Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 4′-hydroxyacetophenone (25.0 g; 183.6 mmol) in DMSO (300. mL) was added KOH (11.3 g; 201.9 mmol.) and the reaction mixture was stirred for 1 hour at RT. After 1 hour the reaction mixture was cooled (0° C.) and 1-bromooctane (34.9 mL; 201.9 mmol) was added. The ice bath was removed and the reaction mixture was stirred overnight at RT. The reaction mixture was extracted with EtOAc/5% aqueous NaHCO3 solution. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3) to afford 1-(4-octyloxy-phenyl)-ethanone (43.08 g)
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[S:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[N+:23]([O-])=O.CCOC(C)=O.O>CCO.Cl>[NH2:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[S:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[CH3:6])[C:19]#[N:20]
Reactant: Cc1ccc(C)c(Sc2ccc(C#N)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)c(Sc2ccc(C#N)cc2N)c1
Temperature: 70 °C
Yield: 74 %

Procedure:
A mixture of Tin (II) chloride dihydrate (25.218 g, 112.0 mmol) in EtOH (85.0 mL) and conc. HCl (12 M, 15.0 mL) was stirred at 70° C. until a clear solution was formed. Compound 24 (8.0 g, 28.14 mmol) was then added over 10 min. The solution was kept slightly refluxing during addition. The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.65). The reaction was complete after refluxing for 1.5 hrs as indicated by the absence of the starting material (TLC). Water (35 mL) was added and the resulting solution was allowed to cool to room temperature. Precipitation occurred during cooling. The mixture was further cooled and stirred for 30 min at 15° C. The precipitate was filtered, washed with water, and dried under vacuum to yield compound 25 as a white solid (5.30 g, 95% HPLC purity, 65% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.20 (d, J=8 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 6.90 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.85 (s, 1H), 5.72 (s, 2H), 2.26 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[C:15]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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>[CH3:15][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: N#Cc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1OC(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-3-trifluoromethoxybenzonitrile (10.0 g, 37.6 mmol), K2CO3 (15.6 g, 113 mmol), trimethylboroxine (5.5 mL, 39.5 mmol) and DMF (150 mL) is degassed for 10 min with nitrogen before Pd(PPh3)4 (4.34 g, 3.76 mmol) is added. The mixture is then sealed and heated to 120° C. for 14 h. The mixture is then concentrated and then partitioned between Et2O and 50% brine solution. The aqueous phase is further extracted with Et2O and the combined organic layers are dried (Na2SO4) and concentrated. The residue is purified via flash chromatography (10% EtOAc/hexanes) to give 4-methyl-3-trifluoromethoxybenzonitrile. H NMR (400 MHz, CDCl3) δ (ppm) 2.40 (s, 3H), 7.40 (d, J=7.7 Hz, 1H), 7.50 (s, 1H), 7.51 (dd, J=7.7, 1.5 Hz, 1H). MS (ESI) m/z 202.1.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[N+:9]([O-])[CH:10]=1)[CH3:3].CO.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:12][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][N:9]=1)(=[O:17])[CH3:16]
Reactant: Cc1ccc(OC(C)C)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OCc1ccc(OC(C)C)cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
5-(1-methylethoxy)-2-methylpyridine 1-oxide (234 mg, 1.40 mmol) was dissolved in acetic anhydride (3.0 mL), and the mixture was stirred at 140° C. for 1 hour. At room temperature, the reaction solution was added methanol, stirred, concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and [5-(1-methylethoxy)pyridin-2-yl]methyl acetate (209 mg (yield 71%)) was obtained as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13]([CH3:16])[C:14]=1[NH2:15])=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:15][C:14]1[C:13]([CH3:16])=[CH:12][C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(N)c(C)cc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2ncccc2c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of 550 mg (2.54 mmol) of 6-amino-7-methyl-quinoline-5-carboxylic acid methyl ester in 11 mL of dioxane and 0.5 mL of methanol, is added 6.4 mL (6.4 mmol) of an aqueous solution of NaOH 1N. The mixture is stirred at ambient temperature for 16 hours. The solvents are evaporated and water is added to the residue. The product is precipitated at pH 6 by addition of concentrated HCl, filtrated, washed with a minimum of water and dried on high vacuum pump. The yellow crude solid (282 mg) obtained is used directly in the next step; LC/MS: 203/204 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][N:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[NH:13]1.ClC1N=NN=C(Cl)C=1Cl.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[Cl:11][N:12]1[N:13]=[C:14]([Cl:19])[CH:15]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:17]1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClC1=CC(Cl)=NN(Cl)N1
Agent: Clc1nnnc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Para-nitroaniline (13.8 g) was dissolved into acetone (150 ml) at room temperature. 2,4,6-Trichlorotriazine (18.4 g) was dissolved into acetone (100 ml). Then the trichlorotriazine solution was dropwisely added to the p-nitroaniline solution as the p-nitroaniline solution was cooled with iced water. After the reaction was carried out for 2 hours at 0° C., an aqueous sodium bicarbonate solution (8.4 g of sodium bicarbonate being dissolved in 100 ml of water) was dropwisely added to the solution over 30 minutes. Then, the cooling was stopped by removing the ice bath and the solution was stirred until the temperature of the solution became room temperature. The reaction product was filtered off, washed with water and vacuum dried to obtain 23 g of 2,4-dichloro-6-p-nitroanilinotriazine. The chemical structure of the reaction product was confirmed by NMR and the melting point.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:30]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: O=S(=O)(Cl)N1CCCCC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)N4CCCCC4)cc3CO1)CC2
Yield: 74.6 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and piperidine-1-sulfonyl chloride (65 mg, 0.353 mmol) according to the procedure described for Example 27. Obtained the title compound as a light yellow foam (110 mg, 75%), MS (ISP) m/e=457.4 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I.O>CN(C)C=O>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: ClCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCn1c(-c2ccccc2)nc2ccccc21
Yield: 95.4 %

Procedure:
2.5 g (12.88 mmol) of 2-phenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) of K2CO3 and 2.0 ml (16.7 mmol) of 1-chloro-4-iodobutane were added to the resulting solution, followed by mixing the mixture at a room temperature for 10 hours. The reactant was combined with 100 ml of water and extracted with ethylacetate (70 ml×5) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=2/1) to obtain 3.5 g (yield 96%) of the title compound.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH2:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[C:14](Cl)(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][NH:6][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCN
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added 2-azidoethanamine (0.102 g, 1.18 mmol), DCM (5 mL) and then triethylamine (0.239 g, 2.37 mmol). To this reaction mixture, tetradecanoyl chloride (0.292 g, 1.18 mmol) was added dropwise and allowed to stir at room temperature for 24 hr. Then, the reaction mixture was concentrated de vacuo and then purified via silica gel column chromatography (100% dichloromethane to 1:40 methanol: dichloromethane) to give N-(2-azidoethyl)tetradecanamide (0.245 g, 79% yield). 1H NMR (300 MHz, CDCl3) δ 5.86 (s, 1H), δ 3.42 (s, 4H), δ 2.18 (t, 2H), δ 1.62 (m, 2H), δ 1.24 (m, 20H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.7, 51.2, 39.1, 36.9, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.4 ppm; HRMS (ESI) calcd for C16H32N4O (M+) 296.2576. found 296.2566.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([N:20]=[C:21]([N:24]([CH3:33])[N:25]=CC1C=CC=CC=1)SC)#[N:19].[OH-].[Na+]>Cl>[CH3:33][N:24]1[C:21]([NH:17][CH2:16][CH2:15][CH2:14][O:13][N:11]2[CH:12]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=[N:10]2)=[N:20][C:18]([NH2:19])=[N:25]1
Reactant: NCCCOn1cc(CN2CCCCC2)cn1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(N)nc1NCCCOn1cc(CN2CCCCC2)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
5 g of 3-(4-piperidinomethylpyrazol-1-yloxy)-propylamine and 4.9 g of methyl N-cyano-1-methyl-2-(phenylmethylene)-hydrazinecarboximidothioate are combined, and heated at 70° C. for 1 hour. Thereafter, the reaction mixture is taken up with 40 ml of 1N hydrochloric acid, stirred for 1 hour at room temperature, rendered alkaline with sodium hydroxide solution and extracted with methylene chloride. The residue which remains after the solvent has been expelled is chromatographed over neutral Al2O3 (activity level III), using methylene chloride/3% strength methanol as the mobile phase. The oily title compound is reacted with tartaric acid in isopropanol to give an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1.[H-].[Na+].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl.[OH-].[Na+]>CN(C)C=O>[ClH:16].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1
Reactant: CN(C)CCCCl
Reactant: Oc1ccccc1CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccccc1CCc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 142.9 %

Procedure:
To a solution of 2.5 g of 2-hydroxy-3',4'-dichlorobibenzyl in 10 ml of dimethylformamide was added 0.23 g of sodium hydride under cooling. The mixture was stirred for 30 minutes and to this was added dropwise 2.2 g of 3-dimethylaminopropyl chloride. The reaction mixture was warmed to about 60° C. and then stirred for 5 hours. Upon completion of the reaction, 2 N-NaOH aqueous solution was added, and the product was extracted with ether. The ether extract was washed well with saturated sodium chloride solution, dried over anhydrous sodium sulfate and then distilled in vacuo to sufficiently remove ether and a small amount of the remaining 3-dimethylaminopropyl chloride. The resultant residue was dissolved in ether and then 20% ethanolic hydrogen chloride was added to yield a precipitate. Recrystallization from ethanol-ether gave 2.6 g (71% yield) of 2-(3-dimethylaminopropoxy)-3',4'-dichlorobibenzyl hydrochloride, m.p. 136°-137° C.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][NH:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[C:28]([O:33][CH3:34])[C:27]([O:35][CH3:36])=[C:26]([O:37][CH3:38])[CH:25]=2.CCN(CC)CC.O>CS(C)=O>[C:1]([Si:5]([CH3:19])([CH3:20])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][N:14]([CH3:15])[C:22]1[NH:23][C:24]2[C:29]([C:30](=[O:32])[N:31]=1)=[C:28]([O:33][CH3:34])[C:27]([O:35][CH3:36])=[C:26]([O:37][CH3:38])[CH:25]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(OC)c1OC
Reactant: CNCc1cccc(OCCO[Si](C)(C)C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2[nH]c(N(C)Cc3cccc(OCCO[Si](C)(C)C(C)(C)C)c3)nc(=O)c2c(OC)c1OC
Temperature: 120 °C
Yield: 82.12 %

Procedure:
{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzyl}-methyl-amine from Step 3 (294 mg, 1.00 mmol) and 2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (prepared as described previously) (270 mg, 1.00 mmol) were dissolved in dry DMSO. Et3N (0.14 mL, 1.00 mmol) was added and the mixture was heated to 120° C. overnight. Upon cooling, the mixture was poured into water and extracted with diethyl ether. The ethereal extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by SiO2 eluted with 99:1 CH2Cl2/MeOH to give 435 mg (82.12%) of a white crystalline solid.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][C:9]([F:19])([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC>>[CH2:1]([O:4][CH:5]=[C:11]([C:10]([C:9]([F:18])([F:19])[F:8])=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
The acetic anhydride (367.6 g, 3.6 moles) is heated to 100-105° C., to which a mixture of crude ethyl trifluoroacetoacetate (˜0.96 mole) and triethyl orthoformate (266.8 g, 1.8 moles) is added drop-wise. The reaction mixture is kept at 100-105° C. for 6 hours. The reaction mixture is cooled to 60-70° C. and then concentrated under vacuum to remove excess acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid (194.6 g) is obtained. The yield of two steps is 81%.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=3)=[CH:14][C:13]=2[CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3cc(OC)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc(-c2cc3cc(O)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of 4-(5-Methoxy-benzofuran-2-yl)-benzoic acid methyl ester (0.5 g, 1.8 mmol) and Pyridine HCl (5 g) was heated to 200° C. After 2 hr, the reaction was cooled and poured into water and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chromatography on silica gel (75% EtOAc/hex) to give a solid (0.21 g, 47%): 1H NMR (DMSO-d6) δ 13.07 (br s, 1 H), 9.29 (br s, 1 H), 8.02 (d, 2 H, J=8.1 Hz), 7.97 (d, 2 H, J=8.7 Hz), 7.46 (m, 2 H), 6.97 (d, 1 H, J=2.9 Hz), 6.79 (dd, 1 H, J=9.3 Hz, 2.9 Hz); MS 253 (M−H)−
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][N:11]=1.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].CCN(CC)CC>CO.C(Cl)Cl>[C:12]([C:9]1[S:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:11][CH:10]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCC(=O)Cl
Reactant: NCCCNc1ncc(C(=O)c2ccccc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCCCC(=O)NCCCNc1ncc(C(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
A mixture of 11.9 mg (0.04 mmol) [2-(3-Amino-propylamino)-thiazol-5-yl]-phenyl-methanone hydrochloride, 5.8 mg (0.048 mmol) pentanoyl chloride and 39 ul (0.28 mmol) NEt3 in 1 ml methanol and 0.5 ml DCM was stirred at room temperature for 16 h. After evaporation to dryness the residue was taken up in 1.5 ml MeOH/formic acid 1/1 and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of product fractions yielded 6 mg (43%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].CN(C)C=O>CC1CCCO1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: COC(=O)c1ccc(F)cc1Oc1cncc(Br)c1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromopyridin-3-ol (1.060 g) in 2-methyltetrahydrofuran (15 mL) was added potassium tert-butoxide (6.09 mL, 1.0M in tetrahydrofuran) dropwise. After stirring for 5 minutes, methyl 2,4-difluorobenzoate (1.049 g) was added as a solution in 2-methyltetrahydrofuran (2 mL) and the reaction was heated to 75° C. N,N-Dimethylformamide (2 mL) was added to the reaction and the reaction was stirred overnight. The reaction was cooled, diluted with ethyl acetate (100 mL) and washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (SF40-80) eluting with a gradient of 5% to 35% ethyl acetate/hexanes gave the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][N:16]2[CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(CCN3CCOCC3)c3cc(Cl)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(C3CCNCC3)cn(CCN3CCOCC3)c2c1
Yield: 123.7 %

Procedure:
4-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (2.6 g, 5.81 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 2.5 g (95%) of a white solid. MS (electrospray): exact mass calculated for C19H26ClN3O, 347.18; m/z found, 348.2 [M++H].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[Cl:28][C:29]1C=[CH:35][CH:34]=[CH:33][C:30]=1CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:35]=[CH:34][CH:33]=[CH:30][C:29]=3[Cl:28])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1Cl
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1Cl)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 90 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 14.20 g (100 mmol) of 2-chlorobenzyl alcohol is stirred at 130° for 90 hours, the mixture is diluted with about 30 ml of methylene chloride and chromatographed on about 300 g of silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained o-chlorobenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 192°-193°.