Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[C:19]([N:21]=[CH:22]OCC)#[N:20].Cl.C(O)C>C(O)C>[C:19]([NH:21][CH:22]=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])#[N:20]
Reactant: CCOC=NC#N
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN=CNC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4.88 g of 2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethanamine (prepared according to British Pat. No. 1,338,169 which is hereby incorporated by reference,) in 75 ml of absolute ethanol, are added 5.55 ml of triethylamine. Then 1.96 g of ethyl N-cyano-formimidate in 15 ml of ethanol are added dropwise under stirring and at room temperature (prepared according to Huffman and Schaefer "J.Org.Chem.",28, 1816, 1963). Stirring is continued for 1 hour, after which are added 2.5 ml of 8N HCl/ethanol. A white solid is separated, which is subsequently crystallized in ethanol, filtered off and dried in a vacuum dessicator in the presence of phosphorus pentoxide and sodium hydroxide. 2.9 g of N-cyano-N'-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]formamidine are obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:23])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[N:47]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48]1.Cl>O1CCCC1>[N:47]1([S:51]([NH:54][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]([O:14][CH2:15][CH:16]3[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:23])=[CH:6][C:7]=2[F:13])(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)O)cc1C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)NS(=O)(=O)N2CCC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a stirred solution of 5-cyclopropyl-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid (0.07 g, 0.22 mmol) in tetrahydrofuran (2 mL) and under an atmosphere of nitrogen was added carbonyldiimidazole (0.053 g, 0.33 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled down to ambient temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was added followed by azetidine-1-sulfonamide (0.051 g, 0.37 mmol) and the stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.022 g, 22%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.75-8.55 (m, 1H), 7.57 (d, J=9.1 Hz, 1H), 6.62 (d, J=14.5 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H), 4.01 (d, J=4.5 Hz, 2H), 2.35-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.86-0.56 (m, 20H); MS (ES+) m/z 439.1 (M+1); MS (ES−) m/z 437.2 (M−1).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14]C)[C:9]#[N:10]>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10]
Reactant: COc1ccc(C#N)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
BBr3 (23 ml, 0.242 mol) was added to 3-Fluoro-4-methoxy-benzonitrile (24.4 g, 0.16 mol) in dichloromethane (200 ml) at −78° C. and stirring continued overnight at room temperature. Another portion of BBr3 (23 ml, 0.242 mol) was added at −78° C. and stirring continued at RT for 2 days under nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. Organic layer was washed with water and brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20 g of the sub-title compound as a solid. This was taken for next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: C1COCCN1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCOCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and morpholine following the procedure outlined in Example 15. 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 8.83 (s, 1H), 8.77 (s, 2H), 7.88 (d, 1H), 7.04 (d, 1H), 4.79 (s, 1H), 3.97 (t, 2H), 3.79 (s, 3H), 3.52 (app t, 4H), 2.29 (br, 4H), 2.22 (t, 2H), 1.74 (m, 2H), 1.39 (m, 4H), 1.30 (m, 2H); MS (ESI): 521.3.
Reaction SMILES: O(C(O[CH2:11][C:12]1[N:13]=[CH:14][N:15]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)=[CH:23][C:22]=2[CH3:34])[N:16]=1)=S)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:22]([CH3:34])=[CH:23][C:24]([C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)=[CH:25][C:26]=2[CH3:27])[N:16]=1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1cnc(COC(=S)Oc2ccccc2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ncn(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)n1
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 54.9 %

Procedure:
To a solution of 5-phenoxythiocarbonyloxymethyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole (130 mg, 0.79 mmol) in 20 ml of toluene was added AIBN (130 mg, 0.79 mmol) and tributyltin hydride (3.2 g, 11 mmol) and the mixture was stirred at 75° C. for 6.5 h. The solvent was concentrated in vacuo and the residue was purified by silica column chromatography (10 cm column, ethyl acetate/hexane, 1/1 - 5/1; methylene chloride/acetone, 4/1 - 0/1) to afford 142 mg (43%) of 5-methyl-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole, m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][OH:27].[H-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:8][CH:9]=1
Reactant: CN(C)CCO
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(C)CCOc1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 12.6 %

Procedure:
In a similar fashion using route 51 general procedure 119, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (200 mg, 0.59 mmol), N,N-dimethyl ethanolamine (210 mg, 2.3 mmol), NaH (60% in mineral oil; 71 mg, 1.79 mmol) and NMP (2 ml) gave the title compound (30 mg, 13%) after purification by column chromatography with DCM/MeOH (98:2) elution.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12].[F-].[K+]>CN(C=O)C>[CH3:9][C:10]([CH3:15])([CH2:14][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]([OH:13])=[O:12]
Reactant: Sc1ccccc1
Reactant: CC(C)(CBr)C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CSc1ccccc1)C(=O)O
Temperature: 120 °C

Procedure:
To a solution of thiophenol (5 g, 45 mmol) in DMF (100 mL) is added 3-bromo-2,2-dimethyl-propionic acid (CAS#2843-17-6, 3.98 g, 22 mmol), and potassium fluoride (1.56 g, 27 mmol). The reaction is heated at 120° C. overnight. The reaction is then cooled to room temperature and poured into ice water. A white precipitate is filtered and washed with ice water. The solid is then dissolved in 1M aqueous NaOH and is washed with dichloromethane. The aqueous solution is acidified with 1M HCl and the resulting precipitate is collected to provide 2,2-dimethyl-3-phenylsulfanyl-propionic acid; 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (s, 6 H), 2.72 (br. s., 1 H), 3.19 (s, 2 H), 7.09-7.21 (m, 1 H), 7.21-7.32 (m, 2 H), 7.40 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11]Br.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2occc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1nccc2occ(Br)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To the solution of 4-chloro-furo[3,2-c]pyridine (4.2 g, 0.03 mol) In CCl4 (77 ml) was added Br2 (2.4 ml, 0.046 mol) at 0° C. and the resultant reaction mixture was stirred for 4 hours at room temperature. The resultant suspension was poured into the mixture of ethyl acetate and 10% Na2SO3. The corresponding organic phase was separated and dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in THF (100 ml) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (5.6 ml) was added at 0° C. The resultant reaction mixture was stirred for 2 hours at room temperature and poured into NaHCO3 and ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on a silica gel column to afford the titled compound (5.4 g) 1H NMR (400 MHz, CDCl3) ppm 8.32 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.44 (d, J=5.8 Hz, 1H), 7.26 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[Cl:7][CH2:8][C:9](=[N:11]O)[NH2:10].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:7][CH2:8][C:9]1[N:11]=[C:4]([CH2:3][C:1]#[N:2])[O:6][N:10]=1
Reactant: NC(CCl)=NO
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: N#CCc1nc(CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 8.50 g of cyanoacetic acid and 10.1 g of chloroacetamidoxime was added 20.6 g of N,N'-dicyclohexylcarbodiimide with ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with 20 ml of ethyl acetate and the insoluble material was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and the residue was dissolved in 50 ml of toluene. The resultant solution was heated under reflux for 20 minutes with a water separator. After cooling and adding 50 ml of ethyl acetate, the solution was decanted and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (50:1) as eluent to give 8.18 g of 3-chloromethyl-5-cyanomethyl-1,2,4-oxadiazole as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16]C)C(C#N)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Br.[OH-].[Na+].CCCCCC.[C:27]([O:30]CC)(=[O:29])[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:16])[C:28]([C:27]([OH:30])=[O:29])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(-c2cccc(F)c2)cnc1C#N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(O)c1ncc(-c2cccc(F)c2)cc1O
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser is charged 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine, 9, (0.912 g, 4 mmol) and a 48% aqueous solution of HBr (10 mL). While being stirred, the reaction solution is heated to reflux for 20 hours. The reaction can be determined to be complete due to the disappearance of 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction is then cooled to 0° C. to 5° C. with stirring and the pH is adjusted to approximately 2 by the slow addition of 50% aqueous NaOH. Stirring is then continued at 0° C. to 5° C. for 3 hours. The resulting solid is collected by filtration and washed with water, then hexane. The resulting cake is dried in vacuo at 40° C. to afford the desired product.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCNCC1
Yield: 95.8 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl 4-ethylpiperidine-1,4-dicarboxylate (above step 2, 4.5 g, 12.96 mmol) in 50 ml DCM was cooled to 0° C. After ten minutes trifluoro acetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.19-1.24 (t, 3H); 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); 4.10-4.17 (m, 2H); 7.07-7.10 (m, 2H); 7.24-7.30 (m, 3H); ES Mass: 186 (100%), [M+1].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCCOC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CCCOC)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
4-(3-Methoxy-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (6 g) was dissolved in methylene chloride (200 ml) under an argon atmosphere, TFA (35.6 ml) was added and the reaction mixture was stirred for 3 hours at RT. The solvent together with most of the TFA was evaporated off, the residue dissolved in methylene chloride (800 ml) and treated with 2M KHCO3 under ice cooling. The layers were separated, the organic layer was washed with water and brine, dried over sodium sulphate and concentrated in vacuo to give 3.63 g of 4-(3-methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester as a light brown oil which was used in next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:6])=[O:7]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cccc(Cl)c3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O

Procedure:
5-[(2,3-Dichlorobenzyl)sulfonyl]-1,3-dihydro-indol-2-one (315 mg, 1 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (170 mg, 1 mmol) to give the titled compound as a solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].CS(O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)(=O)=O>CN(C=O)C>[CH2:1]([S:3][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 0.20 ml (2.6 mmol) of ethanethiol in 7 ml of DMF was added 0.11 g (2.7 mmol) of sodium hydride. The mixture was stirred at 0° C. for 30 min, then 0.50 g, (1.7 mmol) of the title compound from Step A was added. The solution was allowed to stir for 2 h and then quenched with 50 mL of a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a light brown solid that was used without further purification. 1H-NMR (500 MHz, CDCl3) δ 4.00 (s, 2H), 2.90 (m, 2H), 2.82 (m, 1H), 2.58 (q, J=7 Hz, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.45 (s, 9H), 1.29 (t, J=5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]([NH:18][C@H:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH:9]=[CH:8]1.[OH-].[Na+]>C1COCC1.CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]([NH:18][C@H:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH:9]=[CH:8]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4cccc(C(F)(F)F)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3cccc(C(F)(F)F)c3)c12)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methyl 4-{(1S)-1-[({1-[3-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoate (220 mg, 0.458 mmol) was dissolved in THF (2 ml) and MeOH (1.14 ml). 2M NaOH (1.14 ml, 2.29 mmol) was added and the mixture stirred at 50° C. for 1 hour. The mixture was cooled, the organic solvents removed and poured into 1N HCl. The resulting solid was filtered and washed with water. 1H NMR (500 MHz, DMSO-d6): δ 12.90 (bs, 1H), 8.90 (d, 1H), 7.85 (d, 2H), 7.75 (d, 1H), 7.65-7.55 (m, 2H), 7.50-7.40 (m, 3H), 7.25 (m, 2H), 7.15-7.00 (m, 4H), 7.00 (d, 1H), 6.65 (s, 1H), 5.60 (dd, 2H), 5.00 (m, 1H), 1.20 (d, 3H). MS-ESI (464.9).
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O.CCOCC>[C:28]([CH2:27][N:10]1[CH2:11][CH2:12][C@:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C@@H:8]2[CH2:9]1)#[N:29]
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#CCN1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Yield: 99.7 %

Procedure:
To a solution of 3.02 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine in 48 ml of dry dimethylformamide was added 3.6 g of anhydrous potassium carbonate and 0.982 g of chloroacetonitrile. The resulting suspension was heated at 80° under nitrogen for 19 hours. The cooled reaction mixture was diluted with 500 ml of ether and washed with water (4×250 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give 3.48 g (99.9%) of a gum, which crystallized on standing. A 0.35 g portion of this material was recrystallized from ethanol to afford 0.22 g of crystals, m.p. s 93, 94°-96°.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:29]=[C:30]=[S:31])[CH:27]=[CH2:28]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:30]([NH:29][CH2:26][CH:27]=[CH2:28])=[S:31])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: C=CCN=C=S
Solvent: CC#N
Product: C=CCNC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 58 μl (2 molar equivalents) of allyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 90 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=69%) which was characterized as follows:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.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>[CH2:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)Cc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1ccccc1CC(=O)OC
Temperature: 110 °C
Yield: 65 %

Procedure:
To a solution of methyl 2-iodophenylacetate (1.00 g, 3.62 mmol, prepared from the corresponding acid according to litt. Tetrahedron 63, 2007, 9979) in toluene (45 mL) was added Tetrakis(triphenylphosphine)palladium (209 mg, 0.0.181 mmol) and allyl tributylstannane (1.35 mL, 4.34 mmol). The resulting solution was heated to 110° C. for 20 h and then cooled down. The solvents were removed in vacuo. The yellow oil was partitioned between acetonitrile (30 mL) and hexane (30 mL) and the acetonitrile layer was washed with hexane (2*30 mL). The acetonitrile was removed in vacuo and the residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (15/1) to give Methyl 2-allylphenylacetate (colourless oil, 446 mg, 65%). C12H14O2; MW: 190.24; LCMS (method A) RT 1.74 min; ES: 191 (100%, MH+); IR. 2951, 1734 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.14-7.41 (4H, m), 5.99 (1H, m), 5.12 (1H, m), 5.03 (1H, m), 3.73 (3H, s), 3.72 (2H, s), 3.47 (2H, dt) ppm.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:29]>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:32]3[CH2:33][CH2:34][CH:30]([C:28]([O:27][CH3:26])=[O:29])[CH2:31]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: Cl
Solvent: ClCCCl
Product: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Reaction time: 3 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.21 g, 3.26 mmol) in DCL (25 mL) was slowly added to a solution of 3-(methoxycarbonyl)pyrrolidine hydrochloride (0.46 g, 3.58 mmol) and DIPLA (5.6 mL, 32.6 mmol) in DCE (80 mL). The reaction mixture was stirred for 3 h and the solvent was concentrated. The product was purified by MPLC on silica gel using EtOAc as eluent to provide the title compound as white solid. Yield: 0.60 g (39%); 1H NMR (400 MHz, CDCl3) δ 1.49-1.56 (m, 3 H), 1.55-1.58 (m, 1 H), 1.59 (s, 9 H), 1.93-2.13 (m, 2 H), 2.20-2.36 (m, 1 H), 2.89-3.01 (m, 1 H), 3.28-3.41 (m, 5 H), 3.60 (s, 3 H), 3.61-3.66 (m, 1 H), 3.94-4.06 (m, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.44 (dd, J=8.50, 0.49 Hz, 1 H), 7.72 (dd, J=8.59, 1.76 Hz, 1 H), 8.24 (dd, J=1.76, 0.59 Hz, 1 H); MS (ESI) (M+H)+=464.0.