Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)cc1
Product: Fc1cnc(Nc2ccc(Cl)cc2)nc1Nc1ccc(Cl)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted to yield N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3+CD3OD): δ 7.80 (d, 1H, J=4.2 Hz), 7.45 (d, 2H, J=8.7 Hz), 7.33 (d, 2H, J=9 Hz), 7.20 (d, 2H, J=8.7 Hz), 7.14 (d, 2H, J=9.6 Hz); LCMS: ret. time: 28.84 min.; purity: 87%; MS (m/e): 349 (MH+).
Reaction SMILES: [Na+].[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][C:6]([O-:8])=[O:7])[CH3:3].S(=O)(=O)(O)O>O>[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][C:6]([OH:8])=[O:7])[CH3:3]
Reactant: CCN(CC)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC)CC(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Powdery solid N,N-diethylglycine sodium salt (produced by Tokyo Kasei Kogyo K.K. Japan) was dissolved in deionized water. The solubility in water of the N,N-diethylglycine sodium salt was 34% by mass (20° C.). To 342 g of this aqueous 34% by mass solution, was added 98% by mass sulfuric acid to adjust the pH to 6.6. This aqueous solution was condensed at 90° C. under a reduced pressure until the N,N-diethylglycine sodium salt concentration in the solution reached 67% by mass. The condensed solution was cooled to 40° C. and was stirred for one hour. The deposited crystalline sodium sulfate was removed at 40° C. by using a Buchner vacuum filter. Thereby, an aqueous 67% by mass solution of N,N-diethylglycine was obtained in an amount of 125 g. The aqueous N,N-diethylglycine solution contained sodium sulfate at a concentration of 0.9% by mass.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([Cl:11])[C:7](N)=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2].N([O-])=O.[Na+].[PH2](O)=O>O>[Cl:11][C:9]1[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[C:6]([Cl:12])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: O=N[O-]
Agent: O=[PH2]O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
814 g (4 mol) of 4-acetyl-2,6-dichloroaniline, prepared according to patent DD 273,435 of the 15/11/1989, are recrystallised from a mixture of 1200 ml of concentrated hydrochloric acid and 5200 ml of concentrated acetic acid. After cooling to 0° C., a solution of 290 g (4.2 mol) of sodium nitrite in 770 ml of water is run in in a thin stream. After 2 h 30 at this temperature, the solution is run onto 2200 ml of a 50% solution of hypophosphorous acid in water at 5° C. At the end of the addition, the mixture is left to return to room temperature, 10 l of water are then added and the aqueous phase is extracted with dichloromethane. After drying of the separated organic phase, and concentration and distillation of the crude product, there are obtained 591 g (yield 70%, boiling point: 91-95° C. at 1 mm Hg) of (3,5-dichloro)phenyl-ethanone in the form of a pale yellow liquid.
Reaction SMILES: [NH3:1].[NH4+].[C:3](=[O:6])([OH:5])[O-:4].[C:7](=[O:10])([O-])[O-:8].C(=O)=O>O>[C:3](=[O:4])([OH:6])[O-:5].[C:7](=[O:10])([O-:8])[NH2:1].[NH4+:1]
Reactant: O=C([O-])[O-]
Reactant: N
Agent: O=C([O-])O
Agent: O=C=O
Agent: [NH4+]
Solvent: O
Product: NC(=O)[O-]

Procedure:
For the ammonia process, the solvent solution consists of ammonium, bicarbonate ions and to a lesser extent, carbonate, in equilibrium with dissolved ammonia (aqueous), and dissolved CO2 (aqueous). In the absorber, water and ammonia react with CO2 (aqueous) to form bicarbonate ions or ammonium carbamate ions, with the reaction reversed in the stripper by the application of energy. The relevant aqueous phase reactions can be summarized by the following overall equations: CO2+H2O+NH3HCO3−+NH4+  (eqn. 1) CO2+2NH3NH2COO−+NH4+  (eqn. 2) HCO3−+NH3CO32−+NH4+  (eqn. 3) CO32−+H2O+CO22HCO3−  (eqn. 4)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:15][C:16]1[CH:17]=[C:18]([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][CH:13]=1)=[CH:3][C:2]([S:15][C:16]1[CH:17]=[C:18]([C:22]2([C:28]#[N:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:19]=[CH:20][CH:21]=1)=[CH:11][CH:10]=3
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Reactant: Brc1ccc2c(ccc3ncnn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5ncnn54)c3)c2)CCOCC1
Temperature: 110 °C

Procedure:
8b (66 mg, 0.25 mmol) and 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (8c, 90 mg, 0.32 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed for 10 minutes with N2. iPr2NEt (0.15 mL, 0.80 mmol) was added, followed by Pd2dba3 (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol), and the mixture was degassed with N2 for an additional 10 minutes. The reaction was sealed and heated overnight at 110° C. Additional catalyst was added after 24 hours to push the reaction to completion, and the mixture was heated at 110° C. for another 2 hours. The reaction was cooled to room temperature and purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the desired product, 8d.
Reaction SMILES: [CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:35]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)([CH2:1][CH2:2][CH2:3][OH:35])[O:9][C:8]2=[O:10])[CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(Cc3ccccc3)C2)C(=O)O1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-benzylpiperidin-3-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (90 mg, 0.22 mmol) in THF (3 mL) was added BH3/THF (1 M, 0.44 mL) at 0° C. and the mixture was stirred at rt for 2 h. Then the mixture was cooled at 0° C., and H2O (0.2 ml), NaOH (3 M, 0.15 mL), 30% H2O2 (0.4 mL) were added. After the solution was stirred at rt for another 2 h, 1N aq HCl was added, and the mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-3-((S)-1-benzylpiperidin-3-yl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (30 mg, 30%). LC-MS Method 2 tR=0.976 min, m/z=427.7; 1H NMR (CDCl3): 1.28 (m, 2H), 1.36-1.45 (m, 1H), 1.58-1.67 (m, 6H), 1.88 (m, 2H), 2.10 (m, 1H), 2.17 (m, 1H), 2.48 (m, 1H), 2.64 (m, 2H), 3.12 (m, 1H), 3.34 (s, 2H), 3.48 (m, 2H), 4.05-4.15 (m, 1H), 6.94 (m, 2H), 7.15 (m, 5H), 7.22 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[O:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1.CO>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][C:26](=[O:27])[N:25]([CH2:24][C:15]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=2)[CH2:37][CH3:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To {2′-[3-(4-chloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.196 g, 0.35 mmol) in THF (2 mL) and MeOH (2 mL) was added 1N aqueous LiOH (2 mL), and the reaction was stirred at room temperature for 2 hours. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound. M+H is 535.
Reaction SMILES: [F:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:18][C@H:17]1[CH2:19]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[CH2:19]([O:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:14]=1[NH:13]2)[CH:17]1[O:18][CH2:16]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1cccc2[nH]c3c(F)cccc3c12
Product: Fc1cccc2c1[nH]c1cccc(OCC3CO3)c12
Yield: 78.4 %

Procedure:
1-Fluoro-5-hydroxycarbazole (25 mg, 0.124 mmol) and (2R)-(−)-glycidyl 3-nitrobenzenesulfonate, (32 mg, 0.124 mmol) were converted to 25 mg of the title compound substantially in accordance with the procedure of Preparation 122. Yield: 65%. 1H NMR. MS(FD).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C1CCN2C(=NCCC2)CC1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=1[F:22]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cc(O)c(Cl)c(=O)[nH]1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)[nH]1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
3-Chloro-4-hydroxy-6-methyl-1H-pyridin-2-one (19.2 g, 0.12 mol) and DBU (19.9 mL, 0.13 mol) were dissolved in 70 mL of NMP. 2,4-Difluorobenzylbromide (17 mL, 0.13 mol) was added dropwise and the reaction was heated at 80° C. for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with NMP and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (4.4 g, 13%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 7.63 (app q, J=9 Hz, 1H), 7.33 (app t, J=10 Hz, 1H), 7.16 (app t, J=9 Hz, 1H), 6.37 (s, 1H), 5.24 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CCO>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ncccn1
Solvent: CCO
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
Dissolve 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (7.120 g, 25.332 mmol), and 2-aminopyrimidine (5.464 g, 55.729 mmol) in EtOH (40 mL). Heat the mixture to reflux, and stir for 24 hours. Cool to room temperature, and concentrate under reduced pressure. Dissolve the residue in EtOAc (750 mL). Sequentially wash the organic extracts with a saturated NaS2O3 aqueous solution (250 mL), a saturated NaHCO3 aqueous solution (250 mL), and a saturated NaCl aqueous solution (350 mL). Crystallize the orange residue from heptanes/EtOAc. Collect the title compound as a white solid (3.290 g, 46.85% yield). 1H NMR (399.83 MHz, d6-DMSO) δ 8.84 (dd, J=1.9, 7.0 Hz, 1H), 8.54 (dd, J=2.0, 4.2 Hz, 1H), 8.06-8.04 (m, 2H), 7.83-7.81 (m, 2H), 7.10 (dd, J=4.1, 6.9 Hz, 1H), 2.68 (s, 3H). ES/MS (m/z) 277.99.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:22]([NH:25][C:26](=O)[O:27]C1C=CC=CC=1)CC.[Cl-].[NH4+]>CN(C)C=O>[CH3:22][NH:25][C:26]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:8]3[C:5]([C:6]#[N:7])=[CH:4][N:3]=[C:2]([NH2:1])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:27]
Reactant: N#Cc1cnc(N)cc1Oc1ccc2[nH]ccc2c1
Reactant: CCCNC(=O)Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3cc(N)ncc3C#N)ccc21
Temperature: 25 °C
Yield: 22 %

Procedure:
6-Amino-4-(1H-5-indolyloxy)nicotinonitrile (63 mg, 0.252 mmol) was dissolved in N,N-dimethylformamide (1 ml); and sodium hydride (60% in oil, 11.6 mg, 0.29 mmol) was gradually added thereto while stirring at room temperature. After the reaction mixture was stirred for 30 minutes, phenyl N-propylcarbamate (49.5 mg, 0.277 mmol) was added thereto; and the reaction mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride was added thereto; this was subjected to extraction with ethyl acetate, and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol) to yield the title compound (12 mg) and N1-methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide (17 mg).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:11][P:12]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[S:13])[CH2:6][C:7]([O:9]C)=O)=O.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[O:23]1[CH2:22][CH2:21][N:20]([P:12]([CH2:11][NH:5][CH2:6][C:7]([O:31][CH:28]([CH3:30])[CH3:29])=[O:9])([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[S:13])[CH2:25][CH2:24]1
Reactant: COC(=O)CN(CP(=S)(N1CCOCC1)N1CCOCC1)C(=O)C(F)(F)F
Reactant: CC(C)O
Product: CC(C)OC(=O)CNCP(=S)(N1CCOCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
N-trifluoroacetyl-N-[bis(morpholino)phosphinothioylmethyl]glycine, methyl ester (5.35 g, 0.0123 mole) was dissolved in isopropanol and cooled to 0° C. on an ice bath. The solution was stirred and sodium tetrahydrido boron (467 mg, 0.0123 mole) was added portionwise over a ten minute period. The solution was allowed to warm to room temperature and stirred for an additional 45 minutes. The solvent was removed by evaporation under vacuum and the resulting residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was then chromatographed on silica gel employing 25% ethanol in ethyl acetate (V:V) to obtain N-[bis(morpholino)phosphinothioylmethyl]glycine, isopropyl ester (300 mg), having a refractive index ND25 =1.5205 and the following analysis: Calculated: C, 44.33; H, 7.78; N, 11.08. Found: C, 44.83; H, 7.59; N, 10.76.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][O:21][CH3:22])[N:4]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][CH2:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH2:20][O:21][CH3:22])[N:4]=3)[CH2:25][CH2:24]2)=[N:4]1
Reactant: COCn1nc(CCl)cc1-c1cc(OC)c(OC)c(OC)c1
Reactant: C1CNCCNC1
Product: COCn1nc(CN2CCCN(Cc3cc(-c4cc(OC)c(OC)c(OC)c4)n(COC)n3)CC2)cc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3-Chloromethyl-1-methoxymethyl-5-(3,4,5-trimethoxyphenyl)pyrazole (95 mg) and homopiperazine (14 mg) were reacted in the same manner in Example 1 to obtain the title compound.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([O:13][S:14](C1CC1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[CH3:2][C:3]1([S:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:15])=[O:16])[CH2:5][CH2:4]1
Reactant: O=S(=O)(OCc1ccccc1)C1CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(S(=O)(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (0.78 g, 12.25 mmol) was added drop-wise at −78° C. to a solution of Benzylcyclopropane sulfonate (2.0 g, 11.2 mmol) in THF (20 mL) and continued stirring at the same temperature for 10 min. CH3I (3.98 g, 28.0 mmol) was added at −78° C., allowed the reaction to warm to 0° C. with stirring for 30 min. The reaction mixture was quenched with ice cold water, diluted with ethylacetate (100 mL), organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (using silica gel and 4% ethyl acetate in Hexane as eluent) to afford benzyl 1-methylcyclopropane-1-sulfonate (Int-25). 1H NMR (300 MHz, CD3OD) δ ppm 4.2-4.1 (2H, t), 1.7-1.6 (2H, m), 1.4 (3H, s), 1.5-1.3 (2H, m), 1.3-1.2 (2H, m), 1.0-0.9 (2H, m), 0.9 (3H, t).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:36])[C@H:24]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:36])=[O:22])[CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-tryptophan methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.Cl.[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:22]3[CH2:28][CH2:27][NH:26][CH:25]([CH3:29])[C:23]=3[N:24]=2)=[CH:15][CH:14]=1)=[O:11])[CH3:8].C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:22]3[CH2:28][CH2:27][N:26]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH:25]([CH3:29])[C:23]=3[N:24]=2)=[CH:17][CH:18]=1)=[O:11])[CH3:8]
Reactant: O=C1COC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C2COC2)C3C)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
3-oxetanone (0.38 mL, 5.2 mmol) and 1-ethyl-3-(4-(8-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (451 mg, 1.04 mmol) were mixed in 1,2-Dichloroethane (6.2 mL) and N,N-Diisopropylethylamine (0.73 mL, 4.2 mmol). The reaction was stirred at 70° C. for 1 h and at 80° C. for 30 minutes. Sodium triacetoxyborohydride (0.71 g, 3.3 mmol) was added to the reaction, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was quenched with NaHCO3 and water, which was extracted by CHCl3. The organic layers were combined, washed by water and brine (final pH ˜9), dried over Magnesium sulfate and evaporated. The residue was purified to give the desired product sk (269 mg, 57% yield) as white powder: 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.18 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.14 (t, J=5.5 Hz, 1H), 4.62 (m, 3H), 4.53 (t, J=6.2 Hz, 1H), 4.04 (p, J=6.7 Hz, 1H), 3.81-3.64 (m, 5H), 3.54-3.35 (m, 4H), 3.17-3.03 (m, 2H), 2.67 (m, 4H), 1.29 (d, J=6.8 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=453 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:34])=[CH:25][N:26]=[C:27]2[NH:30][C:31]([NH2:33])=[NH:32])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C>CCOC(C)=O.Cl>[ClH:34].[Cl:34][C:24]1[C:23]2[C:28](=[CH:29][C:20]([S:17]([N:8]([C@H:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:7][C:6]([OH:35])=[O:5])(=[O:18])=[O:19])=[CH:21][CH:22]=2)[C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[N:26][CH:25]=1
Reactant: C[C@@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 147.4 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine t-butyl ester (100 mg, 0.19 mmol) was dissolved in a solution of EtOAc saturated with HCl (4.0 mL) and the mixture stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue triturated with EtOAc to give N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine hydrochloride (72 mg, 0.14 mmol) as a white powder.
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[OH-].[NH4+:55]>>[NH2:55][C:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:19])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:5][CH:4]=1)=[O:43]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate was treated with concentrated ammonium hydroxide as described in Example 311 to afford the title compound as a white solid. 1H NMR (DMSO-d6): 0.78 (3H, d), 0.86 (3H, d), 1.2 (1H, dd), 1.4 (1H, br quintuplet), 1.85-1.95 (1H, m), 2.2 (1H, t), 2.65-2.80 (3H, m), 2.9-3.0 (2H, m), 3.25-3.30 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, d), 5.4 (1H, d), 6.18 (2H, d), 6.8 (2H, br d), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25-7.30 (2H, m); MS: 636 (MH+).