Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][C:3]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14].[H-].[Na+].[CH3:23]I.[Na]>CN(C)C=O>[OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH3:23])[C:3]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:14]
Reactant: O=C(Nc1nccs1)C1=C(O)c2sccc2S(=O)(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.329 g (1 mmol) of 4-hydroxy-N-(2-thiazolyl)-2H-thieno-[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide are dissolved in 2 ml of absolute dimethylformamide and added at 0° C to a stirred suspension of 0.026 g (1.1 mmol) of sodium hydride in 1 ml of absolute dimethylformamide. The mixture is stirred at room temperature for a further 1 hour. 0.1 ml (0.226 g; 1.6 mmol) of methyl iodide are then added to the sodium salt solution and allowed to react for a further 1 hour. After distillation of the solvent, the residue is taken up in 200 ml of methylene chloride and 10 ml of 0.5-N hydrochloric acid. The organic phase is separated and shaken out with a total of 50 ml of a 0.5% sodium bicarbonate solution. The aqueous layer, which now contains the desired product, is back-extracted several times with methylene chloride and acidified with hydrochloric acid. The acidic aqueous phase is extracted with methylene chloride and the combined organic extracts dried over sodium sulphate and evaporated. The crystalline residue is digested with a small amount of cold ethanol for purification. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno-[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 217° C (decomposition).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(O)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.4 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxypiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.34 g, 1.33 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 7 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-ylpiperidin-4-ol as a colourless oil (0.194 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 3.75-3.68 (m, 1H); 3.67-3.51 (m, 4H); 3.25-3.17 (m, 1H); 2.66-2.56 (m, 3H); 2.03-1.84 (m, 5H); 1.65-1.53 (m, 2H).
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=O)[CH3:2].[CH3:7][O:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.II.[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:4]=[N:15][C:10]2[C:11]([CH:6]=1)=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH3:7])[CH3:2]
Reactant: C=C(C=O)CC
Reactant: COc1ccccc1N
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1cnc2c(OC)cccc2c1
Temperature: 110 °C

Procedure:
Freshly distilled 2-ethyl acrolein (1.7 ml) was added, over 20 minutes, to a solution of o-anisidine (1.5 g) and iodine (20 mg) in 70% sulphuric acid (10 ml) stirring at 110° C. After 2 hours the reaction was cooled to 0° C. and basified with 25% aqueous sodium hydroxide (pH 13). The aqueous layer was extracted with ethyl acetate (2×100 ml) and the extracts combined. The organic layer was extracted with 2M hydrochloric acid (2×100 ml) and the combined acidic extracts basified once again with 25% sodium hydroxide. The aqueous layer was extracted with ethyl acetate (2×100 ml), the extracts combined, dried over magnesium sulphate, filtered, and the filtrate evaporated in vacuo. The residue was purified by column chromatography, eluting with 25%-50% ethyl acetate in hexane, to yield the title product as a tan oil (0.42 g).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:47]1[CH:52]=[C:51]([S:53][CH3:54])[N:50]=[C:49]([S:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=2[F:64])[N:48]=1.[Cl-].[NH4+]>O1CCOCC1.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]>[F:64][C:58]1[C:59]([F:63])=[CH:60][CH:61]=[CH:62][C:57]=1[CH2:56][S:55][C:49]1[N:48]=[C:47]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:52]=[C:51]([S:53][CH3:54])[N:50]=1
Reactant: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of methane sulfonamide (0.22 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.58 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-(methylthio)pyrimidine (the product of step i) (0.38 g) in dioxane (10 mL) was heated at 100° C. for 18 h. The mixture was cooled and saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% TFA mixtures to give the title compound as a white solid. Yield: 30 mg.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=O)[C:7](=[O:17])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:2]=4[F:1])=[CH:6][C:7]3=[O:17])[CH2:14][CH2:15][CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCC[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.086 g, 0.28 mmol) in dry N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.068 g, 0.34 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.183 g, 0.41 mmol). To this mixture was added N,N-diisopropylethylamine (0.109 g, 0.85 mmol) and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with an ammonium chloride solution, a saturated sodium bicarbonate solution, saturated sodium chloride solution and then dried over magnesium sulfate. The solvents were evaporated and the residue was purified by AnaLogix flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 100% ethyl acetate) which afforded (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.102 g, 75%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.2 Hz, 3H), 1.10-1.43 (m, 2H), 1.25 (s, 3H), 1.30 (s, 3H), 1.77 (q, J=7.7 Hz, 2H), 3.73 (dd, J=8.5, 6.0 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.20 (m, 2H), 4.24-4.41 (m, 2H), 4.61 (d, J=18.7 Hz, 1H), 4.79 (t, J=7.7 Hz, 1H), 5.03 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.27-7.51 (m, 3H), 7.60 (d, J=2.1 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][O:17][C@H:18]1[CH2:25][N:24]2[C:26]3[CH:27]=[C:28]([C:39]([O:41][CH3:42])=[O:40])[CH:29]=[CH:30][C:31]=3[C:32]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:23]2[C:22]2[CH:43]=[CH:44][CH:45]=[CH:46][C:21]=2[O:20][CH2:19]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1([C:32]2[C:31]3[CH:30]=[CH:29][C:28]([C:39]([O:41][CH3:42])=[O:40])=[CH:27][C:26]=3[N:24]3[C:23]=2[C:22]2[CH:43]=[CH:44][CH:45]=[CH:46][C:21]=2[O:20][CH2:19][C@@H:18]([O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][NH:8][CH3:6])[CH2:25]3)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1CCN(C)C(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of methyl (7S)-7-[(1-{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}pyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.06 M) in DCM was treated with an excess of TFA (>50 eq). The mixture was stirred at RT for 2 h. Volatiles were removed in vacuo and the residue partitioned between EtOAc and sat. aq. NaHCO3. The aqueous was extracted with EtOAc and the organics combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (82%). The material was taken on without further purification. (ES+) m/z 546 (M+H)+.
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)=O.O.[NH2:15][NH2:16].C(O)C(C)C>O>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:2])[NH:15][NH2:16])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: NN
Reactant: COC(=O)Nc1cc(F)cc(Cl)c1
Solvent: O
Solvent: CC(C)CO
Product: NNC(=O)Nc1cc(F)cc(Cl)c1
Temperature: 25 °C

Procedure:
N-methoxycarbonyl-3-chloro-5-fluoroaniline (51.8 gms, 254M) is added to a mixture of hydrazine hydrate (125 ml) and isobutyl alcohol (160 ml). The mixture is heated to 100° for 10 hours under nitrogen. The solution is cooled to room temperature, diluted with water and filtered. The solid is rinsed with water (2×) and dried under vacuum to give 4-(3-chloro-5-fluorophenyl)semicarbazide as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:6]=2[NH:5][CH2:4]1.[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:9]=3[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])c1cc2c(c3ccccc13)C(CCl)CN2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2c3c(cc([N+](=O)[O-])c12)NCC3CCl
Temperature: 0 °C
Yield: 76.3 %

Procedure:
A stirred solution of 102 (500 mg, 1.90 mmol) in conc. H2SO4 (5 mL) was cooled to −5° C. and treated with powdered KNO3 (288 mg, 2.85 mmol). The mixture was stirred at 0° C. for a further 15, in, then poured into ice-water and the solid was collected and dissolved in CH2Cl2. The solution was filtered through a column of silica gel and the product was recrystallised from EtOAc/iPr2O to give 1-(chloromethyl)-5,6-dinitro-1,2-dihydro-3H-benzo[e]indole (103) (446 mg, 76%) as a red solid: mp 206-207° C.; 1H NMR [(CD3)2SO] δ 8.23 (dd, J=8.7, 1.0 Hz, 1H), 8.00 (dd, J=7.7, 0.9 Hz, 1H), 7.76 (s, 1H), 7.67 (dd, J=8.4, 7.6 Hz, 1H), 6.72 (s, 1H), 4.32-4.22 (m, 1H), 3.94-3.83 (m, 2H), 3.83-3.75 (m, 2). Anal. (C13H10ClN3O4) C, H, N.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[CH2:7]([NH:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:21][CH2:22]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCNC(=O)CN1CCN(CCCO)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCNCCN1CCN(CCCO)CC1
Yield: 41.1 %

Procedure:
Lithium aluminum hydride (380 mg, 10 mmol) was added to a solution of this amide (1.50 g, 5.0 mmol) in THF (50 ml) with ice-cooling and stirring and the mixture was returned to room temperature and stirred for 15 minutes and then heated to reflux for 2 hours. Under ice-cooling and stirring, a saturated ammonium chloride solution was gradually added thereto until the reaction solution became turbid, the separated matters were filtered off through celite, the filtrate was dried over anhydrous sodium carbonate and the solvent was evaporated therefrom. The resulting residue was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20) to provide 586 mg (yield 41%) of 3-[4-(2-heptylaminoethyl)piperazin-1-yl]propanol as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:35][CH:36]([F:38])[F:37])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1.[NH2:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48])[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:35][CH:36]([F:37])[F:38])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1
Reactant: CCC[C@H](N)CCO
Reactant: CCOC(=O)CCN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)CC(F)F
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CCC(=O)OCC)CC(F)F)cc1OC
Yield: 79 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (190 mg) (S)-3-aminohexan-1-ol (110 mg). The sub-title compound (130 mg) was obtained as a colourless gum; 1H NMR (CDCl3); 6.91 (1H, s), 6.87 (1H, d), 6.79 (1H, d), 5.72 (1H, tt), 5.69 (2H, br s), 4.19-4.15 (2H, m), 4.11 (2H, q), 3.89 (3H, s), 3.65-3.64 (4H, m), 3.45-3.40 (1H, m), 3.21 (1H, ddd), 2.90 (2H, t), 2.78 (2H, dt), 2.48-2.43 (5H, m), 1.85-1.74 (1H, m), 1.49-1.37 (1H, m), 1.32-1.17 (5H, t), 1.09-0.99 (2H, m), 0.77 (3H, t).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1>CC(C)=O>[CH3:21][C:20]1([CH3:25])[O:8][C@@H:7]2[CH2:6][CH2:5][CH2:4][C@@H:3]([N:9]3[C:10](=[O:19])[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17]3=[O:18])[C@@H:2]2[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H](O)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2[C@H](N3C(=O)c4ccccc4C3=O)CCC[C@H]2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 2-[(1R,2S,3R)-2,3-dihydroxycyclohexyl]-1H-isoindole-1,3(2H)-dione (19) (50.0 g, 191.4 mmol) and 2,2-methoxypropane (500 mL, 4.07 mol) in acetone (500 mL), a catalytic amount of p-toluenesulfonic acid was added and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated Na2CO3 solution to adjust the pH to 10 and the solvent was removed. Water (750 mL) was added to the residue and extracted with ethyl acetate (2×750, 500 mL). The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a white solid (55.8 g, 96.8% yield). LC/MS [Method B: rt: 6.16 min; m/z: 302 (M+1)].
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CO>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]=[C:22]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Temperature: 65 °C

Procedure:
KOH (2.12 g, 37.8 mmole), indole (1.0 g, 8.54 mmole) and 1-benzyl-3-piperidone hydrochloride (4.82 g, 21.34 mmole) were suspended in methanol (20 ml) and heated for 8 hours at 65° C. under argon. Water (40 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The methanol was distilled off and the aqueous phase was extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. 3-(1-benzyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-indole was purified by chromatography with cyclohexane/EE (1:1). The product was obtained as a yellow solid in a yield of 860 mg (35%) and an m.p. of 105°-107° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C[O:17][C:18]([NH:20][NH2:21])=[S:19]>C(#N)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]2[CH2:2][S:19][C:18](=[O:17])[NH:20][N:21]=2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: COC(=S)NN
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)CCl
Solvent: CC#N
Product: O=C1NN=C(C=Cc2ccc([N+](=O)[O-])cc2)CS1

Procedure:
A solution containing 11.2 g of 1-chloro-4-(4-nitrophenyl)-2-oxo-3-butene (J. Org. Chem. 28, 2446, 1963) and 6.8 g of hydrazinecarbothioic acid O-methylester in 200 ml of acetonitrile was refluxed for 3 h. The crystals were filtered and washed with acetonitrile and ether. Yield 7.7 g (59%), mp. 231°-240° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])C3C=CC=CC=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:41]C(N)=O)C3CCCCC3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:45].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:16]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:41])[C:5]([NH:6][CH:7]3[CH2:8][CH2:30][CH2:31][CH2:32][CH2:33]3)=[O:45])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc2ccc(N(CC(N)=O)C3CCCCC3)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-(N-cyclohexyl-aminocarbonylmethylamino)benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:6])(=O)C>CO.[OH-].[Na+]>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][N:14]=2)=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(C)=O)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
4 g of the above product (-)-(4-(1-acetoxyethyl) phenyl)-5-decyloxypyrimidine was dissolved in a mixture of 50 ml of methanol and 10 ml of a 20% sodium hydroxide solution, stirred at 30° C. for 2 hours and hydrolyzed, and the resulting reaction solution was extracted by adding 200 ml of water and 200 ml of toluene, followed by liquid separation. The obtained organic layer was dried over anhydrous magnesium sulfate and cleared of solvent in vacuo to yield 3.5 g of (-)-(4-(1-hydroxyethyl) phenyl)-5-decyloxypyrimidine as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[CH2:40][C:39](=[O:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[C:40]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:39]([OH:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Reactant: O=C1CC(=O)OC(CCc2ccc(OCC3CC3)c(Cl)c2)(C2CCCC2)C1
Agent: Cc1nc(CCl)n(C)n1
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(OCC5CC5)c(Cl)c4)(C4CCCC4)OC3=O)cc(=O)n12
Yield: 1 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-(1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-{-[3-chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (from Step 4, below) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 1%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:28]1([CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][N:22]2[C:2]2[N:15]=[CH:14][C:13]3[C:12]4[N:8]([CH:9]=[C:10]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=5)[N:11]=4)[CH2:7][CH2:6][O:5][C:4]=3[CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Clc1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Reactant: C1CCN(CC2CCCN2)CC1
Solvent: CN1CCCC1=O
Product: c1ccc(-c2cn3c(n2)-c2cnc(N4CCCC4CN4CCCCC4)cc2OCC3)nc1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
To a solution of 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (200 mg, 0.671 mmol) in NMP (10 mL) was added TEA (10 mL) and 1-(pyrrolidin-2-ylmethyl)piperidine (135 mg, 0.804 mmol). The reaction mixture was stirred at 160° C. for 24 h. After cooling to room temperature, the reaction mixture was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 129 which was further purified by chiral HPLC (AS-H column, 10% EtOH isocratic) to separate 15.9 mg of one enantiomer and 7 mg of the other (8% total yield). LCMS (ESI): RT=4.55 min, m/z: 431.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.50-8.49 (d, J=4.0 Hz, 1H), 7.97-7.95 (d, J=8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.22-7.19 (m, 1H), 5.95 (s, 1H), 4.49-4.44 (m, 4H), 4.17 (m, 1H), 3.46-3.44 (m, 1H), 3.28-3.25 (m, 1H), 2.54 (m, 1H), 2.45-2.33 (m, 3H), 2.21-2.16 (m, 1H), 2.01-1.97 (m, 2H), 1.94-1.86 (m, 2H), 1.53-1.50 (m, 4H), 1.39-1.38 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[O:15][CH:14]=[N:13][CH:12]=1)[C:5]([OH:7])=O.C(OC([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:30]1([N:29]([CH:26]2[CH2:27][CH2:28][NH:23][CH2:24][CH2:25]2)[C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)=[C:2]([F:1])[CH:3]=2)[CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1

Procedure:
The title compound is prepared from 3-fluoro-4-oxazol-5-yl-benzoic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 1. The deprotection step is accomplished by using trifluoroacetic acid in dichloromethane. LC (method 2): tR=0.98 min; Mass spectrum (ESI+): m/z=330 [M+H]+.