Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[C:14]([C:17]1[C:18]([OH:27])=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[CH3:15].C1CCN2C(=NCCC2)CC1.O>N1C=CC=CC=1>[OH:27][C:18]1[C:17]([C:14](=[O:16])[CH2:15][C:9](=[O:10])[C:8]2[C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Reactant: O=C(Cl)c1cccnc1C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(C(=O)CC(=O)c2cccnc2C(F)(F)F)c1O
Temperature: 80 °C
Yield: 111.9 %

Procedure:
2-(trifluoromethyl)pyridine-3-carbonyl chloride 25 (300 mg, 1.46 mmol) was added to a mixture of methyl 3-acetyl-2-hydroxybenzoate 38 (183 mg, 1.46 mmol) and DBU (446 mg, 2.92 mmol) in pyridine at 0° C. The reaction mixture was heated at 80° C. for 12 h. The resulting mixture was poured into H2O and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated to give 39 (600 mg) which was used with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:24][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([NH:16]C(OC(C)(C)C)=O)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:4].C(Cl)Cl.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>>[F:38][C:37]([F:40])([F:39])[C:35]([O-:41])=[O:36].[CH2:30]([O:29][C:27]([CH2:26][O:25][C:6]1[C:7]2[S:15][C:14]3[CH:13]=[C:12]([NH3+:16])[CH:11]=[CH:10][C:9]=3[C:8]=2[S:24][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:28])[CH3:31]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(NC(=O)OC(C)(C)C)ccc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc([NH3+])ccc12
Product: O=C([O-])C(F)(F)F

Procedure:
6-tert-Butoxycarbonylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (684 mg, 1.5 mmol) was stirred in TFA (12 ml) and DCM (15 ml) for 3 hr. Removal of solvent by rotory evaporation yielded 729 mg (quantitative) of 1-ethoxycarbonylmethoxy-2-methoxycarbonyl-3,8-dithia-cyclopenta[a]inden-6-yl-ammonium trifluoroacetate.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)sc2c1
Yield: 47.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-6-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 76 mg (47%) of the title compound as an amorphous solid. mp 102°-107°. FDMS: m/e=424. α[D]589 =+64.29 (c=0.71, chloroform).
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[N:16]=[C:15](F)[C:14]=1[F:22])([CH3:11])([CH3:10])[CH3:9].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH2:23]([NH:30][C:15]1[C:14]([F:22])=[C:13]([NH:12][C:8]([CH3:9])([CH3:10])[CH3:11])[C:18]([F:19])=[C:17]([F:20])[N:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)Nc1c(F)c(F)nc(F)c1F
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1c(F)c(F)nc(NCc2ccccc2)c1F
Temperature: 115 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To 10 ml of N-methylpyrrolidone were added 6.8 g of 4-(t-butylamino)-2,3,5,6-tetrafluoropyridine together with 7.2 g of benzylamine, and the mixture was stirred at 115° C. for one day and allowed to cool. After adding 40 ml of chloroform, the mixture was washed three times with 400 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about 8.0 g of the title compound as a dark green crude oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1.C(Cl)Cl.CC(C[AlH]CC(C)C)C>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1
Reactant: COCCOc1cc(C(=O)OC)nc(Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: COCCOc1cc(C=O)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
A 25 mL round bottomed flask was charged with methyl 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylate [SAD105-047F1] (45 mg, 1 equiv.) and CH2Cl2 (1 mL). 1 M DIBAL-H (0.2 mL, 1.1 equiv.) was added at −78° C. over 2 min under argon. The reaction mixture was stirred for 3 h at −78° C. but the LC-MS still showed a lot of starting material. Additional 1 M DIBAL-H (0.27 mL, 1.4 equiv.) was added at −78° C. over 2 min under argon and after 0.5 h LC-MS showed no more starting material but mostly 1 peak at 1.20 min (M+1=217, M+l+MeOH=249). The reaction mixture was quenched with MeOH (0.5 mL) and then with 10% NH4Cl (1 mL). The reaction mixture was warmed to RT and then the solvent was concentrated under reduced pressure. The residue was diluted with 10% NH4Cl (4 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 41.9 mg of the crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde as a yellow oil which was used in the next step without further purification, (H NMR δ: 9.91 (s, 1H); 7.23 (s, 1H); 4.59-4.64 (m, 2H), 3.7-3.8 (m, 2H); 3.44 (s, 3H).
Reaction SMILES: C(=O)(O)N.[O:5]1[CH:10]2[CH:6]1[CH2:7][NH:8][CH2:9]2.C([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(OC(C)(C)C)=O>C(#N)C>[N:18]1([CH:10]2[CH2:9][NH:8][CH2:7][CH:6]2[OH:5])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1NCC2OC12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: NC(=O)O
Solvent: CC#N
Product: OC1CNCC1N1CCNCC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
3,4-Epoxypyrrolidine carbamate Wang resin (0.15 g, 0.18 mmol) was placed in a glass reaction vessel (4 mL). LiClO4 (57 mg, 3 eq.), N-Boc piperazine (186 mg, 5.5 eq.) and acetonitrile (2 mL) were added. The glass reactor was closed with a screw cap and the reaction mixture was heated at 80° C. for 43 h. The resin was transferred into syringes and washed with acetonitrile: H2O (1:1, 2×), DMF (3×), MeOH (3×), DMF (3×), and CH2Cl2 (5×). The BOC group was removed by treating the resin with 10% methyl sulfide in TFA (2 mL) for 1 hour. This solution was saved and later combined with a cleavage solution. The product was further cleaved from resin by shaking with a solution of TFA:CH2Cl2:H2O (2 mL of 70:30:1.5) for 2.5 h (2×). All the solutions were combined and condensed to afford 170 mg of crude 4-piperazin-1-yl-pyrrolidin-3-ol (bistrifluoroacetate salt, used without purification). The crude 4-piperazin-1-yl-pyrrolidin-3-ol was dissolved in DMF (dry, 2 mL). To this solution was added 4-chloro-benzoyl chloride (46 μL, 0.36 mmol), diisopropyl ethyl amine (620 μL, 3.6 mmol), and DMAP (2 mg). The solution was stirred at RT for 30 minutes, and then separated by preparative LC-MS to yield 16-mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 448.3 (100).
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl-].[NH4+]>C1COCC1>[Si:12]([O:4][CH2:3][CH:2]([SH:1])[CH2:5][SH:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: OCC(S)CS
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(S)CS
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a solution of 2,3-dimercapto-1-propanol (15.0 ml, 150 mmol) and imidazole (15.3 g, 224 mmol, 1.5 eq) in THF (300 mL) was added t-butyldimethylsilyl chloride (21.4 g, 142 mmol, 0.95 eq) at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. A saturated solution of ammonium chloride was added and the aqueous phase was extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexane and ethyl acetate (90:10) to give the pure compound (32.04 g) in 94.5w yield.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[NH3:10].[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[C:15]([NH:2][CH3:1])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Solvent: CO
Product: CNc1ccc2c(n1)CCN(Cc1ccccc1)C2
Product: N
Temperature: 140 °C

Procedure:
Liquid methylamine (20 mL) was added to a cooled (−70° C.) solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine (WO 9830560) (5.5 g, 21.25 mmol) in methanol (30 mL). The mixture was heated to 140° C. in a sealed vessel for 72 hours, then cooled. The reaction mixture was evaporated under reduced pressure and the residual brown oil purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (97:3:0 to 96:4:0.5) to afford the title compound as a white solid, 2.97 g
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>C(O)C.C(Cl)Cl>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Solvent: ClCCl
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 75 °C
Yield: 100.1 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol) and 40% solution of Dimethylamine (10.66 g, 95 mmol) in ethanol (40 mL) was heated to 75° C. for 1 hour. The mixture was cooled to ambient temperature, diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 (3×100 mL) and brine. The organic was dried (MgSO4), filtered and concentrated to afford 5.27 g (100%) of the title compound. MS (ESI) m/z 168 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[OH-].[Na+]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:8]2[C:9]3[CH:10]=[C:2]([F:1])[CH:3]=[C:4]([NH2:11])[C:5]=3[CH:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: Nc1cc(F)cc2[nH]ccc12
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc2c1ccn2Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-fluoro-1H-indol-4-amine (5 g, 0.033 mol), 4-chlorobenzyl chloride (5.55 g, 0.035 mol) and sodium hydroxide (1.32 g, 0.033 mol) was heated at 60° C. for 3 h. The solvent was evaporated and the residue was dissolved in EA (150 mL) and water (70 mL). The aqueous layer was extracted with EA and washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=8:1) to afford the title compound. LC/MS m/z=275.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([O:12]C)[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([OH:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CCCc1c(OC)cccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1c(O)cccc1O
Temperature: -70 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2,4,-Dimethoxy-3-propylbenzene (7.2 g, 39.94 mmol) was dissolved in 50 ml methylene chloride and the solution was cooled to -70° C. then 87.0 ml of 1M boron tribromide in methylene chloride was added over a period of 1 hour. The reaction mixture was stirred at -70° C. for 1 hour, then at room temperature for 2 hours. The reaction mixture was poured into 250 ml of ice water very slowly. This mixture was extracted 3 times with 100 ml methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to give the product as a white solid (4.9 g, 81.7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+:12].[Na+].O.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[Na+:12].[Br:15][CH2:16][C:17]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:18]
Reactant: O=C(Br)CBr
Reactant: NCCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NCCS(=O)(=O)[O-]
Temperature: 10 °C
Yield: 43.8 %

Procedure:
Taurine (50 g, 0.40 mol) and sodium carbonate (48 g, 0.45 mol) were combined with 250 mL of water in a 1-L flask and chilled in an ice bath (10° C.). Bromoacetyl bromide (100 g, 0.50 mol) in 250 mL of methylene chloride was added dropwise over a 1 hr period with rapid stirring while maintaining the temperature at 10°-15° C. After addition, the ice bath was removed and the mixture was stirred for 3 hr. The aqueous layer was separated and washed with two portions of methylene chloride, and most of the water was evaporated affording a moist white solid. The solid was washed thoroughly with acetone and dried (90 g, 85% yield). The product was purified by dissolving it in 1200 mL of hot methanol, filtering, and evaporating the methanol until the product crystallized out (volume ca 650 mL). This afforded 47 g (44% yield) of product; mp>250° C. Anal. Calcd. for C4H7BrNO4SNa: C, 17.9; H, 2.6; N, 5.4. Found: C, 17.6; H, 2.4; N, 4.5.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([NH:5][C:6](=[NH:8])[NH2:7])=[NH:4].[C:10]([OH:19])(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>C(#N)C>[C:10]([O-:19])(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].[NH2:8][C:6]([NH:5][C:3]([N:2]([CH3:9])[CH3:1])=[NH2+:4])=[NH:7]
Reactant: CN(C)C(=N)NC(=N)N
Reactant: O=C(O)c1ccccc1O
Solvent: CC#N
Product: CN(C)C(=[NH2+])NC(=N)N
Product: O=C([O-])c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
N,N-Dimethylimidodicarbonimidic diamide (metformin free base) (1.66 g, 12.8 mmol) was dissolved in acetonitrile (45 mL) and the resulting solution was filtered through a medium frit to remove a small amount of sodium chloride that precipitated. To the filtrate was added dropwise at room temperature (over a 2 minute period) a solution of salicylic acid (1.42 g, 10.3 mmol) in acetonitrile (20 mL). The reaction solution became warm and a white solid precipitated about 1 minute after the addition was complete. After stirring for 1 h at room temperature, the mixture was chilled to 0° C. for 1 h. The white solid was filtered and the solid was washed with 20 mL ice-cold acetonitrile. The material was dried for 5 minutes on the frit followed by transfer of the solid to a round-bottom flask and the material was left under high vacuum overnight to yield 2.27 g (82%) of the title compound as a crystalline white solid. MP 152-154° C.; 1H NMR (400 MHz, MeOD) 7.82 (dd, J=7.67, 1.66 Hz, 1 H), 7.26 (m, 1 H), 6.76 (m, 2 H), 3.03 (s, 6 H); 13C NMR (101 MHz, MeOD) 176.31, 162.72, 161.33, 160.57, 133.87, 131.77, 120.38, 119.10, 117.25, 38.09; MS (ESI−) for C7H6O3 m/z 137.1 (M-H)−.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]1[C:21]2[C:22]([OH:30])=[C:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH:18]=1>C(Cl)CCl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:18]2[O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([CH2:27][CH2:28][CH3:29])=[C:22]([O:30][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)[C:21]=3[C:17]=2[CH3:16])=[O:10])=[CH:3][CH:4]=1
Reactant: CCCc1cc(F)c2occ(C)c2c1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(F)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1OC(=O)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
A solution of p-anisoyl chloride (2.70 gm; 15.5mmoles) in ethylene dichloride (10 mL) was added slowly to a cooled suspension of aluminium chloride (3.0 gm; 21.8mmoles) in ethylene dichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.79 gm; 3.8mmoles) in dichloroethylene (5 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice-bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the agueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.18 gm (63%) of 2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-fluorobenzofuran.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([CH2:48][C:49](O)=[O:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:49](=[O:50])[CH2:48][C:45]2[CH:46]=[CH:47][C:42]([CH3:52])=[CH:43][CH:44]=2)[C:7]1=[O:12]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CC(=O)Nc2cccc3c(=O)n(CCN(C)C)ccc23)cc1
Yield: 27.5 %

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), p-tolylacetic acid (39 mg, 0.26 mmol) and DIPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 18 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2 gradient) gave N-[2-(2-Dimethylamino-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-2-p-tolyl-acetamide as a white solid (20 mg, 0.055 mmol, 27%).
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H:40]([O:43]CCC)[CH2:39][CH2:38]2)CCCCC1.[CH:47]1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)[CH2:51]CC[CH2:48]1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.COC(C1(NS(C2SC(N)=NC=2)(=O)=O)CCC1)=O>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([O:43][CH2:40][CH2:39][CH3:38])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][C:19]3([C:20]([OH:22])=[O:21])[CH2:51][CH2:47][CH2:48]3)(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Agent: COC(=O)C1(NS(=O)(=O)c2cnc(N)s2)CCC1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: O=C1CCCCC1
Solvent: CCCBr
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NC3(C(=O)O)CCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and 1-(2-amino-thiazole-5-sulfonylamino)-cyclobutanecarboxylic acid methyl ester to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)=[C:18]=[S:19].[N:34]#[C:35][NH2:36]>C(O)(C)(C)C.C(#N)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][N:4]=[C:3]2[C:2]1[S:19][C:18]([NH:17][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:32][CH:33]=2)=[N:34][C:35]=1[NH2:36]
Reactant: COc1cc2ncnc(CBr)c2cc1OC
Reactant: N#CN
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Solvent: CC#N
Solvent: CC(C)(C)O
Product: COc1cc2ncnc(-c3sc(Nc4ccc(OCCN5CCCC5)cc4)nc3N)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(Bromomethyl)-6,7-dimethoxyquinazoline (E-1) (291 mg), 1-(2-(4-isothiocyanatophenoxy)ethyl)pyrrolidine (C-1) (330 mg, 1 eq) and cyanamide (100 mg, 2 eq) were dissolved in 1/1 anhydrous t-butanol/acetonitrile (8 mL). The reaction was stirred for 3 h at room temperature, then quenched with brine. The reaction was extracted with a mixture of ethyl acetate and methanol. The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum and dried overnight under vacuum. The residue was taken up in anhydrous tetrahydrofuran (10 mL) and cooled to −70° C. under nitrogen. Then 2.5 mL of a 1.6 M solution of n-butyllithium in hexanes was added. After 0.5 h at −70° C. the cooling bath was removed. After a total of 4 h the reaction was quenched with water, extracted with a mixture of ethyl acetate and methanol, dried over anhydrous sodium sulfate and concentrated under vacuum. The highly polar product was purified by radial chromatography (chromatotron) eluting with 95% dichloromethane and 5% 2M ammonia in methanol to yield 5-(6,7-dimethoxyquinazolin-4-yl)-N2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine, compound #1, as a bright orange solid (39 mg); 1H NMR (DMSO-d6, 300 MHz) 8.60 (s, 1H), 8.46 (br s, 2H), 7.58 (m, 3H), 7.15 (s, 1H), 6.93 (d, 2H), 4.05 (t, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.83 (t, 2H), 2.50 (m, 4H), 1.70 (m, 4H) ppm; MS (ES) 493.17 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5/[CH:29]=[N:30]\O)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:26])([CH3:28])[CH3:27])=[C:19]5[C:29]#[N:30])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1/C=N\O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C#N

Procedure:
(Z)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)-methyl)-1H-indol-5-yl)cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated at reflux for 3 h. The mixture was cooled in an ice bath and the precipitate was collected and washed with water. The solid was further dried under high vacuum to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-1H-indol-5-yl)cyclopropanecarboxamide ESI-MS m/z calc. 401.5, found 402.5 (M+1)+; retention time 3.70 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.79 (s, 1H), 7.79 (s, 1H), 7.32 (m, 2H), 7.03-7.02 (m, 1H), 6.95-6.89 (m, 2H), 6.03 (s, 2H), 1.47 (s, 9H), 1.43-1.41 (m, 2H), 1.06-1.04 (m, 2H).