over 15 minutes. When addition is completed, the reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ether and washed successively with water, 0.5N aqueous sodium bisulfate solution, 5% aqueous sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated on the rotary evaporator to give the titled compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28]([C:30]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:17]=[CH:16][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[CH:8][CH:7]=4)[CH2:4]3)=[O:31])=[N:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Reactant: c1cc(OC2CNC2)ccc1CN1CCCC1
Product: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 120 °C
Yield: 24 %

Procedure:
A mixture of 1B (1.0 g, 4.3 mmol) and ethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate—see e.g. WO97/05131—(1.2 g, 4.7 mmol) was heated at 120° C. for 4 h. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 0.46 g (24%) of 1 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.69-1.88 (m, 4H), 2.38-2.69 (m, 4H), 3.57 (s, 2H), 4.26-4.38 (m, 1H), 4.61-4.68 (m, 1H), 4.72-4.79 (m, 1H), 5.05-5.20 (m, 2H), 6.74 (d, 2H), 7.29 (d, 2H), 7.52 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 439 [M+H]+, LC purity: 96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:16]([C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)=[O:17]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: O
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
Surprisingly, it has been found that when polyphosphoric acid is used as the catalyst, 1,2-dimethoxybenzene (veratrole) can be acylated directly using 3,4-dimethoxybenzoic acid (veratric acid). The advantages of this reaction are the ready availability of the starting materials coupled with a high yield and very simple product isolation. After water has been added, the 3,3',4,4'-tetramethoxybenzophenone can be isolated by simple filtration.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:42]1(=[O:52])[N:46]([CH2:14][CH2:15][O:16][C@H:17]2[CH2:34][CH2:33][C@@:32]3([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]4[C@@H:31]3[CH2:30][CH2:29][C@@:27]3([CH3:28])[C@:23]4([OH:41])[CH2:24][CH2:25][C@@H:26]3[C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)[CH2:18]2)[C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12
Reactant: C[C@]12CC[C@H](OCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](OCCN3C(=O)c4ccccc4C3=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 70.7 %

Procedure:
A solution of 0.29 ml of diethyl azodicarboxylate was added dropwise, under nitrogen, to a solution of 0.75 g of 3β-(2-hydroxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, 0.28 g of phthalimide and 0.50 g of triphenylphosphine in 7 ml of tetrahydrofuran at room temperature. After 2 hrs the solvent was removed in vacuo, the crude product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 to give 0.70 g of 3β-(2-phthalimidoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol.