Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48]O)[N:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:48][C:46]5[N:47]=[C:43]([CH3:42])[S:44][CH:45]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: Cc1nc(CO)cs1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OCc2csc(C)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.100 g, 0.315 mmol) and triphenylphosphine (0.123 g, 0.47 mmol) was maintained under vacuum for 10 minutes. The mixture was flushed with nitrogen and then charged with dry THF (8 mL) and (2-methylthiazol-4-yl)methanol (Example 1A, 0.049 g, 0.38 mmol). The mixture was warmed to 50° C. and sonicated for 5 minutes. The cooled mixture was treated with a solution of DIAD (0.096 g, 0.47 mmol) in dry THF (2 mL) added in three portions dropwise over 20 minutes. The mixture was homogeneous after 40 min. and was stirred at 22° C. for 6 h. The reaction mixture was diluted with dichloromethane (250 mL), washed with sat. sodium bicarbonate, brine and dried over anhydrous MgSO4. Evaporation gave a semi-solid residue which was purified by chromatography on silica gel (2.5×10 cm, dichloromethane/EtOAc 8:2) to provide the title material (0.103 g, 76%) as white cubes. LC (Method A): 2.224 min. HRMS (ESI) calcd for C19H17N4O4S2 [M+H]+ m/z 429.0686. found 429.0605. 1H NMR (CDCl3, 600 MHz) δ 7.82 (s, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.67 (m, 1H), 6.39 (d, J=1.89 Hz, 1H), 5.25 (d, J=0.9 Hz, 2H), 4.18 (s, 3H), 3.82 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[F:16][C:17]([F:29])([F:28])[C:18]1[N:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:24]([C:21]2[CH:22]=[N:23][C:18]([C:17]([F:29])([F:16])[F:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)c2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 12.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (100 mg, 0.47 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (138 mg, 0.56 mmol), pyridine (0.08 ml, 0.94 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (25 mg, 13%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)C.[C:49]12([CH2:59][C:60](Cl)=[O:61])[CH2:58][CH:53]3[CH2:54][CH:55]([CH2:57][CH:51]([CH2:52]3)[CH2:50]1)[CH2:56]2>>[C:49]12([CH2:59][C:60]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=3)=[O:61])[CH2:58][CH:53]3[CH2:54][CH:55]([CH2:57][CH:51]([CH2:52]3)[CH2:50]1)[CH2:56]2
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Product: CC(C)c1ccc(C(=O)CC23CC4CC(CC(C4)C2)C3)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with adamantaneacetyl chloride; 1H NMR(CDCl3): 1.21 (d, 12H), 1.6-2.0 (m, 15H), 2.15 (s, 2H), 3.4 (m, 2H), 7.15-7.25 (m, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (130 mg, 0.37 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (115 mg, 0.37 mmol) according to general procedure II. Obtained as a red solid (150 mg, 70%). MS (ISN) 586.0 [(M−H)−]; mp 178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[CH:23][N:24]([CH3:26])[CH3:25])[C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCCc2ccc(OCc3ccccc3)cc21
Product: CN(C)C=C1CCc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
7-Benzyloxy-3,4-dihydro-2-dimethylaminomethylene -1(2H)naphthalenone was prepared from 7-benzyloxy-3,4-dihydro-1(2H)naphthalenone (6.0 g, 23.8 mmol) and N,N-dimethylformamide diethylacetal (20 ml, 119.4 mmol) to give the desired compound as a pale yellow solid (4.56 g) m.p. 85-86°. MS(ES+) 308 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:21]Br>C(#N)C>[Br:21][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: COC(=O)c1ccc2c(cnn2-c2ccc(C)cc2)c1
Reactant: BrBr
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)c(Br)nn2-c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Methyl 1-(4-methylphenyl)-1H-indazole-5-carboxylate (327.1 mg, 1.228 mmol) was dissolved in acetonitrile (12.300 mL) at 25° C. Bromine (158 μL, 3.0575 mmol) was added dropwise and the reaction mixture was allowed to stir for 30 min. The reaction was stopped, quenched by addition of saturated aqueous sodium hydrogen carbonate (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 40 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-45%). The title compound (407.3 mg, 1.180 mmol, 96% yield) was recovered as a light yellow/white solid. LC-MS: [M+1]=346.1.
Reaction SMILES: [C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]([N:9]1[CH2:10][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=3)[O:13]2)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NO
Yield: 71.2 %

Procedure:
(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (110 mg, 0.23 mmol) in DCM (8 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (62 mg, hydrochloride salt) as as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].[NH2:20][C:21]1[CH:29]=[CH:28][C:24]2[NH:25][N:26]=[N:27][C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1>COCCO>[N:25]1[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]([O:18][CH3:19])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:22][C:23]=2[NH:27][N:26]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Agent: Cl
Solvent: COCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Yield: 81.7 %

Procedure:
The title compound was prepared by the procedure of Example 166 using 0.442 g of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.22 g 5-amino benzotriazole, 0.190 g of pyridine hydrochloride and 15 ml of 2-methoxyethanol to give 0.48 g (82%) of the desired product :mass spectrum (electrospray m/e): M+H=394.8.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:7]12)C.[NH3:19].C(OCC)C>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:19])=[O:3])[C@H:7]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Solvent: CCOCC
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Reaction time: 18 h

Procedure:
A solution of cis-decahydro-2-oxo-1H-cycloocta[b]pyrrole-1-acetic acid ethyl ester (4.0 g, 0.0157 mole) in methanol (30 ml) is saturated with anhydrous ammonia. The solution is stirred 18 hours. The solution is concentrated at reduced pressure to yield a solid. Trituration with anhydrous diethyl ether yields pure cis-decahydro-2-oxo-1H-cycloocta[b]pyrrole-1-acetamide with mp 110°-112° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Product: O=C(Cl)c1ccc(-c2ccccn2)cc1

Procedure:
Thionyl chloride (10 mL) was added to 4-(pyridin-2-yl)benzoic acid (1.8 g, 9 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give crude 4-(pyridin-2-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (1 g, 6 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) were added the crude 4-(pyridin-2-yl)benzoyl chloride (1.3 g, 6 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(4-(pyridin-2-yl)benzamido)benzoate (1.6 g, yield 76%). LC-MS (ESI) m/z: 349 (M+1)+. (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11]Br.[Li]CCCC>C1COCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[CH2:11][CH2:10][O:9][C:3]=2[CH:4]=1
Reactant: BrCCOc1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
1,4-dibromo-2-(2-bromoethoxy)benzene (136) (922 mg, 2.57 mmol) was dissolved in 25 ml dry THF. After cooled down to −78° C., a solution of 2.5M n-BuLi (1.23 ml, 1.2 q) in hexane was added dropwise. The reaction mixture was stirred at −78° C. for 4 h before poured into ice-water. After extracted twice with ethyl acetate, the org. phase was washed with brine, dried over sodium sulfate and then concentrated to give 504 mg (purity ca 80%) 6-bromo-2,3-dihydrobenzo[b]furan (137) as dark brow oil which was used directly for further reaction.
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])C=1.[CH:13]([OH:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH:13]([O:16][C:6]([N:8]1[CH:9]=[CH:10][N:11]=[CH:12]1)=[O:7])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)OC(=O)n1ccnc1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
To a solution of CDI (2 g, 12.33 mmol), in DCM (25 mL) was added isopropyl alcohol (0.95 mL, 12.33 mmol) at 0° C. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (100 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:10 ethyl acetate:Pet. ether) to provide title compound (330 mg, 77%) as colourless viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:5])[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]([CH2:16][N+:13]([O-:15])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C/C=C/CC(C)C
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(CC(C)C)C[N+](=O)[O-]

Procedure:
0.485 mol (75.8 g) of the (2E)-5-methyl-hex-2-ene carboxylic acid ethyl ester produced according to 2.1. were dissolved under a nitrogen atmosphere in THF (abs.). 0.73 mol (39.1 ml) of nitromethane and 0.49 mol (485 ml) of a 1 molar tetrabutylammonium fluoride solution in THF were added, wherein an orange solution arose. The mixture was refluxed for 20 hours. After cooling, the mixture was combined with 280 ml of water and extracted four times with diethyl ether. The organic phase was extracted three times with 10% aqueous potassium hydrogensulfate solution and washed to neutrality with water. The organic phase was dried with magnesium sulfate and evaporated in a rotary evaporator. An orange liquid was obtained. The crude yield amounted to 95.2 g (90% of theoretical).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18](N=[N+]=[N-])=[O:19])=[CH:12][C:11]([Br:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2].S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:19])=[CH:12][C:11]([Br:23])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)N=[N+]=[N-]
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)OCc1ccccc1
Yield: 86.1 %

Procedure:
3-(3-Azidocarbonyl-propyl)-5-bromo-1H-indole-2-carboxylic acid ethyl ester (1.28 g, 3.4 mmol, 1.0 equiv), TsOH hydrate (65 mg, 0.34 mmol, 0.1 equiv), and benzyl alcohol (0.74 mL, 6.8 mmol, 2.0 equiv) were refluxed in 30 mL of benzene for 16 h. The solution was then poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with 2×50 mL of diethyl ether. The pooled organic fractions were dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography on silica gel using 0% EtOAc in hexanes graded to 20% EtOAc in hexanes to provide 5-bromo-3-[3-benzyloxycarbonyl-propyl]-1H-indole-2-carboxylic acid ethyl ester (1.3 g, 75%). This material was used without further manipulation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:7](=[O:18])[N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:5]2=[O:30].CCOC(C)=O.[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:6]1[C:5](=[O:30])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:37]#[N:38])[CH:3]=2)[N:8]([CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:7]1=[O:18]
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2c(=O)c3cc(Br)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)c3cc(C#N)ccc3n(C3CCOCC3)c2=O)cc1OC

Procedure:
A mixture of 1.22 g of 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 0.3 g of zinc cyanide and 0.089 g of tetrakis(triphenylphosphine)palladium(0) in 10 ml of DMF is irradiated in a microwave field for 3 minutes at 170° C. EtOAc is added and the mixture is washed six times with water. The resulting solution is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 0.804 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:20])[C:15](=[NH:19])OCC)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[C:21]1(N)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:15]2[NH:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:27]=2)[OH:20])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCOC(=N)C(O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Solvent: CCO
Product: COc1cc(C(O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.7 g of ethyl (3,4-dimethoxy-5-nitro-phenyl)hydroxyacetimidate are dissolved in 500 ml of ethanol, 6.73 g of o-phenylenediamine are added, the mixture is stirred at room temperature for 2 hours and subsequently held at the reflux temperature overnight. After distillation of the solvent, the residue is treated with 50 ml of water, made alkaline with sodium carbonate solution and extracted twice with 250 ml of methylene chloride each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The orange residue obtained is chromatographed on 400 g of silica gel with methylene chloride/ethyl acetate (1:1). From ether/hexane there is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol in the form of yellowish crystals of m.p. 50° (dec.).
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[C:6](=O)[CH:5]=1)C.[Mg].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:28]([CH3:36])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:29])[CH:24]=[CH:25][C:26]=1Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:28]([CH3:36])([CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=[CH:25][C:26]=1[C:6]1[CH:7]([CH3:10])[CH2:8][CH2:9][C:4](=[O:3])[CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC1=CC(=O)C(C)CC1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: [Mg]
Product: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2C)c(OCc2ccccc2)c1

Procedure:
Similarly, 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-methylcyclohex-2-enone was prepared as an oil (4.12 g., 77%) using 3-ethoxy-6-methyl-2-cyclohexen-1-one (1.98 g., 12.9 mmoles), magnesium (0.61 g., 25.7 mmoles) and 12.9 mmoles (5.0 g.) of 2-(3-benzyloxy-4-bromophenyl)-2-methyloctane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=[O:20])[N:17]([CH3:19])[NH:18][C:11]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][CH2:41][CH2:42][CH:43](O)[CH2:44][CH2:45][CH3:46].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([O:20][CH:43]([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Reactant: CCCC(O)CCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
A mixture of 200 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one (Example 1, step 5) and 337 mg of triphenylphosphine in 15 mL of dry tetrahydrofuran was treated with 124 mg of 4-heptanol and 224 mg of diethylazodicarboxylate. The mixture was placed under an atmosphere of nitrogen and stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using 15% ethyl acetate/hexane as solvent giving 84 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine as a colorless oil, ms m/z 390 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]1[O:12][CH2:11]1.[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][NH:31]1)=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1>CO>[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][N:31]1[CH2:10][CH2:11][OH:12])=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: C1CO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCO)C1
Temperature: -4 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
DIEA (0.1 mL, 0.57 mmol) and liquid ethylene oxide (3 mL) were added to a stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, prepared as in Example 10 (237.4 mg), in anhydrous methanol (10 mL), at 0° C. and under nitrogen. The resulting solution was stirred at −4° C. for 18 h and evaporated to dryness. The residue obtained was purified by chromatography over silica gel with an eluent of 5% methanolic ammonia in dichloromethane. The desired fractions were evaporated and the residue lyophilized (deuterium oxide/anhydrous acetonitrile, 1:1, v/v, 10 mL) to furnish the title compound as a fluffy white powder (50.1 mg, 30.2%); TLC, Rf=0.68 (14% methanolic ammonia in dichloromethane); 1H NMR (300 MHz) δ 5.40 (d, J=5.8, 1), 4.55 (m, 1), 4.24 (s, 1), 4.17–4.11 (m, 1), 3.99–3.89 (m, 4), 3.69–3.65 (m, 1), 3.47 (d, J=4.4, 2), 3.01 (m, 1), 2.33 (br s, 4), 2.18 (s, 4), 1.57–1.32 (m, 9), 0.94–0.87 (m, 9).