Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:24][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:14]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cccn2S(=O)(=O)c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
Under nitrogen atmosphere, to a solution of 1-benzenesulfonyl-1H-pyrrole (284 g, 1.37 mol) in dichloromethane (1.0 L) were added p-toluoyl chloride (318 g, 2.06 mol) and boron trifluoride ether complex (350 g, 2.47 mol), and the mixture was allowed to stand at room temperature for 7 days. The reaction solution was washed successively with 1N aqueous hydrochloric acid solution (750 mL×2), 1N aqueous sodium hydroxide solution (750 mL) and saturated saline (100 mL), dried, and filtered. The filtrate was concentrated under atmospheric pressure until about 500 ml, and thereto was added hexane (500 mL). The reaction mixture was further concentrated until about 500 ml, cooled to 10° C., and the resulting crystals were collected by filtration. The obtained crystals were washed successively with hexane and toluene to give the title compound (315 g, 71%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:23][CH2:24]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15].C(N(C(C)C)CC)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[OH:15])#[N:5]
Reactant: OC1CCCN1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCCC1O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-fluorobenzonitrile (4.03 g, 33.2 mmol) and pyrolidin-2-ol (2.92 g, 33.5 mmol) was treated with diisopropylethylamine (4.37 g, 33.8 mmol) at room temperature. The mixture was stirred at room temperature (5 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (57).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[IH:14].[O:15]=[C:16]1[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][C:18]2=[C:25]([C:28](SC)=[NH:29])[N:26]=[CH:27][N:17]12>CC#N>[IH:14].[CH3:1][O:2][C:3](=[O:6])[CH2:4][NH:5][C:28]([C:25]1[N:26]=[CH:27][N:17]2[C:16](=[O:15])[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][C:18]=12)=[NH:29]
Reactant: C#CCn1nnc2c(C(=N)SC)ncn2c1=O
Reactant: COC(=O)CN
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCn1nnc2c(C(=N)NCC(=O)OC)ncn2c1=O
Reaction time: 0.17 h

Procedure:
Glycine methyl ester (0.14 mmol) was suspended in dry MeCN (1 mL). Triethylamine (0.14 mmol) was added and the solution stirred for 10 minutes. Methyl 4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide (0.13 mmol) was then added and the reaction stirred at room temperature for 2 hours. The resulting precipitate was then filtered and washed with MeCN and ether. δH (DMSO-d6) 9.70 (2H, bs), 9.22 (1H, s), 5.76 (1H, s), 5.24 (2H, d, J=2.4), 4.45 (2H, s), 3.74 (3H, s), 3.60 (1H, t, J=2.4).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:25])[CH2:23][CH3:24]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, a saturated sodium chloride solution 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated salt solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 1 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 300.6 mg.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([N:1]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]2=3)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCNc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 50 °C

Procedure:
To a solution of 1,2,3,4-Tetrahydro-benzo[b]azepin-5-one (500 mg, 3.1 mmol) in pyridine (2 ml) is added p-toluenesulfonyl chloride (650 mg, 3.4 mmol), and the mixture is heated at 50° C. for 1 hour. The reaction mixture is poured into 1N HCl (100 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated to a solid. The solid is purified by silica gel column chromatography (eluent, 30% ethyl acetate in hexanes) to give the title compound as a solid. Mass spectrum (ES+): 316 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)=O>>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][CH2:30][O:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: Cc1c(C)c2c(c(C)c1OCCC(c1ccccc1)c1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 55 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 3,3-diphenylpropyl methanesulfonate, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:13])[CH:9]=2)[CH:4]=1.[C-:14]#[N:15].[K+]>CC#N>[F:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][C:14]#[N:15])[CH:12]=[CH:11]2
Reactant: Fc1ccc2cc(CBr)ccc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: N#CCc1ccc2cc(F)ccc2c1
Yield: 75.7 %

Procedure:
To a mixture of 2-bromomethyl-6-fluoro-naphthalene (1.5 g, 5.9 mmoL) in CH3CN (30 mL) was added KCN (1.16 g, 17.8 mmoL). The reaction mixture was heated at reflux for 6 h before being concentrated. To the residue was added diethyl ether (100 mL) and H2O (15 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:10) to afford the (6-fluoro-naphthalen-2-yl)-acetonitrile (0.88 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:16]=[C:17](SC)[NH:18][C:19]([O:21]C(C)(C)C)=[O:20])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][NH2:39]>CC(O)=O>[Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:38]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[Cl:31])[N:39]=[C:17]([NH:18][C:19](=[O:20])[OH:21])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
CH3COOH (50 ml) was added to a mixture of methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate, from Example 569, (1.0 g, 2.08 mmol) and (2-chlorophenyl)hydrazine hydrochloride (0.74 g, 4.16 mmol). The resulting mixture was stirred at 120° C. overnight. The reaction mixture was concentrated and purified by silica gel chromatography (Hexanes: EtOAc, 3:1-1:1) to give 5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamic acid (630 mg, 60%). 1H NMR (DMSO, 400 MHz) δ 10.60 (s, 1H), 7.76 (s, 1H), 7.70-7.68 (m, 1H), 7.63-7.60 (m, 2H), 7.52-7.52 (m, 1H), 7.48-7.46 (m, 1H), 7.18 (s, 1H), 7.10-7.07 (m, 1H), 5.45 (s, 1H), 4.42 (s, 4H)
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C(#N)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ncc(Br)c2ccccc12
Solvent: CC#N
Product: COc1ccc(CNc2cnc(C#N)c3ccccc23)c(OC)c1
Yield: 30.3 %

Procedure:
A mixture of compound 470B (699 mg, 3.00 mmol) and 2,4-dimethoxybenzylamine (4.8 mL, 30 mmol) in 15 mL of acetonitrile was refluxed for 16 h. After concentration in vacuo, the residue was purified on a 5×15 cm silica gel column, eluting with 3:2 hexane:ethyl acetate to afford 290 mg (30%) of 470C as a light yellow solid. HPLC: 1.76 min (retention time) (Phenomenex C-18, 5 micron column, 4.6×30 mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 4 mL/min, monitoring at 254 nm).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH3:29].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13]1
Reactant: CCCCBr
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.31 g, 1.18 mmol), acetonitrile (20 ml), potassium carbonate (0.3 g, 2.9 mmol), bromobutane (0.16 ml, 1.3 mmol). Yield: 0.26 g, 70%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 138° C. MS m/z (relative intensity, 70 eV) 319 (M+, 6), 277 (14), 276 (bp), 258 (23) 185 (9).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18].Cl>C(O)C>[CH3:21][O:20][C:16](=[O:19])[NH:17][N:18]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: COC(=O)NN
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: CCO
Product: COC(=O)NN=C1CCC(NC(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea (4.5 g), methyl carbazate (4.0 g), 95% ethanol (150 ml) and concentrated hydrochloric acid (2 ml) is heated at reflux for an overnight period. The mixture is cooled to room temperature and the crystals are collected. The product melts at 230° C. to 233° C. (dec). On recrystallizing from aqueous methanol, the title compound melts at 223° C. to 225° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][C:7]=2[CH3:12])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)c(C)c1

Procedure:
The desired product was prepared by substituting 4-bromo-3-methylbenzoic acid ethyl ester and 4-fluorophenylboronic acid for Example 186B and Example 186A, respectively, in Example 186C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)[CH2:6][C:5]2([CH3:25])[CH3:24].[CH:26]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27]1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:32][S:29]([CH:26]3[CH2:28][CH2:27]3)(=[O:31])=[O:30])=[O:14])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=1)[CH2:6][C:5]2([CH3:25])[CH3:24]
Reactant: NS(=O)(=O)C1CC1
Reactant: CN(C)c1cccc(C2CC(C)(C)c3cc(Cl)cc(C(=O)O)c3N2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)c1cccc(C2CC(C)(C)c3cc(Cl)cc(C(=O)NS(=O)(=O)C4CC4)c3N2)c1
Yield: 20.1 %

Procedure:
A mixture of 6-chloro-2-(3-dimethylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.42 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (120 mg, 0.63 mmol), 4-dimethylaminopyridine (77 mg, 0.63 mmol), cyclopropane sulfonic acid amide (150 mg, 1.26 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [6-chloro-2-(3-dimethylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (39 mg, 20%) as a light yellow solid: MS (ESI) M+1=462.2.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[C:16]([C:20]1[CH:21]=[C:22]([CH2:27][CH:28]([NH2:34])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:27][CH:28]([NH:34][C:6](=[O:8])[CH:2]([NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]([CH3:4])[CH3:5])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[OH:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of Boc-Val-OH (890 mg, 4.09 mmol), 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamine (1.03 g, 3.73 mmol) and CMPI (653 mg, 1.05 mmol) in THF (10 ml), TEA (1 ml) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.88 g, 99%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([C:32](=[O:34])[CH3:33])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CNc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(C)C)c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-boc-4-(2-isobutylamino-phenyl)-piperazine (333 mg, 1.0 mmol, 1.0 eq), Et3N (0.42 mL, 3.0 mmol, 3.0 eq) and DMAP (6 mg, 0.05 mmol, 0.05 eq) in DCM (10 mL) was added acetic anhydride (0.14 mL, 1.5 mmol, 1.5 eq). The mixture was stirred at r.t. overnight. The reaction was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was separated and aqueous layer was extracted with DCM (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford the title compound (375 mg, 1.0 mmol, 100%). LRMS (ESI+): 376.18 (M+1)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[NH2:18][OH:19].[OH-].[K+].CO>C1COCC1>[OH:19][NH:18][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: NO
Reactant: COC(=O)CCCCCSc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCSc1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexanoic acid methyl ester (0.59 g, 2.2 mmol) in distilled THF (13 mL) containing 50% aqueous hydroxylamine (1.3 mL, 19.6 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 3.5 mL, 3.5 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (13 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×25 mL) and the combined extracts were washed with brine (20 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.54 g, 90%) as a white powder, mp 83-85° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH:15]([CH3:17])[CH3:16])[S:5]1(=[O:19])=[O:18].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]=3)=[CH:26][NH:27]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O>[F:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]3[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][N:4]4[C:9]5[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=5[CH2:7][N:6]([CH:15]([CH3:17])[CH3:16])[S:5]4(=[O:19])=[O:18])[CH2:32][CH:31]=3)=[CH:26][NH:27]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CC(C)N1Cc2ccc(F)cc2N(CCCl)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)N1Cc2ccc(F)cc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: 100 °C
Reaction time: 64 h

Procedure:
To a 25 ml two-necked flask equipped with a reflux condenser and in Argon atmosphere, were added 1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(678 mg, 2.2 mmol), 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (523 mg, 242 mmol), anhydrous K2CO3 (1.09 g, 11 mmol) and 10 ml of deionised water. The mixture was vigorously stirred under Argon for 64 hours at 100° C., allowed to reach room temperature and extracted with EtOAc (3×25 ml). The combined organic extracts were dried (Na2SO4) and solvent removed at reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:hexane 1:3) affording 3,4-dihydro-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-7-fluoro-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale yellow solid, m.p. 103-105°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]3[C:10]4[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:12](=[O:22])[C:11]=4[CH:23]=[CH:24][CH:25]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30]([N:35]=[C:36]=[O:37])=[CH:29][C:28]=2[O:27]1>C(#N)C>[O:34]1[C:33]2[CH:32]=[CH:31][C:30]([NH:35][C:36]([NH:1][C:2]3[C:7]4=[CH:8][C:9]5[C:10]6[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:12](=[O:22])[C:11]=6[CH:23]=[CH:24][CH:25]=5)=[C:6]4[CH:5]=[CH:4][CH:3]=3)=[O:37])=[CH:29][C:28]=2[O:27][CH2:26]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CN(C)CCN1C(=O)c2cccc3cc4c(N)cccc4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4c(NC(=O)Nc5ccc6c(c5)OCO6)cccc4c(c23)C1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A solution of 100 mg (0.30 mmole) of 8-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 4) in 4 mL of acetonitrile was stirred at 20° C. 3,4-(methylenedioxy)phenyl isocyanate (4 molar equivalents) in 3 mL acetonitrile were added. The mixture was magnetically stirred at 20° C. during 24 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 volume ratio) to provide 76 mg (yield: 51%). of the desired product (formula below) as an orange powder
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.Br[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:11]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 20 ml of N,N-dimethylformamide, 2.291 g (15.108 mM) of 4-piperidylmethanol hydrochloride, 4.48 g (18.1 mM) of bromodiphenylmethane, and 6.26 g (45.3 mM) of potassium carbonate were stirred together at 100° C. for 3.5 days and, then, at 150° C. for 2 hours. After cooling to room temperature, this reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1 to 1/1) to provide the title compound.