Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=2[OH:52])=[CH:38][N:37]=1>CS(C)=O>[Cl:1][C:2]1[C:3]([O:52][C:43]2[CH:44]=[CH:45][C:46]([C:48]([F:49])([F:50])[F:51])=[CH:47][C:42]=2[C:39]2[CH:40]=[CH:41][N:36]=[N:37][CH:38]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 84.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247, 378.0 g, 0.761 moles) was dissolved in dimethylsulphoxide (1.9 L). Potassium carbonate (117.8 g, 0.8524 moles) was added and stirred to give a suspension to which was added 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 182.8 g, 0.761 moles) in one portion. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (2.7 L) and aqueous sodium hydroxide solution (2.5 L of 1 molar). The organic phase was washed with water (2×2 L) and then saturated aqueous sodium chloride solution (250 mL). The solution was concentrated in vacuo to give the crude title product. The crude product was purified by column chromatography on silica gel (2 Kg) eluting with ethyl acetate/heptane (3:1). The cleanest fractions were combined and the solvents removed in vacuo to give the title compound as a dark red foam, (440 g). This material was dried in vacuo at 45° C. for 48 hours to give the title compound as a red solid (400 g).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:11]=[C:10]2[C:22]1[N:27]=[C:26]([O:28][C@H:29]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]32[CH2:32][CH2:31]3)[CH:25]=[N:24][CH:23]=1)[CH3:6].CC(O)=O>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:4][C:5]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:11]=[C:10]3[C:22]2[N:27]=[C:26]([O:28][C@H:29]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]43[CH2:32][CH2:31]4)[CH:25]=[N:24][CH:23]=2)[CH2:3][CH2:6]1
Reactant: C=[N+]=[N-]
Reactant: C=C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C)CC5)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Diazomethane (˜0.25M in Et2O (prepared according to Aldrich Technical Bulletin AL-180, Aldrich, St. Louis, Mo.); 2.0 mL, 0.500 mmol) was added dropwise to a solution of (4R)-tert-butyl 4-(6-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (110.4 mg, 0.202 mmol) and palladium(II) acetate (4.54 mg, 0.020 mmol) in DCM (2.0 mL) at 0° C. and the resulting solution was stirred at 0° C. for 30 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min. HOAc (0.069 mL, 1.214 mmol) was added to quench excess diazomethane, and the resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (96.3 mg, 0.172 mmol, 85% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (1 H, s), 8.28 (1 H, s), 8.19 (1 H, br. s.), 7.57 (1H, d, J=8.8 Hz), 7.37 (1 H, d, J=8.4 Hz), 5.78 (1 H, d, J=9.0 Hz), 4.68 (1 H, d, J=8.0 Hz), 4.49 (1 H, br. s.), 4.28 (1 H, d, J=11.9 Hz), 4.03 (1 H, d, J=11.3 Hz), 3.70-3.84 (1 H, m), 3.28 (1 H, d, J=13.7 Hz), 2.97 (1 H, t, J=11.2 Hz), 2.57-2.73 (1 H, m), 2.41-2.54 (1 H, m), 2.16-2.28 (1 H, m), 2.07-2.15 (1 H, m), 1.63-1.86 (3 H, m), 1.47 (4 H, s), 1.12 (9H, br. s.), 0.85-0.93 (2 H, m), 0.80 (2 H, br. s.), 0.73 (1 H, br. s.), 0.62 (1 H, br. s.), 0.56 (2 H, br. s.). MS (ESI, pos. ion) m/z: 560.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH2:11][C:12]#[CH:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:26][C:27](OCC)=[O:28].N1CCCCC1>C(O)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:26]1[C:27](=[O:28])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH2:11][C:12]#[CH:13])[CH:9]=2
Reactant: CCOC(=O)Cc1nc2ccccc2s1
Reactant: C#CCN(c1ccc(C=O)c(O)c1)C(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: C#CCN(c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1)C(C)C
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution in which the 2-hydroxy-4-(isopropyl(prop-2-ynyl)amino)benzaldehyde (1.8 g, 8.28 mmol) compound of Chemical Formula 4 was dissolved in ethanol (15 mL), ethyl 2-(benzo[d]thiazol-2-yl)acetate (1.83 g, 8.28 mmol) and piperidine (1.63 mL, 16.56 mmol) were added consecutively at room temperature. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and 3-(benzo[d]thiazol-2-yl)-7-(isopropyl(prop-2-ynyl)amino)-2H-chromen-2-one (1.54 g, 50%) was obtained by filtering the precipitated solid. 1H NMR (500 MHz, CDCl3) d 8.94 (s, 1H), 8.02 (d, 1H, J=8.2 Hz), 7.94 (d, 1H, J=7.8 Hz), 7.54 (d, 1H, J=8.7 Hz), 7.47-7.50 (m, 1H), 7.35-7.38 (m, 1H), 6.88 (dd, 1H, J=2.3, 8.7 Hz), 6.80 (d, 1H, J=2.3 Hz), 4.21-4.26 (m, 1H), 4.04 (d, 2H, J=2.3 Hz), 2.26 (t, 1H, J=2.2 Hz), 1.34 (d, 6H, J=6.4 Hz); 13C NMR (125 MHz, CDCl3) d 161.5, 161.0, 156.7, 152.6, 152.4, 142.0, 136.4, 130.6, 126.2, 124.7, 122.3, 121.7, 113.9, 111.0, 109.8, 98.8, 80.0, 72.3, 49.5, 33.5, 20.2 (2).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5](S(C2C=CC=CC=2)(=O)=O)=[N:4][CH:3]=1.[F-:19].[K+].C(OCC)(=O)C.O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([F:1])=[CH:3][N:4]=1
Reactant: N#Cc1nc(F)cnc1S(=O)(=O)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(F)cnc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
In 4 mL of dimethyl sulfoxide was dissolved 0.40 g of 6-fluoro-3-(phenylsulfonyl)-2-pyrazinecarbonitrile. After adding 0.44 g of potassium fluoride and 0.10 g of tetra-n-butylammonium bromide successively, the mixture thus obtained was stirred at 60° C. for 1.5 hours. The reaction mixture was poured into a mixture of 20 mL of ethyl acetate and 20 mL of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=20:1] to obtain 0.06 g of 3,6-difluoro-2-pyrazinecarbonitrile as a colorless solid product.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[CH2:40]([CH2:42][NH2:43])[OH:41]>>[OH:41][CH2:40][CH2:42][NH:43][C:32]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([N:13]3[CH:14]4[CH2:20][CH2:19][CH:18]3[CH2:17][O:16][CH2:15]4)[N:10]=2)=[CH:22][CH:23]=1)=[O:38]
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: NCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C(NCCO)Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Yield: 52.7 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and ethanolamine (11 mg, 0.18 mmol) gave the title compound as off-white solid (14.4 mg, 53% yield). MS (ESI) m/z 456.5.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1.CCN(CC)CC>CC(O)C.CCOC(C)=O>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)[N:11]=[CH:10]2
Reactant: COC(=O)C1CCNCC1
Reactant: COc1ccc2nc(Cl)ncc2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ncc3cc(OC)ccc3n2)CC1
Temperature: 50 °C
Yield: 101.4 %

Procedure:
A mixture of 2-chloro-6-methoxyquinazoline (Intermediate 8, 700 mg, 3.60 mmol), methyl 4-piperidinecarboxylate (2.58 g, 18.0 mmol) and Et3N (729 mg, 7.20 mmol) in iPrOH (15 mL) was heated to 50° C. for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (30 mL×2) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (0.1% TFA as additive). Most of CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the product (1.10 g, yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22]>C(Cl)Cl.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([S:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)CSC(CCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
To a suspension of the alcohol (0.23 g) (Step VI) in CH2Cl2 (5 mL) and methyl thioglycolate (80 μL) was added ZnI2 (10 mg). The mixture was stirred 2 hrs, buffer (pH 7) was added. The mixture was extracted with ethyl acetate, which was dried and evaporated. Flash chromatography using 5% ethyl acetate in toluene afforded the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].F[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>CCO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COCCNCCOC
Solvent: CCO
Product: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Bis(2-methoxyethyl)amine (Aldrich B4,820-7; 1.6 g; 12 mmol; 3 eq.) was added to a solution of 4-fluoro-3-nitrobenzoic acid (740 mg; 4 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at room temperature for 2 hours then at 70° C. for 20 hours. The solution was concentrated in vacuo and the residue was partitioned between NaOH 0.5M and Et2O. The aqueous layer was acidified to pH 2 with HCl 5M, extracted with ethyl acetate (3×) and the combined organic phase was dried over magnesium sulfate. After evaporation of the solvent, the residue was crystallised from ethyl acetate/n-pentane to afford the title compound (1.12 g, 94%) as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:21][CH:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:19][C:18](=O)[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[CH2:32]([Mg]Br)[CH3:33].N1C=CC=CC=1.S(Cl)(Cl)=O>C1COCC1>[CH2:32]([C:18]1[CH2:19][CH:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:14]2([CH2:13][CH2:12][N:11]([C:9]([C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH3:31])[CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH:17]=1)[CH3:33]
Reactant: CC[Mg]Br
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2cccnc2)O3)ccc1OC(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1=CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2cccnc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
A solution of 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-8-one (148 mg, 0.35 mmol) in THF (1.8 mL) was cooled to 0° C. and treated with ethyl-magnesium bromide (42 μL of 1 M, 0.42 mmol). The reaction mixture was stirred for 2 h and was quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was diluted with dichloromethane (2 mL) and treated with pyridine (34 μL, 0.42 mmol). The reaction mixture was cooled to 0° C. and treated with thionyl chloride (28 μL, 0.39 mmol) dropwise. The reaction mixture was stirred for 90 min, quenched with ice-cold water (5 mL), and diluted with CH2Cl2 (80 mL). The mixture was washed with dilute HCl (5%, 2×15 mL), water (2×20 mL), and sodium bicarbonate (5%, 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified on silica gel utilizing a gradient 50-100% ethyl acetate in hexanes to yield [8-ethyl-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-7-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (90 mg) ESI-MS m/z calc. 434.26, found 435.3 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[OH:8].[C:16]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>CO.O=[Pt]=O>[Cl:15][C:11]1[CH:10]=[C:9]([C@@H:7]([OH:8])[CH2:6][NH:5][CH:25]2[CH2:24][CH2:23][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: O[C@@H](CNC1CCC(c2ccccc2)CC1)c1cccc(Cl)c1
Yield: 3.7 %

Procedure:
Acetic acid (1 ml) and PtO2 (160 mg) were added to a solution of (R)-2-amino-1-(3-chlorophenyl) ethanol (600 mg) and 4-phenylcyclohexanone (610 mg) in methanol (30 ml), and hydrogen addition was carried out at room temperature. After consumption of the starting materials, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Separation and purification by silica gel column chromatography (chloroform:methanol=30:1) gave 43 mg of (1R)-1-(3-chlorophenyl)-2-(4-phenylcyclohexylamino) ethanol (4.0% yield).
Reaction SMILES: I[CH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C([O-])(O)=O.[Na+]>[C:22]([O:21][C:20]([NH:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([CH2:2][C:3]2([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:17][CH2:16]1)=[O:26])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C1(CI)CCCC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of Methyl 1-(iodomethyl)cyclopentanecarboxylate (5.52 g, 0.0206 mol, Step 1), tert-butyl (piperidin-4-ylmethyl)carbamate (8.83 g, 0.0412 mol) and iPr2NEt (10.76 mL, 0.0618 mol) in N-methylpyrrolidone (70 mL) was stirred at 120° C. for 24 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (200 mL), extracted with AcOEt (200 mL) for three times, and the combined organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:1) to give 4.91 g (67%) of title compound as a yellow syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:20]1[NH:25][C:24](=[O:26])[C:23]2=[C:27]([CH3:35])[N:28]=[C:29]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:22]2[N:21]=1)[CH3:2].[ClH:36]>C(OCC)C>[ClH:36].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:19][CH:14]2[CH3:15])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:20]1[NH:25][C:24](=[O:26])[C:23]2=[C:27]([CH3:35])[N:28]=[C:29]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[N:22]2[N:21]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Product: CCOc1ccc(S(=O)(=O)N2CCNCC2C)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 mg (0.42 mmol) of 2-[2-ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 1) are suspended in 20 ml of diethyl ether and, after addition of 20 mg (0.462 mmol) of 1 molar ethereal HCl solution, stirred at room temperature for 30 minutes. The solvent is distilled off under reduced pressure and the residue is dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:14]=[C:15]([OH:20])[C:16]([OH:19])=[CH:17][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:18]2[CH:17]=[C:16]([OH:19])[C:15]([OH:20])=[CH:14][C:13]=2[CH3:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: COc1ccc(S(=O)O)cc1
Product: COc1ccc(S(=O)(=O)c2cc(O)c(O)cc2C)cc1

Procedure:
37.5 g of 4-methoxybenzenesulphinic acid (obtained, for example, by reduction of 4-methoxybenzenesulphonyl chloride with sodium sulphite) are condensed oxidatively with 30.7 g of 4-methyl-1,2-benzenediol in a manner analogous to that described in Example 5a) and, after crystallisation from 1,2-dichloroethane, 4-(4-methoxyphenylsulphonyl)-5-methyl-1,2-benzenediol is obtained in the form of colourless crystals having a melting point of 145°-147.5°.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:13](OC1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(CC)CC)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:43]3[CH2:48][CH2:47][N:46]([C:13]([NH:11][CH:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)=[O:14])[CH2:45][CH2:44]3)=[CH:38][CH:39]=[N:40]2)=[CH:35][CH:34]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCc2ccccc21)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
1,2,3,4-Tetrahydronaphthylamine (36 μL, 0.25 mmol), 4-nitrophenyl chloroformate (51 mg, 0.25 mmol), triethylamine (140 μL, 1.0 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) are treated according to method D delivering the title product as a colorless oil after column chromatography with hexane-EtOAc.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>>[Br-:23].[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][CH2:22][SH+:21][CH2:20][C:11]1([OH:19])[CH2:12][CH2:13][CH:14]([OH:18])[CH:15]([O:16][CH3:17])[CH:10]1[C:2]1([CH3:9])[O:1][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8]
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reactant: BrCc1ccccc1Br
Product: COC1C(O)CCC(O)(C[SH+]CCc2ccccc2Br)C1C1(C)OC1CC=C(C)C
Product: [Br-]
Yield: 8.3 %

Procedure:
As in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) was allowed to react with 2-bromobenzyl bromide (1.51 g) to give 1-(2-bromobenzyl)methylsulfoniomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol bromide (29 mg: yield 8%) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3C(OC)=O)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.[NH3:35].[CH3:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:36](=[O:37])[NH2:35])[CH:25]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cnccc1N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CO
Reactant: N
Product: NC(=O)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reaction time: 4 h
Yield: 96 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-[[1-(3-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino]benzamide (50 mg, 0.10 mmol) and 2 N ammonia in methanol (5 mL), sealed, and placed in a 110° C. bath. After 4 h, the mixture was transferred to a 60° C. bath. After 3 days, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2, 2% methanol in methylene chloride) affording 48 mg (96%) of the title compound.
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: [Li]C(C)(C)C
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in ether (100 mL) under an argon atmosphere at −78° C., was added tert-butyl lithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in ether (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with ether (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil; Yield: 0.47 g (40%). (53% de 3R,4S: 47% de 3S,4S) 1H-NMR (d6-DMSO, 250 MHz): δ 0.37+0.87 (2×t, 3H, J=7.46 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 0.58+0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.38-1.52 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.00 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.28 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.24+4.79 (2×d, 1H, J=5.21+6.16 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.15-7.53 (m, 15H, 3×Bz).