Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([O:38]C)=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([OH:38])=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)cc2cn1
Temperature: 120 °C
Yield: 60.1 %

Procedure:
To a solution of methyl 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (39 mg, 0.070 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.10 mL, 0.10 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated under a nitrogen stream and 1 N aqueous hydrochloric acid (0.10 mL, 0.10 mmol) was added. The solution was concentrated further under an nitrogen stream and water was added followed by ethyl acetate. A solid precipitated. The water layer was removed and ether was added and the solid was isolated by filtration. The solid was dried under a nitrogen stream at 45° C. to afford 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (23 mg, 60%). 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.81 (s, 2H), 8.60 (s, 1H), 8.43 (s, 1H), 8.25-8.10 (m, 2H), 7.75 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.99 (m, 1H), 2.50-2.40 (m, 4H), 2.15-2.05 (m, 1H), 2.00-1.90 (m, 1H). HRMS (ESI) C29H21Cl2N3O4 calculated: 546.0982 [M+H]+, found: 546.0981 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>CN(C=O)C.ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:40][CH2:39][CH2:38][C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[O:26])=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Reactant: NCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)NCCc4ccncc4)cc3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.1 %

Procedure:
A mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (41 mg, 0.1 mmol), 2-(pyridin-4-yl)ethanamine (15 mg, 0.12 mmol), EDCI (77 mg, 0.4 mmol), N-methyl-imidazole (33 mg, 0.4 mmol), dichloromethane (3 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo, triturated with water (10 mL×3), and the residue purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1) to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (12 mg, 24%) as a yellow oil. 1H NMR (300 MHz, DMSO): δ 9.68 (s, 1H), 8.81 (s, 1H), 8.74-8.70 (m, 1H), 8.49-8.47 (m, 2H), 8.23 (s, 1H), 8.03-7.95 (m, 4 h), 7.68 (s, 1H), 7.46 (t, 1H, J=8.4 Hz), 7.30 (s, 1H), 7.29 (s, 1H), 6.75 (d, 1H, J=7.5 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.61-3.56 (m, 2H), 3.47-3.40 (m, 2H), 2.92 (t, 2H, J=6.6 Hz), 2.11-1.99 (m, 3H), 1.71 (s, 1H), 0.85 (d, 3H, J=6.6 Hz). LC-MS: [M+H]+, 519, tR=1.333 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.008 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:4][C:3]=1[Cl:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)c(Cl)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Benzyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (20.8 g, 54.7 mmol) and N-chlorosuccinimide (8.04 g, 60.2 mmol) were dissolved in N,N-dimethylformamide (339 mL) and allowed to stir overnight. The reaction was diluted with water, extracted with diethyl ether, washed with saturated aqueous sodium chloride then dried over MgSO4, filtered and the solvent evaporated. The mixture was purified by silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give an orange oil (13.7 g, 62%). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 6.95 (s, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.61 (d, J=8.0 Hz, 2H), 5.18 (d, J=12.1 Hz, 1H), 5.10 (d, J=12.3 Hz, 1H), 4.98 (d, J=8.2 Hz, 1H), 4.71 (d, J=5.3 Hz, 1H), 4.54 (m, 1H), 3.97 (m, 2H), 2.96 (m, 2H), 1.43 (s, 9H); LCMS found for C21H25ClN2NaO4 (M+Na)+: m/z=427.0.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCN1CCNC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCN1CCNC1=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol), 1-(2-aminoethyl)imidazolidin-2-one (22.46 mg, 0.087 mmol), 4-methylmorpholine (23.45 mg, 0.232 mmol), and HATU (28.7 mg, 0.075 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13.2 mg, 0.024 mmol, 42.0% yield): LCMS=543.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.23 (2 H, m), 7.54-7.73 (7 H, m), 5.11 (1 H, s), 3.32-3.49 (6 H, m), 3.21-3.29 (2 H, m); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: [NH2:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36])=[CH:28][CH:27]=1)[C:3]([NH:5][C@@H:6]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[Cl:17])=[O:8])=[O:4].C(N(CC)CC)C.Cl[Si:46]([CH3:49])([CH3:48])[CH3:47]>C(OCC)(=O)C>[NH2:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([O:37][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH2:35][O:36][Si:46]([CH3:49])([CH3:48])[CH3:47])=[CH:28][CH:27]=1)[C:3]([NH:5][C@@H:6]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[Cl:17])=[O:8])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@@H](CO[Si](C)(C)C)O[Si](C)(C)C)cc1)C(=O)Nc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,3S)-2-{(R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-acetylamino}-N-(2-chloro-4-iodo-phenyl)-3-phenyl-butyramide (330 mg, 0.44 mmol) in dry, degassed tetrahydrofuran (5 mL) were added triethylamine (277 μL, 1.98 mmol) and chlorotrimethylsilane (230 μL, 1.76 mmol) and the mixture stirred at ambient temperature for 30 minutes. The resulting suspension was diluted with ethyl acetate (50 mL) and washed with brine (2×50 mL). The combined brine layers were back extracted with ethyl acetate (2×50 mL), the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2S,3S)-2-{(R)-2-amino-2-[4-((S)-2,3-bis-trimethylsilanyloxy-propoxy)-phenyl]-acetylamino}-N-(2-chloro-4-iodo-phenyl)-3-phenyl-butyramide which was of adequate purity for subsequent use in step 6 without additional purification (330 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH2:32][CH2:31]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccncc1)c1ccc(Br)cc1
Product: Cc1ccccc1C(C/C(=N\O)c1ccncc1)c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
In analogy to example 39, from (E)-3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and 1-methanesulfonyl-piperazine (CAS RN: [55276-43-2]) was prepared the title compound as an off-white foam, MS (ESI+): m/z=479.2 ([M+H]+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:12]1[C:13]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16][C:14]=2[N:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1ccccc1-c1nc(Cl)c2cc(C(F)(F)F)cnc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 970 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one, 0.39 ml of phosphorus oxychloride, 428 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 100° C. for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 996 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-6-trifluoromethylpyrido[2,3-d]pyrimidine (Compound of Present Invention 22).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].I[CH3:14]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:14])[CH:8]=[CH:7]2
Reactant: Clc1cccc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloroindole (610 mg, 4 mmol) in anhydrous DMF (6 mL) was added NaH (170 mg, 60% dispersion in mineral oil, 4.3 mmol) at 0° C. under argon. The mixture was stirred at room temperature for 30 min before adding iodomethane (240 mg, 4 mmol). The resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with saturated NaCl (10 mL×3), dried over anhydrous MgSO4, filtered, and concentrated to give 7-chloro-1-methylindole. The residue was used directly for the next step without further purification. NMR (500 MHz, CDCl3): 4.14 (s, 3H), 6.46 (d, 1H, J=2.5), 6.95-6.98 (m, 2H), 7.12-7.14 (m, 1H), 7.48 (1H, dd, J=1.5, 7.5).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CC(C)([O-])C.[K+].CS(O[CH2:21][CH:22]1[C:26]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=2[O:24][CH2:23]1)(=O)=O.O>CN1C(=O)CCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][CH:22]([CH2:21][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:26]=2[CH:27]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CS(=O)(=O)OCC1COc2ccc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C(CC1COc2ccc(F)cc21)C(=O)OC
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Dimethyl malonate (262 g) was dissolved in NMP (2 l) and potassium tert-butoxide (202 g) was added portionwise keeping the temperature at 15-20° C. The mixture was heated to 60° C. and a solution of 2,3-dihydro-5-fluorobenzofuran-3-ylmethyl methanesulfonate (155 g) in NMP (150 ml) was added dropwise. The mixture was stirred for 4 h at 70-75° C. followed by addition of cold water. Extraction with ether, drying the ether phase over magnesium sulfate, followed by removal of solvent in vacuo gave dimethyl 2-(2,3-dihydro-5-fluorobenzofuran-3-ylmethyl)malonate (160 g) as an oil, which was sufficiently pure for the further synthesis.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:14]([OH:16])=[O:15]>>[F:10][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[C:13]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:14]([OH:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
10.0 mL of conc. HNO3 at 0° C. was treated with 20.0 mL of conc. H2SO4, then 6.4 g (40 mmol) of 3,5-difluorobenzoic acid. The reaction mixture was warmed to room temperature and stirred overnight, then poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to produce 8.0 g (80%) of 3,5-difluoro-2-nitro-benzoic acid. LCMS: 204 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:5]=1)[CH2:28][OH:29]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(C(F)(F)F)cc1
Reactant: NC(CO)CO
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethylphenyl)vinyl]benzoic acid obtained in step A of Example 2-2-38 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.[Li][C:8]([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:1]1[CH:2]=[CH:3][CH2:4][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1C=CCC1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC=C1
Temperature: 20 °C
Yield: 20.2 %

Procedure:
2-Cyclopenten-1-one (14.2 mL, 0.17 mol) was added dropwise over about 30 min. at about -78° C. to t-BuLi (340 mmol) in dry THF (450 mL). The reaction was allowed to warm to about 20° C. and then chilled to about -78° C. to quench with NH4Cl (18.2 g). Solvent was removed in vacuo and the residue was partitioned between Et2O (300 mL) and brine (100 mL). The organic phase was washed with brine, dried over MgSO4 (s), filtered and concentrated in vacuo. The residue of crude 1-tert-butylcyclopent-2-en-1-ol (23.8 g) was treated with benzenesulfonic acid (0.24 g) in refluxing Et2O for 1.5 h. Solvent was removed in vacuo and the residue was vacuum distilled (12 mm, ~27-30° C.) to obtain pure 2-tert-butylcyclopentadiene (4.2 g). This diene (1.3 g, 10.7 mmol) was dissolved in xylene (5 mL) along with a crystal of hydroquinone and trans-β-nitrostyrene (1.95 g, 13.1 mmol). The tube was sealed under N2 (g) and heated to about 140° C. for about 10 h. Flash chromatography on silica (30% CH2Cl2 /hexanes) afforded 1.79 g (GC-MS m/z 271) of the nitro derivative which was reduced by dropwise addition of an etheral (10 mL) solution over 20 min. to LiAlH4 (0.5 g) in Et2O (25 mL). The mixture was refluxed for about 5 h. and quenched by serial additions of H2O (0.5 mL), 15% NaOH (0.5 mL) and H2O (1.5 mL), respectively. The mixture was filtered and the filtrate was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 (s), filtered, and concentrated in vacuo. The residue (1.1 g) was dissolved in dry Et2O (6 mL), chilled to about 5° C., and treated dropwise with 1M HCl in Et2O (6 mL) to precipitate the desired amine as its HCl salt (610 mg; LC-MS m/z 242).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[CH3:33])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[CH3:33])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1-c1ccc(C(=O)NCCC(=O)O)nc1)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.29 mL, 0.88 mmol) was added to a THF (2 mL) and MeOH (1 mL) solution of ethyl 3-(5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinamido)propanoate (165 mg, 0.29 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH:12](OCC)(OCC)OCC>>[O:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:12]1
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: CCOC(OCC)OCC
Product: O=C(O)c1ccc2ocnc2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 3-amino-4-hydroxybenzoic acid (8.0 g, 1.0 eq) and 60 mL CH(OEt)3 was heated to reflux for 3 h, and then cooled to rt. The remaining CH(OEt)3 was removed under reduced pressure to give the desired product (7.8 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (brs, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCNC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 8.6 g. (0.019 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-ureidoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:23])([F:22])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19](=S)[NH2:20])[CH:9]=[CH:10][CH:11]=1>CO>[F:4][C:5]([F:23])([F:22])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([NH:2][NH2:3])=[NH:20])[CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: NC(=S)c1ccccc1Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CO
Product: N=C(NN)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
Hydrazine hydrate (1.80 ml) is added dropwise to a room temperature solution of 2-[(3-trifluoromethylphenyl)amino]benzene thioamide (2.88 g, 9.73 mmoles) in 100 ml of methanol. The solution is stirred at room temperature under nitrogen for six hours. An additional 400 μl of hydrazine hydrate is added, and stirring is continued for one hour. The solution is concentrated in vacuo and purified by flash chromatography eluting with ethyl acetate to give 2.28 g (80%) of a gummy tan solid. This material is used immediately in the next reaction.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:21][CH2:22][C@H:23]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1)[CH3:24]>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([C@H:23]([CH3:24])[CH2:22][NH:21][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=3)=[O:12])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: CC(C)(O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@H](CNC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)(C)O)n1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-hydroxypropan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.43 mmol, 430 mg) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.43 mmol, 400 mg). The product was purified by flash-chromatography. Yield 410 mg. LC-MS: [M+1]=561.21.