Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:44][S-:45].[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][S:45][CH3:44])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (100 mg, 0.17 mmol) was added portionwise to a stirred mixture of sodium thiomethoxide (35 mg, 0.50 mmol) in MeOH (5.0 mL) and the resulting mixture was stirred for 1 hr at RT. The mixture was evaporated in vacuo and partitioned between brine (20 mL) and DCM (30 mL). The organic layer was concentrated in vacuo, the residue pre-adsorbed on silica and purified by column chromatography (12 g, 10-100% EtOAc in iso-hexane, gradient elution). Product fractions were evaporated in vacuo to give N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio) acetamide (Example 6) as a light yellow solid (28 mg, 26%): m/z 610 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 3.53 (2H, s), 5.37 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.26 (1H, dd), 7.35 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.78 (1H, s), 10.60 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O1CCOCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[CH:12]=3)[CH:7]=1
Reactant: COCCN
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(NCCOC)cc21
Temperature: 100 °C
Yield: 72.6 %

Procedure:
To a suspension of Example A6 (0.500 g, 1.507 mmol) in dioxane (10 mL) was added 2-methoxyethylamine (2 mL, 23.22 mmol) and the mixture was heated at 100° C. for 40 h. Solvent from the reaction mixture was evaporated and the residue was diluted with water (50 mL) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried, and the solvent evaporated to provide 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridin-2(1H)-one (405 mg, 73% yield) as an orange-yellow solid. MS (ESI) m/z: 371.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
2-{3-[4-(4-Nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (30 g), stannous chloride dihydrate (74.8 g) and ethanol (500 cc) are heated for one hour at 60° C. under a current of argon. Then sodium borohydride (1.3 g) is added over one hour in small portions. Stirring is continued for one hour at 60° C., then for 15 hours at a temperature of about 20° C. The mixture is poured into water and ice (500 cc) then alkalinized with 4N caustic soda to pH 9. The organic phase is extracted with diethyl ether (4×200 cc), absorbed in charcoal 3S (3 g), dried on anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (200 mm Hg; 2.7 kPa). The residue obtained in purified by recrystallization, first from boiling 1-propanol (250 cc), then twice from boiling ethanol (20 cc). 2-{3 -[4-(4-Aminophenyl)-1-piperazinyl] propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.4 g) is thus obtained, m.p. 113° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(CC(OC)=O)=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:31].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[C:17][C:5]3[CH:6]=[CH:7][C:2]([C:1]([OH:8])=[O:31])=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 76, 45.0 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH4+:20].[OH-]>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([NH2:20])=[O:5])=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[OH:12]
Reactant: [NH4+]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dichloro-5-hydroxy-6-nitrobenzoic acid (Step A) (4.40 g, 17.6 mmol) and thionyl chloride (2 mL, 27 mmol) in toluene (60 mL) was heated under reflux for 1 h and allowed to cool to room temperature. The solution was added to conc NH4OH (40 mL) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for 2 h and then concentrated to give crude 4,6-dichloro-3-hydroxy-2-nitrobenzamide as a brown solid.—1H NMR (CD3OD): δ 7.33 (s, 1H); mass spectrum: m/z 249, 251, 253 (M+−1, 100%, 66%, 11%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(4-chloro-3-fluorophenyl)propan-1-ol (29.3 g) and triethylamine (11.2 ml) in THF (335 ml) was added chloroacetyl chloride (5.37 ml) under ice-cooling, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (35.0 g).
Reaction SMILES: C(O)CCC.[ClH:6].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[CH2:11][CH2:12][NH2:13].C(O[CH:21](OCC)[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)C>Cl.O>[ClH:6].[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([S:23][CH2:22][CH:21]2[C:14]3[C:10](=[CH:9][C:8]([OH:7])=[C:16]([OH:17])[CH:15]=3)[CH2:11][CH2:12][NH:13]2)=[CH:25][CH:26]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CSc1ccc(C)cc1)OCC
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(SCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 106.9 %

Procedure:
To a mixture of n-butanol (10 ml), water (2.5 ml) and concentrated hydrochloric acid (1 drop) were added 3,4-dihydroxyphenethylamine hydrochloride (0.63 g) and (4-methylthiophenoxy)acetaldehyde diethyl acetal (1.0 g), and the mixture was refluxed for 5 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixture solvent of methanol and ether to give 1-(4-methylthiophenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.2 g), mp 270° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH: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][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:37])=[O:36]>>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH: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][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1)(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-octadecylcarbamoyloxymethyltetrahydrofuran IV b2 is allowed to react and worked by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:41])CC)C>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@@H:10]1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@@H](O)[C@@H](OCc1ccccc1)C21CC1
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@@H](OCc1ccccc1)C21CC1
Yield: 45.9 %

Procedure:
To a solution of alcohol 25 (5.1 g, 10.7 mmol) in anhydrous CH2Cl2, (diethylamino) sulfur trifluoride (DAST) (9.3 ml, 70.5 mmol) was added slowly at room temperature. The reaction mixture was quenched with iced H2O after 20 min. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer was then combined, dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel column chromatography (1% EtOAc/Hexane) to give 26 (2.5 g, 49%). [α]24D −98.08° (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 4.92 (ddd, J=6.0, 7.5 & 5.5 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 2H), 2.70 (m, 1H) 1.08-0.94 (m, 28H), 0.72 (m, 1H), 0.68-0.43 (m, 2H), 0.28 (m, 1H); 13C NMR (125 MHz, CDCl3) δ142.6 (d, J=9.2 Hz), 141.8, 137.9, 128.4, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d, J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 29.4, 24.5, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5, 7.9; HR-MS Calcd. For (C27H45FO4Si2+H)+ 509.2840, found 509.2923.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 2-chloro-3-methylbenzoic acid (25.0 g, 146 mmol), conc. sulfuric acid (2 mL) and methanol (160 mL) was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, was diluted with ethyl acetate and neutralized with 8N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure to give the title compound (18.0 g, 66%) as a pale-orange oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:32][N:31]=1
Reactant: COc1cccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 82.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 14) in DMF (1 ml) was added hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.8 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (41 mg, 83%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([C:5](=[O:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Aluminum chloride, (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5°-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition at 5°-10° C. of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0°-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92°-94° C.; 1H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O>[O:11]=[C:9]([CH3:10])[C:3](=[N:2][O:1][CH2:18][CH2:19][CH3:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCI
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCON=C(C(C)=O)C(=O)OCC
Yield: 81.2 %

Procedure:
To a suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15 g.) and potassium carbonate (19.8 g.) in acetone (75 ml.) was added dropwise propyliodide (16.2 g.) with stirring, and the mixture was stirred at ambient temperature for 1,5 hours. The insoluble substance was collected by filtration and washed with acetone. The washings and the filtrate were combined and evaporated to dryness under reduced pressure. To the resultant residue was added water and the aqueous solution was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:6][CH:7]([F:9])[F:8])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:6][CH:7]([F:9])[F:8])[CH3:10])#[N:5]
Reactant: CC(N)(C#N)CC(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CC(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-4,4-difluoro-2-methylbutanonitrile hydrochloride product from Example 74A was initially charged in 109 ml of tetrahydrofuran/water (1:1), and 18.94 g (137.06 mmol) of potassium carbonate and 6.27 g (36.77 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.14 g (6.69 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 7.68 g of the target compound were obtained (61% of theory over two stages, 71% purity).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].[C:14]([NH:16][C:17]([NH2:19])=[NH:18])#[N:15].[ClH:20]>O>[ClH:20].[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15])[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(NC(=N)NC(=N)N)cc(C(C)=O)c1

Procedure:
Compound No. 12. A suspension of 3,5-diacetylaniline (0.531 g) in water (8 mL) was treated with cyanoguanidine (0.285 g) and conc. HCl (0.25 mL) and heated at reflux. After 6 hr the mixture was cooled and concentrated and 0.248 g of off-white solid was filtered out and dried to give N-(3,5-diacetylphenyl)biguanide hydrochloride, mp 260°-70° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:33][CH2:32][C:31](=O)[CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:31]2[CH2:32][CH2:33][O:29][CH2:30]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: O=C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(NC2CCOC2)c1
Temperature: 22 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (100 mg, 0.31 mmol) in MeOH (5 mL) was added AcOH (0.05 mL) and dihydrofuran-3(2H)-one (27 mg, 0.31 mmol). The mixture was stirred at 22° C. for 2 h. NaBH3CN (98 mg, 1.55 mmol) was added and the resulting mixture was stirred at 22° C. for 2 h. The reaction solution was concentrated, and the residue was washed with water, extracted with EA, the organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (22 mg, Yield 18.0%). 1H NMR (CD3OD, 400 MHz): δ 7.14-6.95 (m, 7H), 6.80-6.71 (m, 1H), 4.14-4.03 (m, 2H), 3.99-3.89 (m, 2H), 3.87-3.78 (m, 1H), 3.75-3.69 (m, 2H), 3.67-3.61 (m, 1H), 3.55-3.41 (m, 2H), 2.91-2.79 (m, 4H), 2.71-2.57 (m, 2H), 2.32-2.19 (m, 1H), 1.91-1.79 (m, 1H). LCMS (m/z): 396.2 (M+1).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:30]=1[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(OC)c(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 69 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2,5-dimethoxycinnamic acid under the conditions described in example 86 to yield 69% of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.P([O-])(OCC)(OCC)=O>ClCCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:13][C:11]1[C:10]([F:14])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1cc(F)c(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CCOP(=O)([O-])OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1cc(F)c(CBr)cc1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 18, 4.674 g, 23.35 mmol) in 1,2-dichloroethane (70 mL) were added N-bromosuccinimide (4.57 g, 25.68 mmol) and benzoyl peroxide (56 mg, 0.23 mmol) and the mixture was heated to 70° C. for 2 days. The reaction mixture was allowed to cool, quenched with saturated aqueous sodium thiosulfate (20 mL) and diluted with water (50 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×80 mL). The combined organics were washed with saturated aqueous sodium hydrogen carbonate, followed by brine, then filtered through a phase separator and concentrated in vacuo. The resulting yellow oil was redissolved in EtOAc (70 mL), and N,N-diisopropylethylamine (4.04 mL, 23.35 mmol) was added. The mixture was cooled to 0° C., and diethyl phosphate (2.29 mL, 23.35 mmol) was added. After stirring at 0° C. for 90 minutes, LCMS indicated complete conversion of the dibromomethyl impurity to the desired mono-bromomethyl product. The reaction was quenched at 0° C. with water (70 mL), followed by aqueous hydrochloric acid (2N, 10 mL). The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to yield a yellow residue. The residue was purified by silica gel chromatography eluting with 0 to 3% EtOAc in heptane to afford the title compound as a clear oil (5.78 g, 89%):