Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH:44]([C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1)([CH3:46])[CH3:45]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:51][C:50]4[CH:52]=[CH:53][C:47]([CH:44]([CH3:46])[CH3:45])=[CH:48][CH:49]=4)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)O)c1)C3
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)Nc2ccc(C(C)C)cc2)c1)C3
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 12.6 %

Procedure:
To a mixture of 3-(8,9-dimethoxy-1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid hydrochloride (0.38 mmol, 152 mg), N, N-diisopropylethylamine (1.14 mmol, 0.199 mL), and catalytic DMAP in 2.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.494 mmol, 0.293 mL). After 8 min at rt, 4-isopropylaniline (0.57 mmol, 0.081 mL) was added and the reactions continued for 1.8 hours. Then an additional 0.050 mL propylphosphonic anhydride solution and 0.020 mL 4-isopropylaniline was added, the mixture briefly heated to 80° C. 3 times, and then continued at rt for 2 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with CHCl3/EtOAc/MeOH and then triturated with EtOAc to give the title compound as a light yellow solid (23 mg, 13%).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:16][C@@H:17]([CH:21]=[CH2:22])[C@@H:18]1[O:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:9]([O:16][C@@H:17]([CH:21]=[CH2:22])[C@H:18]([OH:20])[CH2:19][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: C=C[C@H](OCc1ccccc1)[C@H]1CO1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[C@H](OCc1ccccc1)[C@H](O)CC1CCCCC1
Reaction time: 0.17 h

Procedure:
146 mg of copper (I) iodide was suspended in THF, and 3.85 ml of cyclohexyl magnesium chloride (2M diethyl ether solution) was added thereto under an argon atmosphere at -78° C. The mixture was stirred at the same temperature for ten minutes. Then, a THF solution (5 ml) of 969 mg of (2R,3S)-3-benzyloxy-1,2-epoxy-4-pentene was dropwise added thereto over a period of 10 minutes at -78° C. The mixture was stirred at -10° C. for two hours, and then poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The extract layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.2 g of (2R,3S)-3-benzyloxy-1-cyclohexyl-4-penten-2-ol as slightly brown oily substance. This alcohol was dissolved in DMF, and 923 mg of tert-butyldimethylsilyl chloride, 312 mg of 4 -dimethylaminopyridine and 923 μl of triethylamine were added thereto at 0° C. The mixture was stirred at room temperature overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed sequentially with 1N hydrochloric acid, with 4% sodium hydrogencarbonate, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/benzene=10/1) to obtain 1.3 g of the above identified compound as colorless oily substance.
Reaction SMILES: C(N(CC)CC)C.O.[OH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:25])[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>C(Cl)(Cl)Cl>[CH2:18]([O:17][C:16]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCOC(=O)Cl
Reactant: Oc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCOC(=O)Oc1ccncc1
Temperature: 25 °C

Procedure:
100 ml of chloroform and 7.3 ml (0.052 mol) of triethylamine were added and dissolved in 4.5 g (0.040 mol) of 4-hydroxypyridine-monohydrate and stirred at 25° C. To this was dropwise added 8.9 g (0.050 mol) of heptyl chlorocarbonate. After stirring for 30 minutes, a cold aqueous hydrochloric acid solution was added to the reaction mixture for liquid separation, and the chloroform layer separated was washed two times with cold water and dried with Glauber's salt. After the Glauber's salt was filtrated out, the chloroform was distilled out and the remaining precipitate was purified by column chromatography and crystallized in ethanol. The product had a melting point of from 44° to 50° C. Yield: 7.5 g, 83%.
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(=O)=O.CC(C)=O.O=[C:26]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]([F:50])([F:49])[F:48])[CH:41]=1)[C@@H:27]([NH:29][C:30](=[O:39])[O:31]CC1C=CC=CC=1)[CH3:28].[OH-].[K+].Cl>C(O)C.CO.C1COCC1>[CH3:28][C@H:27]1[C@@H:26]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]([F:48])([F:49])[F:50])[CH:41]=2)[O:31][C:30](=[O:39])[NH:29]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cccc(OC(F)(F)F)c1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: O=C=O
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H]1NC(=O)O[C@@H]1c1cccc(OC(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
Lithium tri-tert-butoxyaluminohydride (13.78 g, 54.2 mmol) was added into a cold (dry ice/acetone bath) solution of benzyl {(2S)-1-oxo-1-[3-(trifluoromethoxy)phenyl]propan-2-yl}carbamate (3.98 g, 10.84 mmol) in ethanol (100 ml). LCMS indicated the reaction was completed in 10 min. The reaction was quenched by HCl (1N). The crude mixture was diluted w/ ethyl acetate and filtered through a bed of Celite® 521 (slow filtration). Volatiles were removed from the filtrate under reduced pressure. The resulting pot residue was worked up with aqueous sodium hydrogen carbonate/brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a white solid. This solid was stirred with potassium hydroxide (7.22 ml, 54.2 mmol) in a THF (100 ml)/methanol (50 ml) mixture at room temperature for 2 hrs. LCMS indicated completion of reaction. HCl (1N) was added to acidify the reaction mixture. Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 100% ethyl acetate). Related fractions were pooled and evaporated to a white solid of 1.4170 g as the titled compound. LCMS calc.=261.06. found=260.21 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11]OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: Oc1ccccc1Cl
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccccc1Cl
Reaction time: 72 h

Procedure:
2-Chlorophenol (96.4 g, 0.75 mol), dimethoxymethane (257.9 g, 3.39 mol) and 750 mg of p-toluenesulfonic acid were dissolved in 1.5 L of methylene chloride and the mixture heated at reflux with stirring under nitrogen for 72 hours in a flask equipped with a Soxhlet extraction apparatus containing 400 g of 3A molecular sieves. The mixture was allowed to cool and 3 ml of triethylamine was added. The mixture was then extracted with 2N sodium hydroxide and the organic phase was dried over magnesium sulfate. Evaporation of the volatiles under reduced pressure left 66.9 g of crude 1-chloro-2-methoxymethoxybenzene as a residue. This was distilled and the fraction boiling at 94° C. and 6.5 mm pressure was collected to obtain 51.3 g (40 percent of theory) of purified product. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:39]([CH:36]2[CH2:37][CH2:38][N:35]2[CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]2)=[O:40])[C@H:13]([C:16](=[O:17])[NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20K carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a light brown solid (quant.). MS ISP (m/e): 592.3 (100) [(M+H)]]+.
Reaction SMILES: [CH2:1]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[C:27]([C:26]1[CH:30]=[C:22]([N:21]2[C:11]3[CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:23]=[CH:24][C:25]=1[OH:31])([OH:29])=[O:28]
Reactant: O=C(CC1C(=O)CCc2ccccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 16.6 g. (0.063 mole) of 1-phenacyl-2-tetralone, 9.65 g. (0.063 mole) of 5-aminosalicylic acid, and 60 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours, cooled and filtered. The collected solid was washed with acetic acid and water, dried and recrystallized from acetic acid to provide 16.3 g. (68%) of crystals, m.p. 223°-225°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])[CH:19]=[CH2:18]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 150 g (1 mol) of 2-(1,1-dimethylethyl)phenol, 151.8 g (1.1. mol) of potassium carbonate and 115 g (1.05 mol) of allyl bromide dissolved in 500 ml of acetone was stirred at reflux temperature for 70 hours and then cooled to room temperature. Once cooled, all precipitates were removed by filtration and the resulting filtrate was concentrated to provide a residue. This residue was dissolved in ethyl acetate and the resulting solution was washed with a 1 N hydrochloric acid solution, water and then a saturated brine solution and then concentrated to dryness to provide a residue. This residue was purified by column chromatography, using hexane as eluent, to provide 167.1 g of title compound.
Reaction SMILES: COC1C=CC([C@H]([N:11]2[CH2:15][C@H:14]([C@H:16]([O:18][C:19]3[C:20]4[N:21]([N:37]=[CH:38][C:39]=4[CH3:40])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:27][CH:26]=4)[N:24]=3)[CH3:17])[CH2:13][C:12]2=[O:41])C)=CC=1>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:40][C:39]1[CH:38]=[N:37][N:21]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:24]=[C:19]([O:18][C@@H:16]([C@H:14]3[CH2:15][NH:11][C:12](=[O:41])[CH2:13]3)[CH3:17])[C:20]=12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCOCC5)cc4)cn4ncc(C)c34)CC2=O)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn2cc(-c3ccc(N4CCOCC4)cc3)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Temperature: 60 °C

Procedure:
(R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-4R)-1-(3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.12 (34 mg, 0.061 mmol) was taken up in TFA (1.5 mL) and mixture was heated at 60° C. overnight. After cooling to room temperature, mixture was concentrated under reduced pressure and resulting film was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate. Layers were separated and aqueous was extracted with ethyl acetate. Combined organics were washed with 1:1 brine/saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by prep HPLC and then silica gel column chromatography (0-15% methanol in dichloromethane) to yield (R)-4-((R)-1-(3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.13.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH2:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:20]>>[CH:22]1([N:21]([CH2:19][CH3:20])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CCNC1CCCCC1
Product: CCN(c1cc(C(=O)Nc2ccc(O)cc2C)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and N-ethylcyclohexylamine (Aldrich), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].[NH2:18][C:19]1[C:24]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][CH2:29][CH2:28]3)=[CH:23][C:22](Br)=[CH:21][N:20]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:17])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:23][C:24]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[NH:30][CH2:29][CH2:28]2
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Reactant: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)nc1
Temperature: 90 °C
Yield: 51 %

Procedure:
A mixture of N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (225 mg, 0.6 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (190 mg, 0.6 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) in dioxane (3 mL) was degassed and heated to 90° C. At completion, the reaction was cooled to room temperature and concentrated. The residue was purified by flash chromatography over silica gel to provide 6′-amino-N-ethyl-N-methyl-5′-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (134 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (dd, J=17.9, 2.1 Hz, 2H), 8.17-8.22 (m, 1H), 8.10-8.16 (m, 2H), 7.94 (d, J=7.8 Hz, 2H), 7.43-7.51 (m, 2H), 3.41 (s, 2H), 3.30 (s, 3H), 2.97 (t, J=6.4 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); MS (EI) m/z=438.5 [M+1]+.
Reaction SMILES: Br.C(O)(=O)C.C[O:7][C:8]1[C:9]([O:27]C)=[CH:10][C:11]2[CH2:12][CH2:13][N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[CH2:16][CH:15]3[C:25]=2[CH:26]=1>O1CCCC1>[CH:26]1[C:25]2[CH:15]3[CH2:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19][CH2:20][N:14]3[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([OH:27])[C:8]=1[OH:7]
Reactant: COc1cc2c(cc1OC)C1Cc3ccccc3CCN1CC2
Agent: Br
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C1Cc3ccccc3CCN1CC2

Procedure:
Hydrobromic acid (48%, 30 ml) was added to a glacial acetic acid (3 ml) solution of 5,6,8,9,14,14a-hexahydro-2,3-dimethoxyisoquino[1,2-b][3]-benzazepine (XIIIc, Ex. 20) (0.928 g, 3 mmole), and the resulting solution was heated under reflux for 2.5 hours, then evaporated on a rotary evaporator to give a resinous residue. The residue was dissolved in tetrahydrofurane (about 80 ml), and the solution was allowed to sit at room temperature over a weekend. The crystalline product that was separated was collected on a filter, and washed with tetrahydrofurane to give the titled product which was recrystallized from ethanol. The product (HBr salt) weighed 0.8 g (73%) and melted at 270°-272°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: BrCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 896.8 %

Procedure:
To a solution of 2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL) cooled to 0° C. was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol) followed by p-TSA.H2O (100 mg) was added. Reaction mixture was stirred at 0° C. for 5.0 h. The reaction mixture was washed with aq NaHCO3 and brine, dried over Na2SO4 and evaporated to give the product 25 (75.0 g, 90%). This crude product was taken to next step without purification.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([NH2:19])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35](O)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35]([NH:19][CH:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(CC1CCC1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 19 from α-cyclobutylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid.
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(O)C.[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CO>C(Cl)Cl>[P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[N:31][NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCSP(=O)(OCC)Oc1cccc(C=O)c1
Reactant: NNC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCCSP(=O)(OCC)Oc1cccc(C=NNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl O-(3-formylphenyl) thiophosphate (6.0 grams; 0.016 mole), ethanol (100 ml) and benzoylhydrazine (2.18 grams; 0.016 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred at room temperature overnight. After this time the reaction mixture was stripped of methanol leaving an orange oil. This oil was dissolved in methylene chloride and the resulting solution was washed twice with water (100 ml), twice with aqueous sodium hydroxide (50 ml; 0.1 N) and again twice with water (100 ml). The washed solution was then dried over anhydrous magnesium sulfate and was stripped of solvent under vacuum to yield the desired product O-ethyl S-propyl O-[3-(benzoylhydrazonomethyl)phenyl]thiophosphate as a viscous orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([O:32][C:33]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:47][CH2:46][C:45]4[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=4[NH:43][C:42]3=[O:52])[CH2:37][CH2:36]2)=[O:34])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>Cl.CN(C=O)C>[O:52]=[C:42]1[N:41]([CH:38]2[CH2:37][CH2:36][N:35]([C:33]([O:32][C@H:10]([CH2:9][C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:11]([N:13]3[CH2:14][CH2:15][CH:16]([CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)[CH2:17][CH2:18]3)=[O:12])=[O:34])[CH2:40][CH2:39]2)[CH2:47][CH2:46][C:45]2[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=2[NH:43]1
Reactant: Cc1cc(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCNCC3)CC2)c1

Procedure:
A solution of 101 mg (0.14 mmol) tert-butyl 1′-{(R)-3-(3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4,4′-bipiperidinyl-1-carboxylate (Example 43) in 10 mL 2 M HCl was stirred overnight at RT. The reaction mixture was lyophilised. The crude product was taken up in 1 mL DMF, made alkaline with 0.6 mL saturated K2CO3 solution and purified chromatographically by HPLC.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([OH:27])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([O:27][C:2]2[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:17]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(C#N)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step iii) and the product from example 35 step ii).