Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3cccnc3)ccc2n1C)c1ccc(C(=N)N)cc1
Yield: 70 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 70% of theory, C26H27N7O3 (485.6); EKA mass spectrum: (M+H)+=486; (M+Na)+=508; (M+2Na)++=265.6.
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:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][C:18](=[O:28])[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:3])[CH3:2].Cl[Ce](Cl)Cl.[BH4-].[Na+]>CO>[OH:28][C@H:18]1[CH2:19][C@@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:14]2([CH2:15][CH2:16][N:11]([C:9]([C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([O:31][CH3:32])[CH:7]=3)=[O:10])[CH2:12][CH2:13]2)[CH2:17]1.[OH:28][C@H:18]1[CH2:19][C@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:21][C:14]2([CH2:15][CH2:16][N:11]([C:9]([C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([O:31][CH3:32])[CH:7]=3)=[O:10])[CH2:12][CH2:13]2)[CH2:17]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2ccccc2)O3)ccc1OC(C)C
Agent: Cl[Ce](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)C[C@@H](O)C[C@@H](c2ccccc2)O3)ccc1OC(C)C
Product: COc1cc(C(=O)N2CCC3(CC2)C[C@@H](O)C[C@H](c2ccccc2)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4-isopropoxy-3-methoxy-benzoyl)-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-8-one (4.50 g, 10.3 mmol) in MeOH (110 mL) was added trichlorocerium (2.79 g, 11.3 mmol). The mixture was stirred at room temperature for 5 minutes. Sodium borohydride (467 mg, 12.4 mmol) was added. The mixture was stirred at room temperature for 20 minutes. The reaction was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide [cis-8-hydroxy-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (1.5 g) and [trans-8-hydroxy-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (1.3 g). cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.43-7.33 (m, 4H), 7.33-7.27 (m, 1H), 6.96 (d, J=1.6 Hz, 1H), 6.95-6.90 (m, 1H), 6.86 (d, J=8.2 Hz, 1H), 4.65-4.48 (m, 2H), 4.23-4.05 (m, 2H), 3.95-3.75 (m, 1H), 3.85 (s, 3H), 3.49 (s, 1H), 3.20 (s, 1H), 2.25 (dd, J=20.6, 8.4 Hz, 2H), 1.98 (dd, J=12.5, 2.9 Hz, 1H), 1.73 (s, 2H), 1.62-1.40 (m, 3H), 1.37 (t, J=6.0 Hz, 6H). ESI-MS m/z calc. 439.24, found 440.4 (M+1)+; Retention time: 1.49 minutes (3 minute run). trans-isomer 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.39-7.33 (m, 2H), 7.31-7.24 (m, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.92 (dd, J=8.2, 1.8 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 4.97 (d, J=11.2 Hz, 1H), 4.55 (dt, J=12.2, 6.1 Hz, 1H), 4.44-4.32 (m, 1H), 4.05-3.75 (m, 2H), 3.85 (s, 3H), 3.49 (s, 1H), 3.24 (s, 1H), 2.77 (dd, J=25.2, 13.7 Hz, 1H), 1.96 (d, J=13.4 Hz, 1H), 1.84-1.70 (m, 2H), 1.70-1.54 (m, 5H), 1.37 (d, J=6.1 Hz, 6H). ESI-MS m/z calc. 439.24, found 440.2 (M+1)+; Retention time: 1.61 minutes (3 minute run).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11].O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11])[NH2:16]
Reactant: NN
Reactant: CS(=O)(=O)c1cc(C#N)ccc1F
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1NN
Yield: 79 %

Procedure:
A suspension of 4-fluoro-3-(methylsulfonyl)benzonitrile (1.96 g, 9.83 mmol) in IMS (30 mL) was treated with hydrazine monohydrate (1.19 mL, 24.8 mmol) and then heated at reflux for 1 hr. The reaction mixture was cooled then filtered and the solid residue was collected and dried in vacuo to afford the title compound as a cream solid (1.64 g).
Reaction SMILES: [C:1]([OH:9])(=O)[C@H:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH3:10][NH2:11]>C1(C)C=CC=CC=1>[OH:3][C@H:2]1[CH2:4][C:5](=[O:6])[N:11]([CH3:10])[C:1]1=[O:9]
Reactant: CN
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: Cc1ccccc1
Product: CN1C(=O)C[C@H](O)C1=O

Procedure:
To a stirred solution of 134 g (1 mole) of (S)-malic acid in 700 ml of toluene was added 97 ml of 40% aqueous methylamine. The temperature slowly rose to 50° C. After 0.5 hr the stirred mixture was heated to reflux and the water was collected in a Dean-Stark trap for 48 hr. A total of 93 ml of water was collected. The toluene residue was treated with 300 ml of ethanol and concentrated on the rotary evaporator. The residue was distilled. The yield of product obtained was 101 g (78%), b.p 140°/2 mm; 145°/0.5 mm.
Reaction SMILES: N1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2N=C1.[I:10]N1C(=O)CCC1=O.[C:18](#[N:20])[CH3:19]>>[I:10][C:19]1[N:9]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]2=[N:20][CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC#N
Reactant: c1cnc2nc[nH]c2c1
Product: Ic1cnc2ccccn12
Temperature: 25 °C

Procedure:
A solution of 11.61 g (98.27 mmol) of imidazopyridine in 100 mL of acetonitrile was placed in a 250 mL three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 24.32 g (108.1 mmol, 1.1 eq.) of solid N-iodosuccinimide was added portion-wise to the flask at 0° C., and the resulting yellow suspension was allowed to warm to room temperature overnight. The solvent was removed on rotavap to give the dark solid (39.2 g). This residue was re-dissolved in 0.5 L of dichloromethane and washed with 10% KOH (2×250 mL). The organic phase was separated, washed with water (200 mL), and dried over Na2SO4. The solvent was removed on rotavap, and the remaining dark material was re-crystallized from boiling ethyl acetate upon the addition of hexane. The precipitated solid was filtered, washed with 40 mL of hexane, and dried under nitrogen flow until constant weight. The yield was 20.8 g (86%) of white solid with Rf=0.42 (in EtOAc/hexane=1:1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[N:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[N:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccnc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ncccc2C(=O)O)o1
Yield: 39.6 %

Procedure:
The title compound was prepared from methyl 2-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinate (8 mg, 0.020 mmol) following General Procedure E. Preparative thin layer chromatography (2% AcOH/EtOAc) yielded the title compound as a white solid (3 mg, 38%): 1H NMR (THF-d8, 600 MHz) δ 8.71 (d, 1H, J=4.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.79 (s, 1H), 7.45-7.44 (m, 2H), 7.22-7.19 (m, 2H), 7.16-7.14 (m, 2H), 7.11-7.08 (m, 1H), 3.05 (t, 2H, J=7.8 Hz), 2.60 (t, 2H, J=7.2 Hz), 1.73-1.69 (m, 2H), 1.66-1.61 (m, 2H), 1.43-1.39 (m, 4H); 13C NMR (THF-d8, 150 MHz) δ 185.5, 165.6, 156.4, 150.9, 149.5, 142.7, 141.1, 135.7, 127.0, 126.7, 126.5, 125.9, 123.9, 121.9, 37.1, 24.3, 30.0, 27.6, 27.5, 22.2; MALDI-FTMS m/z 379.1646 (M+H+, C22H23N2O4, requires 379.1652).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([CH3:33])=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH3:33][C:29]1[C:30]([CH3:32])=[CH:31][C:26]2[N:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]3[O:17][CH:16]([C:15]3[CH:18]=[CH:19][CH:12]=[CH:13][CH:14]=3)[C:27]=2[CH:28]=1
Reactant: c1ccc2cnccc2c1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c([Si](C)(C)C)cc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)N1C=Cc3ccccc3C1OC2c1ccccc1
Yield: 68 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.064 g, 59 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 4,5-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.196 g, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=90/10) of the crude reaction mixture afforded 8,9-dimethyl-6-phenyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.127 g, 68% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:2).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][Si](C(C)(C)C)(C)C)=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[C:43](Cl)(=[O:46])[CH2:44][CH3:45].[OH2:48]>C(Cl)Cl.C1COCC1>[C:12]1(/[C:9](/[CH2:10][CH3:11])=[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)\[C:5]2[CH:4]=[CH:3][C:2]([O:48][C:43](=[O:46])[CH2:44][CH3:45])=[CH:7][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(=O)Cl
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)O[Si](C)(C)C(C)(C)C)cc1)c1ccccc1
Reactant: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 30 (0.10 g, 0.20 mmol) in CH2Cl2 (5 mL) was added Et3N (0.072 mL, 0.052 g, 0.51 mmol) and propionyl chloride (0.021 mL, 0.021 g, 0.22 mmol). The mixture was stirred at ambient temperature for 1 h, washed with H2O (2×), dried (Na2SO4), concentrated, and dried in vacuo to give an off-white foam. This residue was dissolved in THF (3 mL) and H2O (0.6 mL) and the mixture was stirred at ambient temperature for 5 h. Solvent was evaporated and the residue triturated with hexanes/Et2O (5:1) to provide 7 (0.064 g, 73%) as an off-white solid, mp 155-157° C. 1HNMR (DMSO-d6): δ 0.86 (t, J=7.4 Hz, 3H), 1.05 (t, J=7.4 Hz, 3H), 2.4 (q, J=7.4 Hz, 2H), 2.49 (q, J=7.4 Hz, 2H), 6.51 (d, J=16 Hz, 1H), 6.79 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.10-7.22 (m, 5H), 7.25 (d, J=8.1 Hz, 2H), 7.59 (d, J=16 Hz, 1H), 7.7 (d, J=8.1 Hz, 2H), 12.33 (br s, 1H); Anal. calculated for C28H26O4.0.25H2O: C, 78.03; H, 6.20; Found: C, 78.02; H, 6.13.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:25][OH:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O.ClCCl>[CH2:17]([O:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:25]=[O:26])=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCCCNC(=O)OCc1ccccc1
Reaction time: 23 h
Yield: 299.8 %

Procedure:
A solution of sulfur trioxide pyridine complex (53.0 g, 333 mmol) in dimethylsulfoxide (300 mL) was added to a solution of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate (8.64 g, 34.4 mmol) and triethylamine (14.4 mL, 103 mmol) in dichloromethane (130 mL) at 0° C. The cold bath was removed, and the reaction mixture was stirred for 23 h. It was then poured slowly into a mixture of ice and saturated aqueous sodium chloride (1000 mL). The resulting mixture was extracted with three 600 mL portions of ether. The ether extracts were then combined, washed with three 150 mL portions of saturated aqueous sodium chloride, and concentrated to 1200 mL. The concentrated ether phase was further washed with three 200 mL aliquots of 5% aqueous citric acid, and a 200 mL portion of saturated aqueous sodium chloride. After drying over magnesium sulfate, volatiles were removed under vacuum to afford (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanal (37.58 g. 93%). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.46-7.23 (m, 6H), 5.02 (s, 2H), 3.85-3.75 (m, 1H), 3.07-2.93 (m, 2H), 1.77-1.60 (m, 1H), 1.56-1.23 (m, 5H), 1.41 (s, 9H).
Reaction SMILES: [ClH:1].[C:2]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.CO>CN(C)C=O>[ClH:1].[C:2]([NH:12][C@H:13]([C:21]([NH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Nα -carbobenzoxy-L-arginine hydrochloric acid salt (69.0 g, 0.2 M) and 7-amino-4-methylcoumarin (17.5 g, 0.1 M) were dissolved in dimethylformamide (DMF) (300 ml). Dicyclohexylcarbodiimide (DCCD) (21 g, 0.1 M) was added to the mixture with stirring at room temperature. This mixture was stirred overnight at room temperature, and the produced dicyclohexyl urea was removed by filtration. The obtained filtrate was concentrated under reduced pressure and to the thus obtained residue methyl alcohol (50 ml) and ethyl acetate (500 ml) were added. The precipitated material was separated by filtration to give crude crystals (19 g). These crystals were dissolved in a mixture of heated DMF (30 ml) and heated methyl alcohol (100 ml) and insoluble material was removed by filtration. To the filtrate ethyl acetate (400 ml) was added and the thereby precipitated white crystals were separated by filtration and dried to give 7-(Nα -carbobenzoxy-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (14.5 g, yield: 29%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:13][C:14]1[C:15]([C:32]#[C:33][C:34]2[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=2)=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:13][C:14]1[C:15]([C:32]#[C:33][C:34]2[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=2)[O:40][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[N:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(O)c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(OCCCNC(=O)OC(C)(C)C)c3)n2)cc1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl N-(3-bromopropyl)carbamate (40.86 mg, 0.1716 mmol) was added to a stirred solution of 3-[2-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenol (45 mg, 0.1144 mmol) and K2CO3 (39.53 mg, 0.2860 mmol) in DMF (1 mL) and the reaction mixture warmed to 65° C. for 16 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and stirred for 5 minutes. The layers were separated by filtration through a phase separation cartridge and the aqueous layer retained was washed with DCM (×2). The combined organics were concentrated in vacuo and used directly in the next step.
Reaction SMILES: [CH2:1]([O:17][C:18]1[C:19](=[O:32])[CH:20]=[C:21]([CH2:24][O:25]C2CCCCO2)[O:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.CCCCCC>C1COCC1.CCOCC>[OH:25][CH2:24][C:21]1[O:22][CH:23]=[C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:19](=[O:32])[CH:20]=1
Reactant: CCCCCCCCCCCCCCCCOc1coc(COC2CCCCO2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Yield: 96 %

Procedure:
A solution of 5-hexadecyloxy-2-tetrahydro pyranyloxymethyl-4-pyrone (1.1 g, 2.5 mmol) and HCl (10% in H2O, 10 ml) in THF (30 ml) was stirred at 25° overnight. TLC (ETAC/hexane: 3/7) indicated reaction was complete. The solution was diluted with ether (200 ml), washed with H2O (3×50 ml), 10% NaHCO3 (1×50 ml), sat'd NaCl (1×100 ml), dried (K2CO3) and concentrated to provide 0.88 g (98%) of 2-hydroxymethyl-5-hexadecyloxy-4-pyrone as a pure white solid mp 68.0°-69.5°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(O)(C)C>C1COCC1.O>[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:25])=[CH:22][CH:21]=1
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc(N(C)C)cc2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.71 g, 7.4 mmol) and dry THF (18 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.4 mmol) and stirred for 20 min. Then a mixture of 4-dimethylamino-benzaldehyde (1.00 g, 6.7 mmol) in dry THF (10 mL) was added and stirred for 2 hour at −78° C. The mixture was quenched with isopropanol (3.1 mL, 40 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (4-dimethylamino-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (1.29 g, 64% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH2CH3), 2.04 (d, J=3 Hz, 1H, OH), 2.93 (s, 6H, N(CH3)2), 3.85 (s, 3H, OCH3), 4.07 (q, J=7 Hz, 2H, CH2CH3), 5.72 (d, J=3 Hz, 1H, CH), 6.68-7.23 (m, 7H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]3[NH:16]/[C:17](=[N:25]\[C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)/[N:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][CH:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>>[CH:35]([S:37]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]2[C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:15]=[CH:14][C:13]=3[NH:16]/[C:17]/2=[N:25]\[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23]1)(=[O:39])=[O:38])([CH3:36])[CH3:34].[CH2:35]([S:37]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]2[C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:15]=[CH:14][C:13]=3[NH:16]/[C:17]/2=[N:25]\[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23]1)(=[O:39])=[O:38])[CH3:34]
Reactant: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1C1CCNCC1)c1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CCS(=O)(=O)N1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 19 %

Procedure:
The title compound was prepared from (E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide and 2-propanesulphonyl chloride using a method analogous to the preparation of (E)-N-(1-(1-(ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (20 mg, 19.0% yield). MS m/z=555.2 [M+H]. Calc'd for C28H38N6O4S: 554.3
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:5][CH2:6]OC)[CH3:3].[H-].[Na+].[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].O.[O:31]1CCC[CH2:32]1>>[CH3:3][N:2]([CH:4]([C:9]1([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)[CH2:5][CH2:6][CH2:32][O:31][CH2:23][CH2:22][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH3:1]
Reactant: C1CCOC1
Reactant: COCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reactant: C=Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(CCCOCCc1ccncc1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[1-(4-chlorophenyl)cyclobutyl]-3-dimethylaminopropan-1-ol (3 g prepared as described in Example 211) in tetrahydrofuran (50 ml) was added to a stirred suspension of sodium hydride (1.02 g of a 50% dispersion in mineral oil) in tetrahydrofuran (60 ml). The mixture was stirred at ambient temperature for one hour and a solution of 4-vinylpyridine (5.74 ml) in tetrahydrofuran (10 ml) was added and the mixture allowed to stand for 72 hours at ambient temperature and then heated under reflux for 48 hours. Water was added dropwise to the cooled reaction mixture which was then extracted with ether. The extracts were washed, dried and evaporated togive an oil which was dissolved in ether, filtered and the filtrate evaporated. The residue was heated at 95° C./0.5 mm Hg for 2 hours and then purified by flash chromatography on a silica column using a 9:1 mixture of light petroleum (b.p. 60°-80° C.) and propan-2 -ol as eluant followed by high performance liquid chromatography. The product was heated at 80° C./20 mm Hg for 5 hours to leave N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-4-[2-(4-pyridyl)ethoxy]butylamine as an oil the boiling point of which was not determined.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([S:10]C(=O)C)[CH2:6]1)=[N+:2]=[N-:3]>O1CCCC1.C[O-].[Na+].CO>[N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([SH:10])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=NC[C@@H]1C[C@H](S)CO1
Yield: 64.8 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.310 g of product from Example 61 in 4.5 ml of tetrahydrofuran and 0.30 ml of sodium methoxide/methyl alcohol to give 0.159 g of the desired product.