Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([N:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:12]=3[S:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1>C1C=CC=CC=1>[CH:5]1([N:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[S:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(=O)n(C3CCCC3)sc2c1
Agent: BrB(Br)Br
Solvent: c1ccccc1
Product: O=c1c2ccc(O)cc2sn1C1CCCC1
Temperature: 25 °C
Yield: 85 %

Procedure:
BBr3 (0.54 g, 2 mmol) was added dropwise to a solution of 2-cyclopentyl-6-methoxybenzo[d]isothiazol-3(2H)-one (0.250 g, 1 mmol) in anhydrous benzene (20 mL) at 0° C. The mixture was gradually warmed to room temperature and then heated at 80° C. for 30 min. The reaction mixture was then cooled to room temperature and carefully quenched with H2O (20 mL). The resulting mixture was then heated to reflux for an hour and filtered; the precipitate was washed with H2O and dried under vacuum to give the crude product. The material was purified by flash chromatography (silica gel, CHCl3: CH3OH, 9:1) to afford (0.200 g, 85%) of 2-cyclopentyl-6-hydroxybenzo[d]isothiazol-3(2H)-one as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 10.36 (s, 1H), 7.60 (d, 1H, J=8.5 Hz), 7.20 (s, 1H), 6.80 (d, 1H, J=8.6 Hz), 4.84-4.81 (m, 1H), 2.12-1.98 (m, 2H), 1.75-1.60 (m, 6H). LC-MS (ESI) Calcd for C12H13NO2S [M+H]+: 236.0667. Found: 235.95.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1)#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(CC#N)cc2)cs1
Temperature: 25 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
NaCN (115 mg), KI (130 mg) and water (1.8 ml) were combined, and then a solution of N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (230 mg) in DMF (7 ml) was added dropwise to the mixture at 0° C. The reaction mixture was stirred at r.t. for 19 hours, poured into water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residual solid was washed with ethyl ether to give N-(4-{2-[4-(cyanomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (149.1 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15](OS(C)(=O)=O)[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11].[NH3:22]>O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH2:22])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Reactant: N
Solvent: CO
Solvent: O
Product: Cc1cccc(C)c1N(CC(C)N)S(C)(=O)=O

Procedure:
A mixture of 1.0 g (3 mmoles) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-methanesulfonyloxy-propane, 10 ml of methanol and 5 ml of concentrated aqueous ammonia is heated at 110° C. for 6 hours in a steel bomb. The mixture is cooled, diluted with 30 ml of water, and methanol is evaporated under reduced pressure. The residue is extracted thrice with 20 ml of chloroform, each. The chloroform solutions are combined, washed thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is triturated with 3 ml of diisopropyl ether. 0.55 g of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-amino-propane are obtained; m.p.: 106°-109° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)[N:7]=1)=[O:5])[CH3:2].[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@@H:26]([CH2:34][OH:35])[NH:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:35][CH2:34][C@@H:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][N:25]1[C:14]([C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[N:8]1[C:9]([CH3:11])=[CH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]1)=[O:16]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.8 %

Procedure:
To an ice cooled solution of 2-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-5-nitrobenzoic acid (25.0 g, 78.4 mmol) in DMF (250 mL) were added (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (31.0 g, 62.7 mmol), EDC.HCl (23.0 g, 117.5 mmol), HOBT (13.75 g, 101.9 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water, extracted with EtOAc (500 mL×2) twice. The combined organic layers were washed with water (500 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the ‘off white’ title compound 18 g (49%). Rf=0.45 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.70-8.35 (m, 2H), 8.15-7.98 (m, 1H), 7.25-6.95 (m, 4H), 6.82-6.58 (m, 1H), 5.20-3.80 (m, 8H), 3.40-2.40 (m, 2H), 2.38-2.10 (m, 3H), 1.30-0.80 (m, 3H); ES-MS: m/z 465.3 (M+H).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[C:29]1([S:39](Cl)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>N.CO>[C:29]1([S:39]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Naphthalene-1-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.5 mg). MS m/z 379 [M+H]+.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C@H:14]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:46](Cl)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>N1C=CC=CC=1>[C:46]([O:11][CH2:10][C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@H:14]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@H:6]1[OH:7])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)OCCCCCCCCCCCCCC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@H](CO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@H](O)[C@H]1O)OCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 7 h
Yield: 85.2 %

Procedure:
3-O-(α-D-Galactopyranosyl)-1,2-di-O-tetradecyl-Sn-glycerol (3) (647 mg) was dissolved in pyridine (5 ml). Trityl chloride (558 mg) was added to the solution. The mixture was stirred at 60° C. for 7 hours and concentrated in vacuo. The residue was subjected to column chromatography (SiO2, C-300, 50 g) and eluted with 5% methanol-containing chloroform to obtain 3-O-(6-O-trityl-α-D-galactopyranosyl)-1,2-di-O-tetradecyl-Sn-glycerol (4) (758 mg, 85.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
10% Palladium on carbon (250 mg) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 11.0 mmol) dissolved in methanol (150 mL). The flask was repeated evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. Purged with nitrogen gas. Filtered the crude reaction mixture through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (2.25 g, 100% yield) as a blackish/grey waxy solid. LC-MS (M+H)+204.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.69 (s, 1H) 7.01 (d, J=8.55 Hz, 1H) 6.82 (s, 1H) 6.33 (d, J=2.14 Hz, 1H) 6.30 (d, J=8.55 Hz, 1H) 3.78 (s, 3H) 2.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:22][N:36]=[C:25]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([NH2:33])(=[O:34])=[O:35])=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(Cl)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) (157 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as a light yellow solid (60 mg, 24%). MS (EI) 492.1 [(M)+]; mp 260° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[Cl:8]
Reactant: c1cn[nH]c1
Reactant: CS(=O)c1nc(N)c(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-n2cccn2)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
1 g (3.7 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)pyrimidine-4-amine (intermediate 2) was suspended in 10 ml of DMF. To this suspension were added 0.33 g (4.8 mmol) de pyrazole and 0.8 g of cesium carbonate. The reaction mixture was turned immediately light yellow color and allowed to stir at room temperature for about 1 to 2 hours. After nearly complete conversion to the corresponding monosubstituted derivative as was indicated by TLC the solution was poured onto 100 ml of cool water. The formed precipitated was filtered, washed with water and dried to afford 0.66 g (65%) of the desired product.
Reaction SMILES: C[O-].[Na+].[CH2:4]([OH:7])[CH2:5][OH:6].Br[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.[I-].[Na+]>[Cu]=O.CO>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[O:6][CH2:5][CH2:4][OH:7]
Reactant: Brc1cccs1
Reactant: OCCO
Agent: O=[Cu]
Agent: C[O-]
Agent: [I-]
Solvent: CO
Product: OCCOc1cccs1
Temperature: 80 °C
Reaction time: 175 h

Procedure:
323.7 ml of 5.4M sodium methylate solution (1.75 mol) are added to 1,600 ml of absolute ethylene glycol. The reaction mixture is heated and the methanol formed is distilled off over a reflux divider, while passing through nitrogen, until the bottom temperature rises to 130° C. When the removal of methanol has ended, 187.5 g (1.15 mol) of 2-bromothiophene, 55.5 g of finely ground copper oxide and 5.6 g of sodium iodide are added, the apparatus is further flushed briefly with nitrogen and closed with a flask and the mixture is stirred at 80° C. for 175 hours.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[O:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[O:11]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: c1ccc(Oc2ccc(NC3CN4CCC3CC4)cc2)cc1
Reaction time: 0.33 h

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) in acetic acid (25 mL) was treated with 4-phenoxyaniline (Aldrich, 0.93 g, 5.0 mmol), Na2SO4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)3 (Aldrich, 3.16 g, 15 mmol) at ambient temperature for 15 hours. The reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHCO3, stirred for 20 minutes, and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×20 mL). The organic phase was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as a solid (1.46 g, yield, 99%). 1H NMR (MeOH-d4, 300 MHz) δ 1.78–1.90 (m, 1H), 2.00–2.10 (m, 2H), 2.22–2.35 (m, 2H), 3.05 (ddd, J=12.9, 4.7, 2.0 Hz, 1H) 3.20–3.40 (m, 4H), 3.78 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.90–3.98 (m, 1H), 6.65–6.75 (m, 2H), 6.80–6.90 (m, 4H), 6.99 (tt, J=7.5, 1.0 Hz, 1H), 7.20–7.29 (m, 2H) ppm. MS (DCl/NH3) m/z 295 (M+H)+.
Reaction SMILES: CC1C=CC=CC=1O[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:24][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccccc1OCCCCC(=O)O
Reactant: Cc1cc(C)cc(O)c1
Product: Cc1cc(C)cc(OCCCCC(=O)O)c1

Procedure:
5-(3,5-Dimethylphenoxy)pentanoic acid 26d was prepared in the same manner as 26b, except that 3,5-dimethylphenol was used as the starting material. 1H NMR (CDCl3, 400 MHz): 6.58 (s, 1H), 6.51 (s, 2H), 3.94 (t, 2H, J=5.6 Hz), 2.44 (t, 2H, J=7.2 Hz), 2.27 (s, 6H), 1.83 (m, 4H). MS (ESI): 245 [M+Na]+.
Reaction SMILES: C([O:5][C:6](=[O:32])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[N:18]=[C:19]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:20]=[CH:21][C:22]=3[N:23]=2)=[CH:11][CH:10]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:19]1[N:20]=[CH:21][C:22]2[N:23]=[C:15]([C:12]3[CH:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:32])=[O:5])=[CH:14][CH:13]=3)[O:16][C:17]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Yield: 122 %

Procedure:
A solution of 145 mg (E)-3-{4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenyl}-acrylic acid tert-butyl ester in 2 ml of dichloromethane and 1 ml of trifluoroacetic acid was stirred at room temperature for 1.5 h. Then the mixture was concentrated in vacuo and freeze-dried. 154 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=[O:9])[C:7]#[CH:8]>C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:9])[CH3:2]
Reactant: CCNCC
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(C=CC(=O)Oc1ccc(-c2ccccc2)cc1)CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Diethylamine (66 mg, 0.89 mmol) and compound 1 (200 mg, 0.89 mmol) were dissolved in dry THF (20 mL), and the solution was stirred at RT for 15 min. The solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate:hexane (7:3) to give compound 2 (237 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.0 Hz, 6H), 3.28 (br. s, 4H), 4.79 (d, J=13.0 Hz, 1H), 7.20 (d, J=8.6 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.8 Hz, 2H), 7.62 (m, 4H), 7.63 (d, J=13.0 Hz, 1H). HRMS ESI (m/z): Calculated for C19H21NO2 ([M+H]+): 296.1572. found: 296.1647.
Reaction SMILES: Cl.[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([NH:36][CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:36][CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NC1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(=O)O)c(NC3CCOCC3)c2)cn1
Temperature: 100 °C
Yield: 35.6 %

Procedure:
5 ml of 1N hydrochloric acid are added to a solution of 0.47 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate in 4 ml of dioxane. The reaction mixture is heated at 100° C. in a microwave for 2 hours and then concentrated under reduced pressure. The residue is purified twice by silica gel chromatography, elution being carried out successively with a mixture of dichloromethane and methanol (98/2 by volume) and then with a mixture of cyclohexane and ethyl acetate (50/50 by volume), so as to give 150 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid in the form of a yellow powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Br:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27](I)=[CH:26][C:25]=1[Cl:33].C(=O)([O-])[O-].[Cs+].[Cs+].COC1CCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O)(C)C>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[CH:26]=[C:25]([Cl:33])[C:24]([Br:23])=[CH:29][C:28]=2[O:30][CH3:31])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: COc1cc(Br)c(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC1CCCC1
Solvent: CC(C)O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(Br)cc1OC
Temperature: 90 °C
Yield: 89.4 %

Procedure:
A flask was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (50.0 g, 160 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (66.5 g, 191 mmol), xantphos (4.62 g, 7.98 mmol), Pd2(dba)3 (3.65 g, 3.99 mmol), and cesium carbonate (72.8 g, 223 mmol). A reflux condenser was attached and the reaction placed under nitrogen atmosphere. CPME (319 ml) was added and the reaction was heated at 90° C. for 36 h. The mixture was cooled to rt and partitioned between 1000 mL of EtOAc and 1000 mL of water. The layers were separated and the aqueous layer was extracted with 200 mL of EtOAc. The combined organic layers were poured through a silica plug to provide a brown solution. The solution was concentrated until about 100 mL of solvent was left, giving a heterogeneous brown sludge. Isopropanol (500 mL) was added to the solution and a yellow solid precipitated. The yellow solid was collected by vacuum filtration (rinsing with 200 mL isopropanol) to provide desired product (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (76.4 g, 143 mmol, 90% yield) as a yellow solid. m/z (ESI) 531.9 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:35][CH:36]=1)(=[O:39])[CH3:38]
Reactant: COc1cccc(N(CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(N(CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c1
Yield: 96.4 %

Procedure:
Using 4-amino-N-{3-[4-(4-fluorobenzoyl)piperidino]propyl}-N-(3-methoxyphenyl)benzamide (300.0 mg, 0.61 mmol) and acetic anhydride (0.069 ml, 0.73 mmol), the procedure of inventive Example 94 was repeated to obtain 312.6 mg (96.5%) of the title compound in a light yellow amorphous form.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:6]1(=[O:23])=[O:22].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:27][CH:24]2[CH2:26][CH2:25]2)[S:6]1(=[O:23])=[O:22]
Reactant: O=S1(=O)N(CCCBr)Cc2ccccc2N1c1ccccc1F
Reactant: NC1CC1
Agent: Cl
Product: O=S1(=O)N(CCCNC2CC2)Cc2ccccc2N1c1ccccc1F
Yield: 94 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(3-bromopropyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{3-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propyl}cyclopropanamine (0.089 g, 94%) as a white solid: