Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:9]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:25]C(OC(C)(C)C)=O)[CH2:17][C@:18]([CH2:23][OH:24])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1.CCN(CC)CC>CC(C)=O>[C:1]([O:6][CH2:7][O:21][C:19](=[O:20])[C@@:18]([CH2:23][OH:24])([CH3:22])[CH2:17][C@H:16]([NH2:25])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Chloromethyl butyrate (49 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:2][CH2:3][CH2:4][O:5][CH3:6])[CH:11]=[O:12]
Reactant: COCCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
Commercially available 1-bromo-3-methoxypropane (24.0 g, 157 mmol) was added to a solution of commercially available 3,4-dihydroxybenzaldehyde (21.7 g, 157 mmol) and sodium carbonate (25.0 g, 236 mmol) in N,N-dimethylformamide (50 mL) under nitrogen atmosphere at room temperature. The reaction liquid was stirred at room temperature for 3 days and 4 hours. 2 M hydrochloric acid, ethyl acetate, and water were added to the reaction liquid at 0° C. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The insoluble matters were separated by filtration with dichloromethane and the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1) to obtain the title compound (17.2 g, 52%).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(#N)C>[CH3:15][C:2]1[N:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:17]2=[N:16][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1
Reactant: Nc1ncccn1
Reactant: CC(Br)C(=O)c1ccc2sc(=O)[nH]c2c1
Solvent: CC#N
Product: Cc1c(-c2ccc3sc(=O)[nH]c3c2)nc2ncccn12
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 5-(2-bromopropionyl)-2-benzothiazolinone (2.9 g) and 2-aminopyrimidine (2.9 g) in acetonitrile (100 ml) was refluxed for 15 hours with stirring. The reaction mixture was cooled to ambient temperature to give a precipitate, which was collected by filtration. The precipitate was added to a mixture of water and ethyl acetate and the resulting mixture was adjusted to pH 8.0 with 20% aqueous potassium carbonate solution. The precipitate was collected by filtration, washed successively with water and ethanol and dried over phosphorus pentoxide to give 5-(3-methylimidazo-[1,2-a]pyrimidin-2-yl)-2-benzothiazolinone (1.45 g).
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.[CH3:25]C(C)=O>O>[C:4]1(=[O:19])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([O:16][CH3:25])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: CC1=C(C(=O)O)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Reactant: CC(C)=O
Solvent: O
Product: COC(=O)C1=C(C)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Reaction time: 3 h

Procedure:
To a solution of 17.3 g. (0.05 mol.) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid in 50 ml. of acetone and 20 ml. of water, 5 g. (0.05 mol.) of KHCO3 were slowly added. The resulting solution was evaporated to dryness, and 38 ml. of DMF and 5 ml. of methyl iodide were added to the residue. The mixture was stirred for 3 hrs. at room temperature. To this mixture were then added 100 g. of ice, and the resulting solid product was filtered. The product was crystallized from a mixture of 100 ml. of 2-propanol and 100 ml. of acetone. Yield: 7.91 of crystals, m.p. 187°-188°; ir (CHCl3) 1790 and 1735 cm-1, nmr (CDCl3) δ 2.31 (s, 3, CH3), 3.0 and 3.75 (ABq, 2, J=15 Hz), 3.85 (s, 3, CH3), 5.15 (d, 1, J=4.4 Hz), 5.74 (d, 1, J=4.4 Hz) and 7.73 (m, 4, ArH).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][CH:6]=[N:7][N:8]=1.[Li]CCCC.[N:14]#N.CCOCC.[C:21]([C@:28](N)([CH2:31][CH3:32])[CH:29]=[O:30])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[C:21]([C@@H:28]([CH2:31][CH3:32])[C:29]([NH2:14])([C:6]1[O:5][C:4]([CH2:3][O:2][CH3:1])=[N:8][N:7]=1)[OH:30])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: COCc1nnco1
Reactant: N#N
Reactant: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](C(=O)OC(C)(C)C)C(N)(O)c1nnc(COC)o1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methoxymethyl-1,3,4-oxadiazole (4.6 g, 40 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in 25.2 mL of hexane) dropwise under N2 at −78° C. After 1 h, MgBr.Et2O (10.4 g, 40.3 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 h before being treated with 2(S)-Boc-aminobutyraldehyde (5.28 g, 28.25 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield 2(S)-Boc-amino-1-(5-methoxymethyl-[1.3.4]-oxadiazol-2-yl)-1-butanol (500 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=C[C:5]([C:8]2[CH:12]3[CH2:13][N:14]([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])[CH2:15][CH:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[N:53]1C=CC=CC=1C1[C@@H]2CNC[C@@H]2ON=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:14]3[CH2:15][CH:11]4[CH:12]([C:8]([C:5]5[CH:4]=[CH:3][CH:2]=[CH:7][N:53]=5)=[N:9][O:10]4)[CH2:13]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Reactant: c1ccc(C2=NO[C@H]3CNC[C@@H]23)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccccn5)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 4e. Acid 104 was isolated as a tan solid.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:22]([C:25]1[C:26]([C:30]([OH:32])=O)=[N:27][NH:28][CH:29]=1)([O-:24])=[O:23].Cl.Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH2:46])[C:40]([NH2:45])=[CH:41][C:42]=1[O:43][CH3:44]>CN(C=O)C>[NH2:45][C:40]1[CH:41]=[C:42]([O:43][CH3:44])[C:37]([O:36][CH3:35])=[CH:38][C:39]=1[NH:46][C:30]([C:26]1[C:25]([N+:22]([O-:24])=[O:23])=[CH:29][NH:28][N:27]=1)=[O:32]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: COc1cc(N)c(N)cc1OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of EDC (4.81 g 25 mmol), HOBt (3.40 g, 25 mmol) and triethylamine (4.67 g, 46 mmol) in DMF (100 ml) was added 4-nitro-1H-pyrazole-3-carboxylic acid (3.63 g, 23.09 mmol) and 4,5-dimethoxy-benzene-1,2-diamine dihydrochloride (5.06 g, 20.99 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between EtOAc (50 ml) and saturated aqueous NaHCO3 (50 ml). A precipitate was formed and removed by filtration. The filtrate was washed with water followed by diethyl ether and then azeotroped with MeOH and toluene to yield 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 36%). 4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35 g, 7.65 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140° C. for 5 hours. The solution was left to cool and the solvent removed in vacuo. The resulting solid was partitioned between EtOAc (25 ml) and brine (25 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield 5,6-dimethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazol (2.08 g, 94%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14]>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[N:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: CC(=O)N(C)C
Product: CC(C)C(=O)Nc1cn2nc(I)ccc2n1
Yield: 73.2 %

Procedure:
Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol), N,N-dimethylacetamide (8.0 mL) and isobutyryl chloride (0.44 mL, 4.23 mmol) as starting materials and in the same manner as in Reference Example 5, the title compound (0.93 g, 73%) was obtained as a dark brown powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].[CH:18](N(C(C)C)CC)(C)C.CI>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Yield: 94.1 %

Procedure:
Compound 107 (1.50 g, 6.69 mmol) was dissolved in DMF (25 mL), and diisopropylethylamine (16.0, 92.7 mmol) and MeI (2.3 mL, 39 mmol) were added. The solid which formed was filtered and the filtrate was concentrated to dryness on a rotary evaporator to provide 15 (1.50 g, 94.3%) as a yellow solid: mp 123°-124° C. (ethanol). The literature (Appleton et al., 1970) reports mp 127° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:7][NH:8][C:9](=[O:31])[C:10]1[C:15]([F:16])=[C:14]([S:17][C:18]2[S:22][C:21]([NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)=[N:20][CH:19]=2)[CH:13]=[CH:12][N:11]=1.C(=O)(O)[O-].[Na+]>CC(C)=O.O.C1COCC1.Cl>[F:16][C:15]1[C:10]([C:9]([NH:8][CH2:7][C:6]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:2]=[O:1])=[O:31])=[N:11][CH:12]=[CH:13][C:14]=1[S:17][C:18]1[S:22][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)=[N:20][CH:19]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC(c4ccccc4)(c4ccccc4)C4OCCO4)c3F)s2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC(C=O)(c4ccccc4)c4ccccc4)c3F)s2)c1
Yield: 104.3 %

Procedure:
A solution of N-(2-(1,3-dioxolan-2-yl)-2,2-diphenylethyl)-3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamide (0.248 g, 0.4040 mmol, described in Example 50) in acetone (10 mL), water (5 mL), THF (5 mL) and conc. HCl (1 mL) was heated at gentle reflux for 10 hours. The reaction was then neutralized with aq. sat. sodium bicarbonate and the volatiles were evaporated. The solid was collected by filtration and vacuum dried to give the crude title material (0.240 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 2.30 (3H, s), 4.27 (2H, d, J=6.32 Hz), 6.83 (1H, d, J=4.55 Hz), 6.89 (1H, s), 7.03 (1H, t, J=5.31 Hz) 7.22 (4H, d, J=7.07 Hz) 7.31-7.37 (2H, m), 7.40 (4H, t, J=7.33 Hz) 7.77 (1H, s), 8.15 (1H, d, J=5.05 Hz), 8.19 (1H, d, J=5.05 Hz), 8.28 (1H, t, J=6.19 Hz). 9.99 (1H, s) 11.82 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:37]([CH2:42][CH3:43])[CH2:38][CH2:39]CO)[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:36][CH2:35][N:37]([CH2:42][CH3:43])[CH2:38][CH3:39])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN(CC)CCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN(CC)CCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 41.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-(diethylamino)-1-propanol (34 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (32 mg, yield 36%).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:23]([CH3:38])[CH:22]=2)[CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[CH3:38][C:23]1[CH:22]=[C:21]([O:20][CH2:19][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[O:39])=[CH:10][CH:11]=2)[CH:16]([CH3:18])[CH3:17])[CH:26]=[C:25]([CH3:27])[C:24]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(COc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(OCC(c2ccc(C(=O)NCCC(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
Racemic 3-{4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-2-methyl-propyl]-benzoylamino}-propionic acid ethyl ester (50 mg, 0.09 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) is added. The reaction may be monitored by HPLC. After a period of 3 h, the reaction is neutralized with 5N HCl (1 mL), and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated to provide the title compound without further purification. MS (ES): 526.2 [M+H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccncn2)cc1
Product: O=CC=Cc1ccc(-c2ccncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 18) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:31]3[C:27](=[O:37])[C:28]4=[CH:36][CH:35]=[CH:34][CH:33]=[C:29]4[C:30]3=[O:32])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc(CN3C(=O)c4ccccc4C3=O)c(=O)n(CC3CC3)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (220 mg, 0.57 mmol) in N,N-dimethylformamide (5 mL) was added potassium phthalimide (160 mg, 0.87 mmol), and the mixture was stirred at 80° C. for 2 hours. Water (30 mL) was added to the reaction mixture. After stirring under cooling over ice water, precipitated crystals were collected by filtration, dried in air, and recrystallized from chloroform-hexane to yield the title compound as colorless needles (202 mg, 81.0%).
Reaction SMILES: OC[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10](C)(C)C)[CH2:4][O:5][CH3:6].O1CCCC1.CC(C)([O-])C.[K+]>O>[CH3:6][O:5][CH2:4][C@H:3]1[CH2:10][O:9][C:8](=[O:14])[NH:7]1
Reactant: COC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl [(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (synthesized according to the procedure described in Sowinski, J. A.; Toogood, P. L. J. Org. Chem. (1996), 61(22), 7671-7676) (8.3 g, 40.4 mmol) tetrahydrofuran (100 mL), 1M solution of potassium t-butoxide in tetrahydrofuran (80.9 mL, 80.9 mmol) was added dropwise at 0° C. and the mixture was stirred at the room temperature for 2 hours. Water (20 ml) was added to the reaction mixture and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine and dried over Na2SO4. Yield: 5.0 g (94%). 1H NMR (300 MHz, DMSO-d6) δ: 3.3 (s, 3H), 3.3 (m, 2H), 3.9 (m, 1H), 4.0 (dd, 1H), 4.3 (t, 1H), 7.7 (d, 1H). [α]D25=−5.876.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[NH:40]1[CH:44]=[C:43]([C:45](O)=[O:46])[N:42]=[CH:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([C:43]2[NH:42][CH:41]=[N:40][CH:44]=2)=[O:46])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(O)c1c[nH]cn1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1cnc[nH]1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure E using 4-imidazolecarboxylic acid. The final product was obtained in 20% yield.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O[CH:13](O)[CH:14]([F:16])[F:15])C.[OH-].[Na+].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.CO.C(Cl)Cl>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:13][CH:14]([F:16])[F:15])[CH3:6]
Reactant: CCOC(O)C(F)F
Reactant: CCOC(CN)OCC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(CNCC(F)F)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A solution of 3 g (22.5 mmol) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mmol) of difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120° C. with a Dean-Stark trap for 1.5 hours. The mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was diluted with 80 ml of methanol, and 3.4 g (90 mmol) of sodium borohydride were added in small quantities. The reaction mixture was then stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. 3.7 g of crude substance were obtained as a colorless oil. The residue was subjected to a flash chromatography on 40 g of SiO2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[C:26]([CH2:32][C:33]#[N:34])(=O)[C:27]([CH3:30])([CH3:29])[CH3:28]>Cl.O>[NH2:34][C:33]1[N:1]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][N:8]3[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])=[CH:4][CH:3]=2)[N:17]=[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:32]=1
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CC2
Reactant: CC(C)(C)C(=O)CC#N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)N(C(=O)C(F)(F)F)CC3)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
To an ice-cold solution of 1-(6-aminoindolin-1-yl)-2,2,2-trifluoroethanone (7.00 g, 30.4 mmol) in 6N HCl (50 mL) was dropwise added a solution of NaNO2 (2.10 g, 30.4 mmol) in H2O (5 mL). The resulting slurry was stirred at 0° C. for 30 min. A solution of SnCl2.2H2O (11.5 g, 60.8 mmol) in conc. HCl (60 mL) was added dropwise and after the addition was complete the resulting slurry was stirred at RT for 2 h. The mixture was filtered and the resulting solid was redissolved in EtOH (200 mL). Pivaloyl acetonitrile (4.57 g, 36.5 mmol) was added and the solution was heated at reflux overnight. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL), dried (MgSO4), concentrated and purified by recrystallization from ethyl acetate/hexanes to yield 1-(6-(5-amino-3-t-butyl-1 H-pyrazol-1-yl)indolin-1-yl)-2,2,2-trifluoroethanone (3.2 g, 30% yield) as a light-brown solid. 1H-NMR (400 MHz, acetone-d6): δ 8.49 (d, J=2.0 Hz, 1H), 7.51 (dd, J=8.4, and 2.0 Hz, 1H), 4.41 (t, J=8.2 Hz, 2H), 3.32 (t, J=8.2 Hz, 2H), 1.32 (s, 9H), pyrazolamine protons not observed; MS (ESI) m/z: 353.2 (M+H+).