Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:13][CH2:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:13]=[CH:12][N:11]3[C:5]2=[C:6]([CH:25]=1)[C:7]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=13
Reactant: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Cl)cc2c43)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3-n3ccc4cc(Cl)cc2c43)CC1
Yield: 63.7 %

Procedure:
To a solution of 4-chloro-6-(4-methyl-1-piperazinyl)-1,2,dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (6 g, 17 mmoles), in chloroform (150 ml) was added manganese dioxide (10.5 g). The mixture was heated under reflux for 24 hours. The mixture was cooled, filtered and the solid was washed with dichloromethane (200 ml). The filtrate was then concentrated to dryness. The residue was purified by flash chromatography over a silica gel column (150 g), eluted with 2% methanol in dichloromethane (4 l) and 3% methanol in dichloromethane 2 l). Evaporation of the eluent gave 3.8 g (63%) of product. Recrystallization from toluene (40 ml) yielded the analytical sample, mp 170°-172° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.14 mmol), 4-chloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL), and acetic acid (0.070 mL) was added NaBH3CN (0.63 mmol) in methanol (1.3 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5/1 (6 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (44 mg, 53%): ESI/MS m/e 596.3 (M++H).
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:11][C:12]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:13]=1[O:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:17][CH:16]=1>CCOCC>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:23](=[O:24])[CH:22]=[CH:21][CH:20]([O:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:12]=2[Cl:11])=[CH:28][CH:27]=1)[CH3:26])[C:2]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C=CC(=O)Cl)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)C(C(=O)C=CC(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)OC
Reaction time: 2 h
Yield: 79.5 %

Procedure:
From 4.6 g of sodium, 26 g of dimethyl malonate and 60 ml of ether a dimethyl sodium malonate solution is prepared which is added dropwise under stirring to a mixture of 37 g of 4-[4'-(2",4"-dichloro-phenoxy)-phenoxy]-2-pentenoyl chloride and 50 ml of ether. The reaction mixture is heated to boiling for 2 hours and worked up as described in Example 1. Thus 37 g of the faint yellow crystalline desired compound are obtained, yield 79%, mp.: 60°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16]C)[C:5](N)=[N:6][CH:7]=1.N(OC(C)(C)C)=O>C(O)(=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=3[O:16][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)cnc1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2oc3ncc(Cl)cc3c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
Solution of 5-chloro-3-(5-chloro-2-methoxyphenyl)pyridin-2-amine (5.2 g, 19.3 mmol) in 50 mL of glacial acetic acid and 20 mL of THF was cooled down to -10° C. and tert-butyl nitrite (4.6 mL) was added dropwise. The reaction mixture was stirred overnight at 0° C., warmed to room temperature, diluted with 100 mL of water. Solid material was filtered and dried, providing 2.9 g of pure 3,6-dichlorobenzofuro[2,3-b]pyridine.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].O=[C:9]([CH2:15][CH3:16])[CH2:10][C:11](OC)=[O:12].C[O-].[Na+].O>CO.C(O)(=O)C>[CH2:15]([C:9]1[N:7]=[CH:5][N:6]=[C:11]([OH:12])[CH:10]=1)[CH3:16]
Reactant: N=CN
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
Formamidine acetate (2.64 g, 25.4 mmol) and methyl 3-oxopentanoate (3.0 g, 23.05 mmol) were added to a mixture of sodium methoxide (2.68 g, 49.6 mmol) in methanol (20 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. Water (6 mL) and acetic acid (3 mL) were added and the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting solid was triturated with ethyl acetate, filtered and washed with a small volume of ethyl acetate. The solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (932 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C#N)[CH:3]=1.[CH3:10][Mg]I.Cl.[C:14](=[O:17])(O)[O-].[Na+]>C1C=CC=CC=1.CCOCC>[C:14]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)(=[O:17])[CH3:10]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: C[Mg]I
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 4-chloro-2-pyridinecarbonitrile (5.35 g, 38.6 mmol) in benzene (50 ml) and ether (50 ml) cooled to 0° C. was added dropwise over 20 min a 2M solution of MeMgI in ether (23 ml, 46.3 mmol). After 0.5 h, the mixture was allowed to warm to ambient temperature, and stirring continued for 2 h. The mixture was cooled to 0° C. and 2M aqueous HCl (100 ml) added. The mixture was made basic with saturated aqueous sodium bicarbonate (˜80 ml) and the organic layer separated and dried (MgSO4). After removal of solvent, the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:5) to afford 3.60 g (60%) of 2-acetyl-4-chloropyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:6](=[O:18])[CH2:5]2.[H-].[Na+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[C:6](=[O:18])[CH:5]2[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CCOC(OCC)N1C(=O)Cc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2cc(Br)ccc21
Reaction time: 2 h
Yield: 73.2 %

Procedure:
5-Bromo-1-diethoxymethyloxindole (942 mg, 3 mmol) and sodium hydride (138 mg, 5.8 mmol, pre-washed with petroleum ether) were added successively to a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (269 mg, 1 mmol), (prepared as described for the starting material in Example 2), in THF (25 ml) at ambient temperature. After stirning for 2 hours at ambient temperature, the volatiles were removed by evaporation and the residue dissolved in methylene chloride. The solution was washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and the solvent evaporated. The residue was purified by column flash chromatography using an increasingly polar mixture of methylene chloride and ethyl acetate followed by a 7/3 mixture of methylene chloride/acetonitrile as eluent. The purified product was triturated with ether, collected by filtration, washed with a 1/1 mixture of ether/petroleum ether and dried under vacuum to give 4-(5-bromo-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (400 mg, 73%) as a yellow-orange solid.
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][NH2:7].[CH3:8][C:9]([CH3:23])([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[C:10](=O)[CH2:11][C:12]#[N:13].[OH-].[Na+]>O>[CH3:8][C:9]([C:10]1[CH:11]=[C:12]([NH2:13])[O:6][N:7]=1)([CH3:23])[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CC(C)(COC1CCCCO1)C(=O)CC#N
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(COC1CCCCO1)c1cc(N)on1
Temperature: 25 °C

Procedure:
Hydroxyamine sulfate (0.729 g, 4.439 mmol) is added to a stirred solution of 4,4-dimethyl-3-oxo-5-(tetrahydro-pyran-2-yloxy)-pentanenitrile (2 g, 8.878 mmol) and sodium hydroxide (0.764 g, 19.1 mmol) in water (20 mL). The reaction mixture is stirred at reflux for 18 hours. After this time, the reaction mixture is cooled to room temperature and extracted with ethyl acetate. The organic layers are combined and washed with brine, dried (Na2SO4), filtered and concentrated to yield the title compound, m/z 157 [M+H+−84]. 1H NMR (400 MHz, DMSO-d) δ ppm 1.17 (6H, d), 1.45 (4H, br), 1.58 (1H, br), 1.68 (1H, br), 3.26 (1H, d), 3.4 (1H, br), 3.59 (1H, d), 3.68 (1H, br), 4.5 (1H, br), 4.88 (1H, s), 6.43 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCBr)ccc21
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To 11.6 g (46.5 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 200 ml acetone 18.6 g (134.8 mmol) K2CO3 (powdered) and 13.7 g (115.7 mmol) 1,4-dibromobutane were added. The mixture was stirred at reflux for 4 h and at RT over night. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. EtOAc and water were added, the inorganic phase was extracted with EtOAc and the combined organic phases were washed with water and dried over Na2SO4. The crude product was purified by column chromatography on silica gel with hexane/EtOAc 9:1 to yield 11.1 g (63%) 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil, MS: 383 (M, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[O:10][N:9]=1.C([Li])CCC.[I:24]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.CCOCC.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[C:16]([I:24])[C:11]=2[O:10][N:9]=1
Reactant: II
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(-c3ccccc3F)noc2c1I
Reaction time: 1 h

Procedure:
10 g of 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole are dissolved in 400 ml of dry THF at -40° C. and treated with 21 ml of 2.2M n-butyllithium. After stirring for one hour, I2 (11.7 g) in 90 ml of ether is added. The reaction mixture is poured into Na2S2O3, then H2O. Drying and concentration gives 3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole, mp 135°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N+:32]([C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=4)(=[O:42])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc([N+](=O)[O-])c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-nitro-benzenesulfonyl chloride. Purity (ELSD, based on MW=606.6)=75%.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:12]([C:17]([NH2:24])([CH2:12][CH2:13][CH2:14][CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccccc1
Reactant: [Li]CCCC
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(N)(CCCC)c1ccccc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Cerium chloride heptahydrate (15.0 g 40.2 mmol) was dried with magnetic stirring at 140°-150° under 0.1 mm vacuum for two hours. Nitrogen was admitted and the flask containing the solid was cooled with an ice bath. Anhydrous tetrahydrofuran (80 mL) was added and the suspension was stirred at room temperature for 2 hours. n-Butyllithium (24 mL of a 1.6M solution in hexanes, 40 mmol) was added below -55° by syringe, and the mixture was stirred in a dry ice acetone bath for 30 minutes. Benzonitrile (1.34 g, 13 mmol) in 2 mL of anhydrous tetrahydrofuran was added, and the cooling bath was removed. Aqueous ammonium hydroxide (25 mL) was added after 2 hours, keeping the temperature below 0°, and the mixture was filtered with the aid of celite™. The solids were washed three times with methylene chloride, and the aqueous layer of the filtrate was extracted twice with methylene chloride. The combined organic phases were dried and concentrated and the residue was short-path distilled to give 2.53 g (90%) of the title compound distilling at a bath temperature of 80°-130° (0.003 mm). 1H-NMR (in CDCl3) ∂0.8 (t, J=6 Hz, 6H), 1.0 (m, 2H), 1.2 (m, 6H), 1.4 (br, 2H), 1.6 (m, 2H), 1.8 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.88 g (88%) of the product 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup.
Reaction SMILES: [I:1]I.[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:4].C(=O)(O)[O-].[Na+]>O.C(O)C>[I:1][C:19]1[N:18]=[CH:17][N:16]2[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: II
Reactant: O=C(O)CCCCCc1cccc2cncn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCc1cccc2c(I)ncn12
Reaction time: 0.75 h

Procedure:
Iodine crystals (1.9 g) are added to a well-stirred solution of 1.16 g of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine and 1.68 g of sodium bicarbonate in 10 ml of water and 1 ml of ethanol. Additional 4 ml of ethanol are added to dissolve the bulk of the iodine and stirring is continued for 45 minutes. The reaction mixture is diluted with 125 ml of water and extracted twice with methylene chloride at pH 8 (NaHCO3 added if necessary). The aqueous phase is concentrated in vacuo, charcoaled and adjusted to pH 4.5 with 2 N HCl. The precipitate is collected, dried and recrystallized from methanol/ether to give 1-iodo-5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 163°-165°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH2:23]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:27]3[CH2:26][CH2:25][N:24]([CH2:28][C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH2:23][CH:22]3[CH2:21][O:20][CH3:19])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: COCC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (0.36 g) in dichloromethane (6 ml) is added dropwise, at 0° C. while stirring, to a mixture of 3-methoxymethyl-1-(3,4,5trimethoxybenzyl)piperazine (0.4 g) obtained in Reference Example 14, triethylamine (0.3 g) and dichloromethane (6 ml). After stirring at room temperature for one hour, the reaction mixture is added to water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=2:2:1) to afford 1-(2,3-dimethoxy-6,7-dihydro-5H-benzo-cyclohepten-8-ylcarbonyl) -2-methoxymethyl-4-(3,4,5-tri-methoxybenzyl)piperazine (0.6 g) as a colorless oily product. This product is converted to the hydrochloride, and treated with ethyl ether to give pale yellow powder.
Reaction SMILES: [Al].[Cl:2][C:3]1[C:4]2[C:11](I)=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C1COCC1.[Cu]I.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.CN(C=O)C>[Cl:2][C:3]1[C:4]2[C:11]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 250 ml round-bottomed flask, protected from light with aluminum foil, are added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 4.6 mmol), copper(I) iodide (0.17 g, 0.93 mmol), trimethylsilylacetylene (0.96 ml, 6.97 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.23 mmol) dissolved in anhydrous THF (60 ml), anhydrous DMF (20 ml) and triethyl amine (0.64 ml, 4.65 mmol). The reaction mixture is stirred at room temperature under nitrogen for 16 hrs. The solvent is removed in vacuo, and the residue is dissolved in methylene chloride (250 ml). The reaction mixture is washed with water (3×50 ml), and the combined organic layer is dried over Na2SO4, and concentrated in vacuo. The crude residue is purified by flash-chromatography on silica gel and eluted with 70% EtOAc in cyclohexane. Fractions containing the desired product (TLC) are pooled and evaporated to afford 4-chloro-5-trimethylsilylethynyl-7H-pyrrolo[2,3-d]pyrimidine as a tan white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([N:25]1[CH2:29][CH2:28][C:27](=O)[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:28]3[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:29]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
N-(3,4-dichlorophenyl)piperazine-1-carboxamide (0.548 g, 2 mmols) and 1-N-BOC-3-pyrrolidinone (370 mg, 2 mmols) were stirred at room temperature in dichloromethane (20 ml) for approximately 15 minutes. Added to this mixture was sodium triacetoxyborohydride (1.06 g, 5 mmols) and the reaction stirred overnight at room temperature. Saturated sodium bicarbonate solution (5 ml) was added and the mixture stirred for 1 hour then poured onto a hydromatrix column and the product eluted with dichloromethane (100 ml). The crude product was subjected to chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 10% methanolic ammonia in dichloromethane to give the title compound as a white solid (780 mg).