Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].[H-].[Na+].[F:31][CH2:32]Br>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH2:32][F:31])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: FCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CF)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 26.5 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (975 mg), sodium hydride (61 mg) and fluoromethyl bromide (121 mg) in DMF (10 ml) was stirred at 10° C. for 1 hour. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate =1:2) and recrystallized from ethyl acetate to provide the title compound as colorless solid (121 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:11]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([C:11]2[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CCCCC2)s1
Product: O=C=Nc1nnc(C2CCCCC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetae (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-Cyclohexyl-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel, and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized from a dimethyl formamide-water mixture to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer having a melting point of 237° to 239° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:18]([CH:15]2[CH2:17][CH2:16]2)=[O:19])[CH:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: Nc1cnc(-c2ccncc2)c(Cl)n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2ccncc2)c(Cl)n1)C1CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a stirred solution of 6-chloro-5-pyridin-4-ylpyrazin-2-amine (Preparation 7, 0.73 g, 3.56 mmol) in pyridine (15 mL) was added cyclopropanecarbonyl chloride (648 μL, 7.1 mmol). The solution was stirred at 70° C. for 1 h 30 min, evaporated, partitioned between dichloromethane and a 4% sodium bicarbonate aqueous solution, the aqueous phase extracted twice with dichloromethane, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and methanol and the precipitate was collected by filtration and dried to furnish the title compound as a light brown solid (0.69 g, 70%).
Reaction SMILES: [C:1]([C@@H:3]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19]([C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:11])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:1]([C@@H:3]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19]([C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:11])[CH2:4][CH2:5][C:6]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:8])#[N:2]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)O)cc2ccccc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)N2CCOCC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
The (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid (140 mg, 0.341 mmol), morpholine (50 μL, 0.57 mmol), EDCI hydrochloride (102 mg, 0.532 mmol), HOBT (50 mg, 0.37 mmol) and N-methyl morpholine (0.10 mL, 0.91 mmol) were dissolved in 5.0 mL of DMF and stirred at room temp for 4 hours. The reaction mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate. The organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered and concentrated to give 98 mg (60%) of 1-Methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-4-morpholin-4-yl-4-oxo-butylcarbamoyl)-cyclohexyl]-amide as a white amorphous solid. MS: 480 (M+H+).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:11]1([CH2:10][C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)c1nsc(CC2CCCCC2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(CC2CCCCC2)n1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
300 mg of 3-methylsulfonyl-5-(cyclohexyl)methyl-1,2,4-thiadiazole and 89 mg of 2-butyn-1-ol were dissolved in 2.5 g of N,N-dimethylformamide, 55 mg of sodium hydride (60% in oil) was added thereto, and the reaction mixture was stirred for 30 minutes under ice-cooling. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 222 mg of 5-(cyclohexyl)methyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (5)).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: Cc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1CSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, and thereto were added 1.2 g of anhydrous potassium carbonate and 1.0 g of α-chloro-o-xylene. The resulting mixture was heated to 80° to 110° C. under stirring for 2 hours. After allowed to cool to room temperature, the mixture was incorporated with 100 ml of water and then stirred. The precipitated solid was filtered off, washed with water, dried and recrystallized from ethanol to give white needle-like crystals having the following physical properties (yield: 72.7%):
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1>CO>[Br:1][C:2]1[C:10]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(Br)c23)c1
Temperature: 125 °C
Yield: 39.8 %

Procedure:
To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.13 g, 0.57 mmol) in dry methanol (2 ml) was added m-aminophenyl acetylene (0.08 g, 0.68 mmol). The suspension was heated in a sealed pressure tube at 125° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (10 g, 40 mm mesh) using 3% methanol/methylene chloride to afford the title compound as a yellow powder (71 mg, 39%). TS-MS: 314 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:12]([NH:14][NH:15][C:16]([CH:18]2[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)=O)=[O:13])[C:7](=[O:43])[C:6]1=[O:44])[CH2:2][CH2:3][CH3:4].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.Cl>ClCCCl.CCOC(C)=O>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:12]2[O:13][C:16]([C@H:18]3[C@@H:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:21][CH2:20][NH:19]3)=[N:15][N:14]=2)[C:7](=[O:43])[C:6]1=[O:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(C(=O)NNC(=O)C2C(c3ccccc3)CCCN2C(=O)OC(C)(C)C)c2ccccc2)C(=O)C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCN1CCN(C(c2ccccc2)c2nnc([C@@H]3NCCC[C@@H]3c3ccccc3)o2)C(=O)C1=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-({2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazino}carbonyl)-3-phenylpiperidine-1-carboxylate (15.5 mg, 0.026 mmol) in 1,2-dichloroethane (1.5 ml) was added Burgess reagent (21.9 mg, 0.078 mmol). The reaction vessel was sealed and heated to 120° C. for 10 min in an Emry's Optimizer microwave reactor. Additional Burgess reagent (21.9 mg, 0.078 mmol) was added to the solution, and the reaction was sealed and heated again to 120° C. for 10 min in a microwave reactor. The reaction was concentrated in vacuo to yield the cyclodehydration product. A solution of the crude material in EtOAc (5 ml) at 0° C. was saturated with HCl gas and allowed to stir for 2 h. The reaction was concentrated in vacuo and purified via reverse phase HPLC to yield 1-butyl-4-(phenyl[5-(cis-3-phenylpiperidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl)piperazine-2,3-dione. HRMS (ES, M+H), cal'd for C28H33N5O3: 488.2656, found: 488.2646. 1H NMR (400 MHz, CD3OD) δ 7.42-7.22 (m, 7H), 7.09 (m, 3H), 6.87 (m, 2H), 5.36 (dd, J=14.6, 5.4 Hz, 1H), 3.88 (t, J=13.2 Hz, 1H), 3.53 (m, 1H), 3.44 (m, 6H), 3.24 (m, 1H), 3.11 (m, 1H), 2.55-2.38 (m, 1H), 2.25 (m, 1H), 2.00 (m, 2H), 1.56 (m, 2H), 1.33 (sext, J=7.4 Hz, 2H), 0.94 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@:5]([OH:11])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[H-].[Na+].[Br:15][C:16]1[N:21]=[C:20]([C:22]2([CH3:37])[CH2:24][N:23]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26])[C:19]([F:38])=[CH:18][CH:17]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C@:5]([O:11][CH2:37][C:22]([C:20]1[C:19]([F:38])=[CH:18][CH:17]=[C:16]([Br:15])[N:21]=1)([NH:23][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35])(=[O:26])=[O:27])[CH3:24])([CH3:10])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: CC1(c2nc(Br)ccc2F)CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (715 mg, 3.84 mmol) in DMF (4 ml) was added NaH (55%) (154 mg, 3.84 mmol) at room temperature and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 6-bromo-3-fluoro-2-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine (800 mg, 1.922 mmol) in DMF (9 ml) was added and the reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was poured onto a mixture of ice/2N HCl/t-butyl-methylether. The organic layer was washed with sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. Silica gel chromatography (cyclohexane/ethyl acetate) afforded the title compound as a mixture of 2 diastereoisomers. 300 mg (26% yield). TLC (cyclohexane/ethyl acetate 2:1) Rf=0.42; LCMS RtH5=1.25 min (100%, TIC ES+ 602, 604).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH2:22][CH2:21][O:17][N+:18]([O-:20])=[O:19])#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (5 ml), 2-nitroxyethylamine nitrate (0.57 g, 3.4 mmol) was added, and sodium methoxide (0.18 g, 3.4 mmol) was further added gradually. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was crystallized from dichloromethane-diethyl ether to give the title compound (0.44 g, 0.20 mmol, yield: 63%) as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Nc1ccccc1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To an ice cooled solution of ethyl-o-aminobenzoate 1 (33 g, 0.2 mole) in acetone (270 ml) was added with stirring an ice cooled solution of potassium carbonate (36.7 g, 0.27 mole) in water (214 ml) followed by addition of ethyl chloroformate (43 g, 0.4 mole). Stirring was continued at 0° C. for 11/2 hour and at 25° C. for 2 hours. The mixture was poured in water (300 ml) and extracted with three 300 ml portions of ether. The combined and dried (MgSO4) ether phases were evaporated in vacuo to give pure 2 (46.7 g, 98%). The product was recrystallized (EtOH, H2O) to give colorless crystals, mp <40° C. (Calc. for C12H15NO4 : C 60.75; H 6.37; N 5.90). (Found C 60.75; H 6.29; N 5.85) 1H NMR (CDCl3) δ= 1.3 (3H, t, J=7 Hz) 1.4 (3H, t, J=7 Hz) 4.2 (2H, q, J=7 Hz) 4.3 (2H, q, J=7 Hz) 6.9-8.5 (4H, AA'BB'). IR (CCl4): 3300(m), 2980(m), 1735(s), 1690(s), 1600(s), 1510(w), 1450(s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc2cc(C(=O)OC)[nH]c2c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a light brown, homogeneous solution of methyl 6-hydroxy-1H-indole-2-carboxylate (1.4862 g, 7.77 mmol) and 1-bromo-2-methoxyethane (0.731 mL, 7.77 mmol) in DMF (38.9 mL) under nitrogen was added cesium carbonate (2.53 g, 7.77 mmol). The reaction was heated to 55° C. and stirred overnight. The reaction was cooled to room temperature, diluted with EtOAc (200 mL) and filtered through CELITE®. The filtrate was washed with water (4×50 mL) and brine (2×50 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 20-60% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give desired product (0.8592 g) as a white solid. Mixed fractions were combined and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 80 g column eluting with 20-60% EtOAc/hexanes to give another crop of desired product (0.1673 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH:5]=1.C([NH2:22])=O.C[O-].[Na+]>CN(C=O)C.CO>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:22])=[O:2])[CH2:11][CH2:12]1)[CH2:17][CH3:18]
Reactant: NC=O
Reactant: CCCN1CCC(c2cccc(C(=O)OC)c2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCN1CCC(c2cccc(C(N)=O)c2)CC1

Procedure:
A solution of 3-(1-Propyl-piperidin-4-yl)-benzoic acid methyl ester (0.6 g) and formamide (320 μL) in DMF (9 ml) was heated to 100° C. under a blanket of argon. Sodium methoxide in methanol (30%, 770 μL) was added dropwise and after 1 h, GC analysis revealed the complete absence of starting material and indicated the titled compound as the sole product. After cooling, CH2Cl2 was added and the resulting solution was filtered through a pad of celite and evaporated to dryness. The residue was chromathographed on a silica column using MeOH: CH2Cl2 (1:3 (v/v)) as eluent. The fractions containing pure titled compound were collected, and the solvent was removed in vacuum, affording 400 mg of the titled compound. m.p. 182° C. (oxalate) (MS m/z (rel. intensity, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:36])[C:25]#[CH:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:36])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCN1Cc2ccccc2C1=O
Product: Cc1nnc2n1-c1ccc(C#CCN3Cc4ccccc4C3=O)cc1C(c1ccccc1F)=NC2

Procedure:
Reaction of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 2,3-dihydro-(2-propynyl)-1H-isoindol-1-one [ref. J. I. Neumeyer, U. V. Moyer, J. A. Richman, F. J. Rosenberg and D. G. Teiger, J. Med. Chem. 10, 615 (1967)] gave after chromatographic purification as described in example 17 and crystallization from ethyl acetate colorless crystals of the title compound with m.p. 165°-168° C. According to spectral and analytical data, these crystals contained 0.5 molar amounts of water and traces of ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[O:4][CH2:5][C:6]=1Br.C([O-])([O-])=O.[Cs+].[Cs+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[O:4][CH2:5][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C1OCC(Br)=C1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCC(N2CCOCC2)=C1Br
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a stirred solution of 3,4-dibromofuran-2(5H)-one (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3 (1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) at room temperature under a N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 3-bromo-4-morpholinofuran-2(5H)-one (0.87 g, 85%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH2:31]([NH2:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:17][C:16]([S:18]([NH:43][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: CCCCCCCCCCCCN
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]thiophene-2-sulfonyl chloride (2.00 g, 5.85 mmol), DIEA (1.134 g, 8.78 mmol) in DCM (20 mL) was added dodecyl amine (1.41 g, 7.61 mmol) at rt and the reaction mixture was stirred for 2 h at rt. A 1 M aqueous solution of HCl (10 mL) was added and the aqueous layers were extracted with DCM (2×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford a yellowish oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 4/1 in about 0.5 h) to give the title compound as a white solid (2.10 g, 73%). 1H NMR (CD3OD, 300 MHz) δ 7.91 (m, 2H), 7.85 (m, 2H), 7.43 (d, 1H, J=3.7 Hz), 7.17 (d, 1H, J=3.7 Hz), 5.05 (s, 2H), 2.90 (t, 2H, J=6.9 Hz), 1.50-1.38 (m, 2H), 1.35-1.16 (m, 18H), 0.86 (t, J=7.9 Hz, 3H) M−(LC/MS): 489.3; M+(LC/MS): 491.2. HPLC (Condition A), Rt: 6.64 min (HPLC purity: 95.9%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([O:37][CH3:38])[CH2:31][CH2:32][C:33](OC)=[O:34]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][CH:30]([O:37][CH3:38])[O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: COC(=O)CCC(OC)OC
Agent: Cl
Product: COC(CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)OC

Procedure:
The title compound, white solid (110 mg, 96%), MS (ISP) m/z=461.4 [(M+H)+], mp 204.5° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 4,4-dimethoxy-butanoate.