Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O1CCCC1>[CH2:7]([NH:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccc(O)cc1)NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(CCCNCc2ccccc2)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
Add lithium aluminum hydride (8.00 g, 211 mmol) to anhydrous tetrahydrofuran (150 mL) and cool to 0° C. under nitrogen. Add N-benzyl-3-(4-hydroxy-phenyl)-propionamide (9.74 g, 38.2 mmol) to anhydrous tetrahydrofuran (80 mL) and add this solution slowly via cannula to the lithium aluminum hydride/tetrahydrofuran mixture at 0° C. under nitrogen. Once this addition is complete, remove the ice bath and heat to reflux for 18 h under nitrogen. Cool the reaction to 0° C. and slowly quench with water (200 mL). Adjust the pH of the solution to pH=8 with 4 M hydrochloric acid. Saturate this solution with sodium chloride, extract with ethyl acetate (3× 100 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 9.00 g (98%) of 4-(3-benzylamino-propyl)-phenol: mass spectrum (ion spray): m/z=242.1 (M+1); 1H NMR (DMSO-d6): 7.31-7.16 (m, 6H), 6.95-6.92 (m, 2H), 6.66-6.62 (m, 2H), 3.65 (s, 2H), 2.48-2.43 (m, 5H), 1.68-1.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:22])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 10.65 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid and 8 ml of thionyl chloride heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and subjected to distillation under reduced pressure (110° C./5 mmHg) to obtain 8.39 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride of the formula:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[C:17]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][N:2]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7])[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCCNC(=O)OC(C)(C)C)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C

Procedure:
To a mixture comprising 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (2-methylamino-ethyl)-amide (Intermediate E) (0.5 g, 2.0 mmol) and 4-(Boc-amino)butyl bromide (0.8 g, 3.1 mmol) in DMF (5 mL) is added sodium carbonate (0.4 g, 4.0 mmol). The resulting mixture is heated at reflux for 3 h and then allowed to cool to RT, filtered and concentrated in vacuo. The crude product is dissolved in DCM and filtered to remove any undissolved impurities. The filtrate is concentrated in vacuo to yield the title compound which is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=1.[CH:18](OC)(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C1COCC1>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[N:1]=[CH:18][N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: Nc1nccc(Nc2cc(Br)c(F)cc2N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccc(-n2cnc3cc(F)c(Br)cc32)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
To a solution of 4-N-(2-amino-5-bromo-4-fluorophenyl)pyrimidine-2,4-diamine (500 mg, 1.68 mmol) in methanol (6 mL) and THF (20 mL) was added trimethyl orthoformate (5.59 ml, 50.32 mmol) and TsOH (0.03 ml, 0.17 mmol). The reaction mixture was stirred at 70° C. for 1.5 hr. Reaction had only progressed 6% by LC-MS. Extra trimethyl orthoformate (6 mL, 54.23 mmol) was added and stirred at 70° C. for 1 hr. Reaction mixture was cooled and sat NaHCO3 (10 mL) was added. The product was extracted with DCM (3×10 mL) and the organics were washed with brine and then dried (Na2SO4), filtered and concentrated in vacuo to obtain title compound as a beige solid (500 mg, 63.8% yield); 1H NMR (500 MHz, DMSO) delta 9.17 (s, 1H), 8.97 (d, J=6.7 Hz, 1H), 8.37 (d, J=5.5 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.20 (s, 2H), 7.14 (d, J=5.6 Hz, 1H); LC-MS: m/z=+309.75 (M+H)+.
Reaction SMILES: C([O-])=O.[NH4+].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OCC4C=CC=CC=4)=O)[CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[N:6]1>C(O)C.[Pd]>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3[nH]ncc3c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)C1CCNCC1
Yield: 68.6 %

Procedure:
Ammonium formate (250 mg) and 10%-Pd/C (50 mg) were added to a solution of benzyl 4-[(1H-indazol-5-ylamino)sulfonyl]piperidine-1-carboxylate (250 mg, 0.603 mmol) in ethanol (15 ml) at room temperature, and the resulting mixture was refluxed for 1 hour. The reaction mixture was filtered by the use of Celite, and the filtrate was concentrated and the resulting residue was dissolved in a mixture of chloroform and methanol, followed by adding thereto diethyl ether. The solid precipitated was collected by filtration and dried under reduced pressure to obtain N-(1H-indazol-5-yl)piperidine-4-sulfonamide (116 mg, 69%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3]1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[OH:8][CH2:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: OCc1cnn(O)c1
Product: CN(C(=O)On1cc(CO)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-hydroxymethylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (62%, oil).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:3]=2[O:2]1.[H][H]>[Ni].C(O)CC>[CH2:10]([OH:11])[C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: [H][H]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Ni]
Solvent: CCCO
Product: OCc1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 10 h
Yield: 30.2 %

Procedure:
In a 500-ml autoclave were placed 90 g (0.60 mol) of heliotropin, 270 ml of 1-propanol and 3 g of a Raney nickel catalyst (Raney-Ni). Hydrogen gas was filled therein up to 4 MPa. The autoclave contents were stirred at 90° C. for about 10 hours. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 27.6 g of piperonyl alcohol as white crystals (yield: 30.3%, G.C. purity: 98.4%)
Reaction SMILES: [Li]C.[CH3:3]COCC.[C:8]([O:12][C:13]([N:15]1[C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[N:32]=[CH:31][CH:30]=[N:29]3)[CH:23]=2)[CH2:19][O:18][CH2:17][C:16]1=[O:33])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([O:12][C:13](=[O:14])[NH:15][C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:29]=[CH:30][CH:31]=[N:32]2)[CH:23]=1)[CH2:19][O:18][CH2:17][C:16](=[O:33])[CH3:3])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@H]1Cc1cccc(-n2nccn2)c1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)COC[C@@H](Cc1cccc(-n2nccn2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
MeLi 1.6 M in Et2O (3.6 mL, 5.82 mmol) was added dropwise to a −78° C. solution of (R)-3-oxo-5-(3-[1,2,3]triazol-2-yl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester I-5 (1.49 g, 4.16 mmol) in THF (15 mL) and the resulting mixture was stirred at −78° C. for 3 h. The reaction mixture was quenched with sat. aq. NH4Cl, warmed to RT and the solvent was removed in vacuo. The remaining aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (eluting with 20% to 50% EtOAc in hexane) to give the title compound as a yellow solid. LC-MS B: tR=0.81 min; [M+H-Boc]+=259.17.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([CH:33]1[O:35][CH2:34]1)Br.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[OH:35][CH:33]([CH2:34][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (322 mg, 1.00 mmol), (prepared as described in Example 49), potassium carbonate (414 mg, 3.00 mmol) and epibromohydrin (274 mg, 2.00 mmol) in DMF (7.0 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue taken up in dichloromethane (10 ml). An aliquot (5 ml) of this solution was treated with morpholine (48 ul, 0.6 mmol) and stirred for 24 hours at ambient temperature. The solvent was removed by evaporation, treated with water and stirred vigorously for 30 minutes. The precipitate was filtered, washed with water and dried. The resultant solid was stirred as a suspension in acetone, filtered, washed with diethyl ether and dried to give 7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (127 mg, 27%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.[H-].[Na+].[Cl:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]2[C:32]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=3)[CH:36]=O)=[C:31]3[C:26]([C:27]([C:41]([F:44])([F:43])[F:42])=[CH:28][CH:29]=[CH:30]3)=[N:25]2)=[C:21]([F:47])[CH:20]=1>CN1C(=O)N(C)CCC1.C(O)C.[Pt]=O>[Cl:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]2[C:32]([C:33]3[CH:40]=[CH:39][CH:38]=[C:35]([CH2:36][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:34]=3)=[C:31]3[C:26]([C:27]([C:41]([F:44])([F:43])[F:42])=[CH:28][CH:29]=[CH:30]3)=[N:25]2)=[C:21]([F:47])[CH:20]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(Cl)cc2F)c1
Agent: O=[Pt]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCN(C)C1=O
Product: Fc1cc(Cl)ccc1Cn1nc2c(C(F)(F)F)cccc2c1-c1cccc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of benzyl-phosphonic acid diethyl ester (20 μL, 1 eq) and sodium hydride (6 mg, 1.5 eq) in DMPU (0.5 mL), 3-[2-(4-chloro-2-fluoro-benzyl)-7-trifluoromethyl-2H-indazol-3-yl]-benzaldehyde (45 mg, 1 eq) was added. The reaction mixture was stirred for 45 minutes at room temperature, quenched with water and extracted with diethyl ether. The volatiles were removed and the residue purified by flash chromatography (silica, ethyl acetate/n-heptane, 2:8). The product obtained was dissolved in ethanol (2 mL) and hydrogenated at 1 atm using 7% platinum oxide as a catalyst. Filtration through Celite® and flash chromatography, eluent: dichloromethane/n-hepatane, 1:1, furnished the title compound in 11% overall yleld.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[C:5]([O:12][CH3:13])=[CH:4][N+:3]=1[O-]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([NH2:9])[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: COc1c[n+]([O-])c(Cl)c(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cnc(Cl)c(C)c1N
Temperature: 100 °C

Procedure:
Iron powder (700 mg, 12 mmol) was added to a solution of C3 (350 mg, 1.60 mmol) in acetic acid (8 mL), and the reaction mixture was heated at 100° C. for 1 hour, then cooled to room temperature. After filtration through Celite and thorough washing of the filter pad with ethyl acetate and methanol, the combined filtrates were concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 50% to 75% ethyl acetate in heptane) afforded the product as a white solid. Yield: 240 mg, 1.39 mmol, 87%. LCMS m/z 173.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 4.38 (br s, 2H), 3.91 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1(=[O:18])[CH2:17][CH2:16][CH2:15]C1.N>CCOCC.[Zn]>[OH:18][C:13]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)CC1(O)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
Trimethylchlorosilane (1.14 mL, 8.92 mmol) was added by syringe to a suspension of zinc powder (7.97 g, 0.122 mol) in absolute Et2O (200 mL). The mixture was stirred for 15 minutes at room temperature, heated to reflux, the heat source was removed, and ethyl bromoacetate (10.3 mL, 92.9 mmol) was added at such a rate that the ether solution gently boiled. After being heating for one hour at reflux, the mixture was stirred for one additional hour at room temperature. A solution of cyclopentanone (6.00 g, 75.9 mmol) in ether (30 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. The mixture was stirred for 1 hour at room temperature and poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether, the combined organic phases were dried over K2CO3 and the solvent was evaporated to yield the title compound as a colorless oil (6.50 g, 54%). 1H-NMR (400 MHz, CDCl3) δ 1.29 (3H, t, J=7.3 Hz), 1.47-1.64 (1H, m), 1.76-1.87 (1H, m), 1.93-2.06 (2H, m), 2.12-2.22 (2H, m), 2.67 (2H, s), 3.70 (1H, s), 4.19 (2H, q, J=7.3 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([NH:12][NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=S)=[O:11])=[CH:2]1>CO.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:17]1([NH:16][C:14]2[O:11][C:10]([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)=[N:12][N:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NNC(=S)Nc1ccccc1)c1c[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CO
Product: c1ccc(Nc2nnc(-c3c[nH]c4ncccc34)o2)cc1

Procedure:
610 mg of 1-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-phenylthiosemicarbazide and 686 mg of mercury(II) acetate in 6 ml of MeOH are stirred at 80° C. for 2 hours in a sealed screw-lid vial. 1 drop of Na2S solution is added to the cooled reaction solution, everything is filtered through kieselguhr with suction and rinsed with warm MeOH.
Reaction SMILES: [C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([OH:50])=[O:49])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[N+](C)C)C.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 19-{(S)-1-tert-Butoxycarbonyl-3-[2-(2-{[2-(2-carboxymethoxyethoxy)ethylcarbamoyl]-methoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}nonadecanoic acid tert-butyl ester (3.1 g) in acetonitrile (50 ml) was added TSTU (1.39 g) and DIPEA (0.91 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (100 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil. Yield 99% (3.4 g). LC-MS (electrospray): m/z: 971.8.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.O.Cl.Cl.[CH:19]1([CH2:29][CH2:30]N2CCN(C3C=CC=CC=3OC)CC2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][O:20]1>>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:29][CH:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][O:20]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Solvent: O
Product: Clc1cccc(N2CCN(CCC3OCCc4ccccc43)CC2)c1

Procedure:
Following the general procedure of EXAMPLE 1 and making non-critical variations but using 1-(3-chlorophenyl)piperazine dihydrochloride (XI, 0.5169 g (1.92 mmol) in place of 1-(2-chlorophenyl)piperazine dihydrochloride (XI), the title compound is obtained, mp 176.75-179°; MS (m/z) 356; IR (mineral oil) 2269, 2295, 2166, 2130, 2200 and 1449 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+]>CN(C)C=O.O>[CH2:9]([N:3]1[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[N:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCBr
Reactant: Cc1n[nH]c(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCn1nc(C)nc1C
Temperature: 120 °C

Procedure:
A mixture of 3,5-dimethyl-1,2,4-triazole (6.0 parts; 0.062 mol ex (b) above) and 1-bromodecane (14.4 parts; 0.065 mol) in dimethylformamide (16 ml) was heated together at 120° C. for 23 hours. The cooled reaction mixture was diluted with water (100 ml), a solution of sodium hydroxide (2.62 parts; 0.065 mol) in water (100 ml) added, and the product extracted into ether (3×50 ml). After drying over magnesium sulphate the solution was evaporated to yield a pale yellow oil (3.3 parts; 22% theory).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=O)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH2:13][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc([C@H](CCN2CCOCC2)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (40 mg, 0.09 mmol) and morpholine (15 μL, 0.17 mmol) in dichloroethane (2 mL) was stirred for 30 minutes. The mixture was then acidified (pH=4) with acetic acid (9 μL, 0.2 mmol) and then sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added. After 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by silica gel chromatography using a gradient of 0-10% methanol in EtOAc. The solid material from the column was purified a second time by reversed-phase HPLC using a 20 minute gradient of 5-95% MeCN (0.1% TFA) in H2O (0.1% TFA) (flow rate=25 mL/minute). Desired fractions from the column was made basic with saturated aqueous sodium bicarbonate (2 mL), concentrated to half of the original volume and extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH3:17])=[CH:4][CH:3]=1.P(=O)(O)(O)O.N>O>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][C@H:7]3[N:8]([CH3:17])[CH2:9][CH2:10][C@@:11]4([C:4]=2[CH:3]=1)[C@H:16]3[CH2:15][CH2:14][CH2:13][CH2:12]4
Reactant: Cc1ccc(CC2C3=C(CCCC3)CCN2C)cc1
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C)CC3
Temperature: 135 °C
Yield: 27.5 %

Procedure:
(+)-1-p-methylbenzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (26.5 g) was added to 85% phosphoric acid (130 ml) and the mixture was heated to 130-140° C. for 72 h. After the reaction was complete, the reaction mixture was poured into ice-water and the solution was made strongly alkaline by the addition of conc. ammonia solution (about 300 ml) and diluted with water (500 ml). The solution was then extracted with ether (500 ml×2). The ether layers were combined and washed with water (200 ml), and dried (K2CO3), filtered and evaporated to yield an oil. The oil was immediately vacuum-distilled to produce a faint yellow oil (10 g; by 130-136° C./0.3 mm Hg) which was crystallized on standing. Recrystallization from acetone (˜10 ml) provided white prisms ((7.3 g) of (+)-3-methyl-17-methyl-morphinan; MS (ESI+): m/z 256 (M+1). This procedure is similar to the procedure in U.S. Pat. No. 3,786,054, incorporated by reference herein in its entirety.