Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].[NH3:16]>O1CCCC1>[NH2:16][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3]
Reactant: N
Reactant: CON=C(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CON=C(Cl)c1ccccc1S(N)(=O)=O
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the oil prepared in Example 3 in 100 ml of tetrahydrofuran, cooled at -30° C. with external cooling, was added dropwise 1.7 ml of ammonia. After stirring at -30° C. for about 15 minutes, the suspension was purged with N2 to remove excess ammonia, then evaporated at less than 30° C. under vacuum. After adding ice-water to the residue, the suspension was extracted with methylene chloride, dried (MgSO4) and evaporated under vacuum. The residue was triturated with hexane to yield 2.5 g of the subject compound as a crude solid, m.p. 155° to 158° C., NMR(CDCl3 +DMSO):
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 110 %

Procedure:
(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (13.6 g, 50 mmol) was dissolved in anhydrous THF (200 mL) and cooled to −10° C. (ice/MeOH bath). Phenylmagnesium bromide solution in THF (100 mL of 1.0 M, 100 mmol, 2 equiv) was added slowly. After 15 min, the reaction mixture was warmed up to rt slowly and stirred for 1 hour. LC-MS showed the reaction was complete. 5% Aq HCl (100 mL) was added slowly to quench the reaction and the mixture was stirred for 20 min. After separation, the aqueous layer was extracted with ether (2×200 mL). The combined organic layers were washed with satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded crude (R)-tert-butyl 3-benzoylpiperidine-1-carboxylate (16.45 g, 110%) as a clear oil which was used for the next step without further purification. LC-MS (3 min) tR=1.91 min, m/z 302 (M+Na). 1H NMR (CDCl3) □ 7.94 (d, 2H), 7.54 (t, 1H), 7.47 (t, 2H), 4.28 (br d, 1H), 4.09 (d, 1H), 3.38 (t, 1H), 2.92 (br t, 1H), 2.72 (t, 1H), 2.01 (d, 1H), 1.79-1.45 (m, 3H) 1.42 (s, 9H). Chiral HPLC indicated 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[CH:7]=1.C(O)(C(F)(F)F)=O.[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:17]([N:24]1[CH2:28][C@:3]2([O:2][CH3:1])[C:4](=[O:9])[NH:5][C:6](=[O:8])[C@@H:7]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC1=CC(=O)NC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@]12CN(Cc3ccccc3)C[C@H]1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a 0° C. solution of 3-methoxy-1H-pyrrole-2,5-dione ({see M. Couturier, J. L. Tucker, B. M. Andresen, P. Dube, J. T. Negri, Org. Lett., 2001, 3, 465-467}, 950 mg, 7.47 mmol) and TFA (0.070 mL, 0.897 mmol) in DCM (70 mL) was added slowly a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (3.06 mL, 12.0 mmol) in DCM (30 mL) at a rate such to maintain the internal reaction temperature <2° C. The resulting bright yellow solution was slowly warmed to ambient temperature and stirred for 18 hrs. The reaction mixture was then cooled to 0° C. and a solution of N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (0.956 mL, 3.74 mmol) in DCM (1 mL) was added dropwise and was warmed to rt and stirred for 3 hrs. The reaction mixture was diluted with saturated sodium bicarbonate (25 mL), the layers were separated and the organic solution was dried (magnesium sulfate), filtered and concentrated under reduced pressure, giving a thick, yellow oil. The crude residue was purified by column chromatography eluting with 5%-50% EtOAc/heptane and again with 0%-25% EtOAc/Heptane to afford the titled compound (1.19 g, 61% yield, 70% purity) as a clear oil that was carried forward to the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:25]([CH3:27])=[O:26])=[C:21]([CH2:23][NH2:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:21]2[CH:22]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[S:25]([CH3:27])=[O:26])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)c1ccc(Cl)cc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 23.4 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.04 g), 1-[5-chloro-2-(methylsulfinyl)phenyl]methanamine hydrochloride obtained in Step 3 (2.5 g) and potassium carbonate (3.59 g) were stirred in ethanol (40 ml) at 85° C. for 14 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (3 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[Cl:15][C:16]1[N:17]=[N:18][CH:19]=[C:20](Cl)[CH:21]=1>CN(C)C=O>[Cl:15][C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:12][C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH:21]=1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Reactant: Clc1cnnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Oc2cnnc(Cl)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-fluoro-5-(trifluoromethyl)phenol (1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, is added Sodium hydride (100 mg) and the reaction mixture is allowed to stirred at 0 degree for 20 minutes. 3,5-dichloropyridazine (1.6 mmol) is added and the reaction mixture is warmed to room temperature. The reaction mixture is stirred at room temperature until formation of the desired compound. The reaction mixture is quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers are dried over Sodium Sulfate and solvent is removed under reduced pressure. The residue can be purified by Prep-HPLC.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][C:10]=1[C:31]([F:34])([F:33])[F:32])C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[N:25]1([C:17]2[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([C:31]([F:33])([F:32])[F:34])[CH:11]=3)[CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(N3CCOCC3)n2)ccc1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Nc1ccc(-c2cc3ncccc3c(N3CCOCC3)n2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of dibenzyl-[4-(5-morpholin-4-yl-[1,6]naphthyridin-7-yl)-2-trifluoromethyl-phenyl]-amine, 4 (29.1 mg, 0.06 mmol, 1 eq) in dry EtOH (3 mL) was added Pd(OH)2 (15 mg, 50% w/w) and 1,4-cyclohexanediene (110 μL, 1.15 mmol, 20 eq) under Ar(g). The mixture was heated at 80° C. overnight. More Pd(OH)2 (15 mg, 50% w/w) and 1,4-cyclohexanediene (110 mL, 1.15 mmol, 20 eq) were added and the mixture was again heated at 80° C. overnight. Once cooled down, the reaction mixture was filtered through a short celite pad, and eluted with MeOH (10 mL). The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (0:1) to yield the product as a pale yellow solid (10.0 mg, 51%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8](=[O:18])[CH:9]([CH:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH:13]=[CH:14]2)[OH:10]>C(OCCO)C.C(O)(=O)C>[CH:12]12[CH2:17][CH:15]([CH:14]=[CH:13]1)[CH2:16][CH:11]2[C:9](=[O:10])[C:8]([CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)=[O:18]
Reactant: O=C(C(O)C1CC2C=CC1C2)C1CC2C=CC1C2
Solvent: CC(=O)O
Solvent: CCOCCO
Product: O=C(C(=O)C1CC2C=CC1C2)C1CC2C=CC1C2

Procedure:
49.9 g (204 millimoles) of VII in 130 ml of 2-ethoxyethanol and 40 ml of glacial acetic acid are heated to 105° C., while stirring. 25.0 g (53.6 millimoles) of Bi2O3 are then added all at once. After a reaction time of 2 hours, the elemental bismuth is filtered off and washed with 300 ml of chloroform. The organic phase is washed neutral with water. The solvent is stripped off and the residue subjected to fractional distillation. The product is then recrystallized from petroleum ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23](=O)[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].B.Cl>O1CCCC1>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)N(CC)CC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC

Procedure:
A solution of 0.82 g. of 5-chloro-2[(diethylcarbamoyl)methyl]-3-phenylisoindole-1-carboxylic acid ethyl ester in 5 ml. of tetrahydrofuran is added dropwise under argon at room temperature to 3 ml. of a 1-M solution of borane in tetrahydrofuran. Subsequently, the mixture is boiled at reflux for 4 hours and then treated at 15°-20° C. with 0.8 ml. of 6-N hydrochloric acid. Then, the tetrahydrofuran is removed by distillation at atmospheric pressure. The residue is partitioned between 3 ml. of water and 5 ml. of ether. After cooling in an ice-bath, the crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 1, and there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([N+:25]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.[Fe]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:15][CH:16]=2)=[C:6]([NH2:25])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A suspension of the product from Example 1B (22.8 g, 56 mmol), Fe powder (16.4 g, 282 mmol) and NH4Cl (15.1 g, 282 mmol) in aqueous EtOH [prepared from EtOH (228 mL) and H2O (228 mL)] was gradually heated to reflux and gently refluxed for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite pad. The filtrate was evaporated. The aqueous residue was portioned between Ethyl acetate and H2O, made basic to pH 9 with K2CO3, and then filtered through celite pad. The organic layer was separated, washed with H2O and brine, dried over MgSO4 and evaporated. The oily residue was crystallized in the treatment with i-Pr2O (200 mL) and stirred at room temperature for 30 minutes. The resulting crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. overnight under reduced pressure gave the title compound as colorless crystal (13.9 g, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25]>Cl.C(O)C>[ClH:1].[C:24]([NH:23][N:22]=[C:10]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[NH:25])[NH2:26]
Reactant: N=C(N)NN
Reactant: O=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(C=Cc1ccccc1Cl)C=Cc1ccccc1Cl
Yield: 124.6 %

Procedure:
Following the general procedure of Example 1, 9.1 grams of 1,5-bis(2-chlorophenyl)-1,4-pentadien-3-one, 4 grams of amino-guanidine hydrochloride, 10 drops of concentrated hydrochloric acid and 250 ml. of ethanol, and employing a 6.5 hour reflux period, 7.4 grams of the title compound is obtained, melting at 243°-244° C.
Reaction SMILES: [ClH:1].C([O:5][C:6]1[CH:15]=[C:14]([O:16]C(=O)C)[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[ClH:1].[OH:5][C:6]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1
Reactant: COc1cc(Cc2nccc3c(OC(C)=O)cc(OC(C)=O)cc23)cc(OC)c1OC
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1cc(CC2NCCc3c(O)cc(O)cc32)cc(OC)c1OC
Temperature: 50 °C
Yield: 93 %

Procedure:
0.78 g of 5,7-diacetoxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline hydrochloride is dissolved in 200 ml of ethanol, and 0.3 g of platinum dioxide is added thereto. The mixture is shaken at 25° C in a hydrogen atmosphere. After the hydrogen uptake is completed, the catalyst is removed by filtration. 50 ml of a hydrochloric acid-ethanol solution (the content of hydrochloric acid: 9%) are added to the filtrate, and this mixture is heated at 50° C for 5 minutes. Then, the mixture is evaporated to remove solvent, and the residue thus obtained is recrystallized from a mixture of ethanol and isopropyl ether. 0.6 g of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride is thereby obtained. Yield: 94.6% M.p. 240° - 243° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:12]2[CH:13]=[C:14]([P:18](=[O:25])([O:22]CC)[O:19]CC)[CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[N:3]=1.C[Si](Br)(C)C>ClCCl>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:12]2[CH:13]=[C:14]([P:18](=[O:19])([OH:22])[OH:25])[CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1cccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc(OC)cc2)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2cccc(P(=O)(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of diethyl 3-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphonate, 5-e, (0.99 g, 1.81 mmol) in dichloromethane (20 ml) was added TMSBr (5.6 g, 36.2 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 days. Then it was concentrated under vacuum and the residue was purified on prep-HPLC to provide the product, 5-1, (400 mg, 45%). 1H NMR (DMSO-d6, 300 MHz,): δ 8.80-8.82 (m, 1H), 8.37-8.40 (m, 1H,), 8.07-8.12 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 2H), 7.38-7.43 (m, 2H), 7.23-7.25 (m, 2H), 6.92-6.95 (m, 2H), 6.25-6.28 (m, 1H), 3.73 (s, 3H). (M−H)−=491.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][CH2:24][CH2:25]I)[CH:21]=2)[C:16]([C:29]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[CH:30]=2)=[CH:15]1.O>C(#N)C.C(OCC)(=O)C>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][CH2:24][CH2:25][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH:21]=2)[C:16]([C:29]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[CH:30]=2)=[CH:15]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCOCC1
Temperature: 60 °C

Procedure:
0.11 g of potassium carbonate and 0.14 ml of morpholine are added to a solution of 0.24 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 24 ml of acetonitrile, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is heated at 60° C. for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The oil obtained is taken up with 10 ml of water and 10 ml of ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (silica, 30/70 by volume ethyl acetate/cyclohexane as eluents). The fractions containing the product are concentrated under reduced pressure. 0.24 g of 2-[1-methyl-5-methoxy-6-(2-morpholin-4-ylethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=2[CH2:8]1.[OH-].[Na+].CO>O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]=2[CH2:8]1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1ncc[nH]1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCC(Cc1ncc[nH]1)C2
Yield: 54.8 %

Procedure:
A mixture of 2.31 g of ethyl 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate, 0.49 g of sodium hydroxide, 60 ml of methanol and 20 ml of water was heated under reflux for 4 hours. Methanol was distilled off in vacuo and 50 ml of water was added to the residue. Chloroform was added to the mixture and the aqueous layer was separated. The aqueous solution was adjusted to pH 6 with 2 normal hydrochloric acid. The precipitate formed was collected by filtration and washed with water to give 1.14 g of 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid as a colorless powder with m.p. 224°-226° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([F:23])([F:22])[CH2:5][N:6]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)(=O)C.[Fe]>[Cl:21][C:14]1[N:15]=[CH:16][C:17]2[NH:18][C:3](=[O:2])[C:4]([F:23])([F:22])[CH2:5][N:6]([CH:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[C:12]=2[N:13]=1
Reactant: COC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
To a solution of 6.16 g (0.016 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-difluoro-propanoic acid methyl ester (IV-100) in 120 mL of acetic acid was added 6.0 g (0.11 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the residue with ethyl acetate and hexane gave 2.94 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-100).
Reaction SMILES: C(Cl)CCl.ON1C2N=CC=CC=2N=N1.[CH:15]12[CH2:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]2[CH2:22][C:23]([OH:25])=O.[NH:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1.C(N(C(C)C)C(C)C)C>ClCCl.C(OCC)(=O)C>[CH:15]12[CH2:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]2[CH2:22][C:23]([N:31]1[CH2:32][CH2:33][C:34]2[NH:26][CH:27]=[N:28][C:29]=2[CH2:30]1)=[O:25]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: c1nc2c([nH]1)CCNC2
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CC1CC2CCC1C2)N1CCc2[nH]cnc2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
At 0° C., EDC (0.45 g, 2.4 mmol) was added to a solution of 1-hydroxy-7-azabenzotriazole (0.32 g, 2.4 mmol) and 2-norbornaneacetic acid (0.338 mL, 2.4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 20 min at 0° C. 4,5,6,7-Tetrahydroimidazo[4,5-c]pyridine dihycrochloride (0.50 g, 2.3 mmol) was added. Ethyldiisopropylamine (0.40 mL, 2.3 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. It was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous solution of sodium hydrogencarbonate (100 mL). The aqueous solution was extracted with ethyl acetate (2×60 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 120 mg of the title compound.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[CH2:16][CH:17]=[CH2:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CN=C1.[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([Si:29]([CH3:32])([CH3:31])[O:19][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)[CH2:16][CH:17]=[CH2:18])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CCC(O)c1ccc(CCCCCCCC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC(O[Si](C)(C)C(C)(C)C)c1ccc(CCCCCCCC)cc1
Reaction time: 72 h
Yield: 115.4 %

Procedure:
1-(4-octylphenyl)but-3-en-1-ol (11.5 g, 44.2 mmol) and imidazole (3.16 g, 46.4 mmol) were combined in DMF (221 ml). Tert-butyldimethylchlorosilane (6.66 g, 44.2 mmol) was added and the reaction stirred for about 72 h. The reaction was quenched by addition of water and ethyl acetate (500 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with 5% LiCl solution (3×). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to provide tert-butyldimethyl(1-(4-octylphenyl)but-3-enyloxy)silane (19.108 g, 51.0 mmol, 115% yield) as a colorless oil. LC/MS (method f) Rt=5.32, 3.89 min.; MS m/z: 243.21 (M-OTBDMS)+.