Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[CH2:8][CH2:7][NH:6]1)[CH3:4].C(N(CC)C(C)C)(C)C.[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:33][C:34]([N:6]1[CH2:7][CH2:8][C:9]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[CH:5]1[CH2:3][CH3:4])=[O:35])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CCC1NCCc2nccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1c2nccnc2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Ethyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine dihydrochloride (Intermediate 32, 26 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (DMF, 0.75 mL) containing N,N-diisopropylethylamine (0.046 mL, 34 mg, 0.26 mmol). (3R)-3-(tert-Butoxycarbonylamino)4 (2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 36 mg, 0.11 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and a portion of molecular sieve pellets (4 Å) were added, followed 10 min later by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol). After stirring for 16 h at room temperature, the mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was washed with saturated aqueous brine (10 mL) and the aqueous layers were extracted in succession with ethyl acetate (25 mL). The organic layers were dried over sodium sulfate, decanted, and evaporated. Purification by flash column chromatography (silica gel, 15-20% ethyl aceate/0.75-1.0% methanol/dichloromethane) gave the title compound as a mixture of diastereomers. Separation was accomplished by EPLC using a Chiralcel OJ column, eluting with 8% ethanol in hexanes. The first-eluting diastereomer was used in Step B to produce the more active final product. LC/MS: 501 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dichloroaniline (8.87 g, 54.8 mmol) in ethanol (40 mL) was added to a solution of 2,4,6-trichloropyrimidine (10.0 g, 54.8 mmol) in ethanol (20 mL) followed by aqueous Na2CO3 (4.61 g, 43.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. The crude mixture was diluted with water (100 mL), and the resulting precipitate was filtered and dried (10.2 g, 61%). ESI-MS m/z: 307 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20](O)=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:27])=O.CN(C)C=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20]([Cl:27])=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O

Procedure:
5.7 g (19 mmol) of 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid and 3.1 g (24 mmol) of oxalyl chloride were dissolved in dichloromethane (10 mL), and 0.026 g (0.35 mmol) of dimethylformamide was added thereto. The mixture was heated to reflux for 2 hours while stirring. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride as yellow crystals (Compound No. of Production Intermediate: IX-73).
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:37]([O:39][CH3:40])=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OCC1C=CC=CC=1)=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O>CO>[NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:37]([O:39][CH3:40])=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 145.8 %

Procedure:
Dilysine 10 (7.43 g, 0.0113 mol) was dissolved in MeOH (100 mL). After being purged with nitrogen, 10% Pd/C (0.30 g) was added. The flask was then purged with hydrogen and the reaction mixture was stirred for overnight. The Pd/C was removed by filtration through a pad of celite. Trifluoroacetic acid (TFA, 1.8 mL, 0.023 mol) was added into the filtrate and then the solvent was removed in vacuo to give viscous oil. A white gluey substance was obtained by triturating with 20 mL diethyl ether. The resulting substance was dried in vacuo to give the glassy solid product 11 (6.4 g, 92%): 1H NMR (500 MHz, d6 DMSO) δ 8.19 (d, J=7.5, 1 H), 7.90 (br s, 6H), 6.82 (d, J=8.0, 1 H), 4.23 (m, 1H), 3.91 (m, 1H), 3.61 (s, 3H), 2.75 (m, 4H), 1.36-1.61 (m, 21H); 13C NMR (125 MHz, d6 DMSO) δ 172.4 (2), 158.4 (q, 2), 155.3, 117.2 (q, 2), 78.0, 53.9, 51.6, 38.7, 38.6, 31.2, 30.3, 28.1 (3), 26.7, 26.5, 22.3, 22.2; HRMS (FAB) m/z calcd for C22H38F6N4O9 (M+H)+ 389.2764, found 389.2767.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:15].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Br:5])=[C:7]([OH:15])[CH:8]=1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
1.5 ml of thionyl chloride was added to 40 ml of MeOH at 0° C. The solution was stirred for 10 min and 5 g of 4-Bromo-3-hydroxy-benzoic acid was added. The reaction was stirred for 16 h at RT then heated to 50° C. for 3 h. The solvents were removed under reduced pressure. The residue was used directly in the next step. Yield 5.92 g.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 256 (20), 86 (bp), 70 (6), 57 (8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9](B(O)O)([CH3:11])=[CH2:10].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]([CH3:11])=[CH2:10])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C=C(C)B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C=C(C)c1cccc(Br)n1
Temperature: 100 °C

Procedure:
In a tube were placed 2,6-dibromopyridine (100 mg, 0.422 mmol), isopropenylboronic acid (40 mg, 0.464 mmol), DME (1.5 mL), EtOH (500 μL), and 1M aqueous Na2CO3 (1 mL, 1.0 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (37 mg, 0.032 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for 1 hour. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5% EtOAc/hexanes) afforded 2-bromo-6-isopropenylpyridine. Rf=0.45 (15% EtOAc/hexanes). LCMS=200.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.49 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 5.93 (s, 1H), 5.32 (m, 1H), 2.17 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]([O:11]CC)=O)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1.[C:14](#[N:16])[CH3:15]>C1(C)C=CC=CC=1>[CH:3]1([C:9]([CH2:15][C:14]#[N:16])=[O:11])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: CC#N
Reactant: CCOC(=O)C1CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCC(=O)C1CC=CCC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a suspension of 1.25 g (2.60 mM) of 50% sodium hydride in 10 ml of toluene is added dropwise a solution of 2.01 g (1.30 mM) of ethyl 3-cyclohexenylcarboxylate 11 and 0.96 g (2.34 mM) of acetonitrile in 4 ml of toluene under nitrogen atmosphere in an hour and the mixture is stirred at 85° C. for 8 hours. After cooling, ice-cold water is added to the mixture. The aqueous phase is separated, washed with toluene, made acid with 10% hydrochloric acid and extracted with toluene. The extracted solution is washed with a dilute aqueous sodium hydrogencarbonate, and then with water, dried on magnesium sulfate and evaporated under reduced pressure. The resulting residue is chromatographed over silica gel and eluted with chloroform to give 1.91 g of the titled compound 8 as an yellow oil in 98.4% yield,
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: COc1cc(C(=O)c2ccccc2)ccc1-c1cccc(C)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(-c2ccc(C(=O)c3ccccc3)cc2O)c1
Temperature: -78 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Ketone 17 was dissolved in dry DCM and the resulting solution was cooled to −78° C. BBr3 (1.5 eq, 0.49 mM) was then added drop wise and the reaction mixture was allowed to warm to room temperature and was stirred for an additional 12 hours. After the completion of the reaction as determined by TLC, the reaction mixture was diluted with methanol, and then washed with bicrab, water brine. The product was then subjected to column chromatography using 20% EtOAc/hexanes as the solvent system. Yield=46.5% (Rf=0.31; 20% EtOAc/Hexanes) 1H NMR, 300 MHz Varian, CDCl3 δ 7.88 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.47 (m, 2H), 7.43 (d, J=6.3 Hz, 2H), 7.38 (s, 1H), 7.34 (s 7.27 (m, 1H), 2.46 (s, 3H), MS: m/z (ESI, pos.)=325.5 ([M+23]). HPLC retention time: 11.246 min. and 10.804 min; purity 97.92%.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:8]([C:10]1[CH:25]=[CH:24][C:13]([CH:14]=[C:15]([C:21](=O)[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)#[N:9].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:8]([C:10]1[CH:25]=[CH:24][C:13]([CH:14]2[N:4]3[N:5]=[N:6][N:7]=[C:3]3[NH:2][C:21]([CH3:22])=[C:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)#[N:9]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Nc1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 5-amino-1,2,3,4-tetrazole hydrate (1.0 g, 9.7 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (2.6 g, 10.7 mmol, 1.1 eq.) were dissolved in DMF (50 ml), and solid sodium bicarbonate (4.1 g, 48.5 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered and the DMF from the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol and stirred overnight. The product was filtered off and dried under high vacuum. This gave 950 mg (32% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9]CC)=O)[N:5]=[C:4]2[C:12]([CH3:30])([CH3:29])[N:13]([C:15]([NH:17][C@@H:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][N:20]([CH3:22])[CH3:21])=[O:16])[CH2:14][C:3]=12.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[C:46](C(Cl)=O)=[C:45]([F:50])[C:44]([CH3:51])=[CH:43][CH:42]=1.[OH-].[Na+]>>[Cl:40][C:41]1[C:46]([C:7]([NH:6][C:2]2[C:3]3[CH2:14][N:13]([C:15]([NH:17][C@@H:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][N:20]([CH3:21])[CH3:22])=[O:16])[C:12]([CH3:30])([CH3:29])[C:4]=3[NH:5][N:1]=2)=[O:9])=[C:45]([F:50])[C:44]([CH3:51])=[CH:43][CH:42]=1
Reactant: CCOC(=O)n1nc2c(c1N)CN(C(=O)N[C@H](CN(C)C)c1ccccc1)C2(C)C
Reactant: Cc1ccc(Cl)c(C(=O)Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)c(C(=O)Nc2n[nH]c3c2CN(C(=O)N[C@H](CN(C)C)c2ccccc2)C3(C)C)c1F

Procedure:
To a 13×100 mm test tube were added one 3×6 mm stir bar, compound 71b, (0.1 M in CH2Cl2, 80 μmol, 1.0 eq), DIPEA solution (2 M in CH2Cl2, 160 μmol, 2.0 equiv), and 6-chloro-2-fluoro-3-methylbenzoyl chloride (0.1 M in CH2Cl2, 160 μmol, 2.0 eq.). The reaction was covered and stirred at RT for 12 h. NaOH (1M, 1000 μmol, 12.5 equiv) was added, and the reaction mixture was agitated for 15 minutes. After centrifugation, the top layer was removed. The organic layer was evaporated. MeOH (500 μL) and TEA (500 μL) were added, and the reaction mixture was allowed to stir at RT overnight. The solvents were evaporated, and the residue was reconstituted in DMSO. 1H NMR (500 MHz, D2O) d ppm 1.52 (s, 3H) 1.59 (s, 3H) 2.13 (s, 6H) 2.21 (s, 3H) 2.34 (dd, J=12.22, 5.63 Hz, 1H) 2.59 (dd, J=12.91, 10.16 Hz, 1H) 4.48 (d, J=11.81 Hz, 1H) 4.52 (d, J=12.09 Hz, 1H) 4.81 (q, J=5.77 Hz, 1H) 6.18 (br. s., 1H) 7.14 (t, J=7.55 Hz, 1H) 7.21-7.27 (m, 3H) 7.28-7.38 (m, 3H). LCMS: M+H+: 513.2
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C@@H:13]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][O:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:15])[CH3:10])C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:32]1([C@H:13]([NH:12][C:11](=[O:38])[C@@H:9]([NH:7][CH3:6])[CH3:10])[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH2:21][O:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:15])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1CCC[C@H]1COC1Cc2ccccc2C1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1COC1Cc2ccccc2C1)C1CCCCC1
Yield: 21.7 %

Procedure:
((S)-1-{(S)-1-Cyclohexyl-2-[(S)-2-(indan-2-yloxymethyl)-pyrrolidin-1-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (Q) (0.54 g, 1 mmol) is dissolved in DCM (8 mL) and treated with trifluoroacetic acid (4 mL) for 45 minutes. The reaction mixture is concentrated in vacuo, purified by preparative reverse-phase hplc to give 0.096 g of the methylamine (34) as a clear gum: LCMS (ES) 442.26 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][CH2:13][Mg+].[Br-].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CC[Mg+]
Reactant: COc1cc(Cl)ccc1C=O
Agent: O=[Cr](=O)([O-])Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Cl)cc1OC
Reaction time: 1 h
Yield: 66.1 %

Procedure:
4-Chloro-2-methoxy-benzaldehyde (0.54 g, 3.2 mmol) in 10 mL of THF was treated with 3.0 M EtMgBr (2 mL, 6.0 mmol) at room temperature. The solution was stirred for 1 hour and quenched with MeOH. The solution was poured into water, treated 10 mL of 10% HCl, extracted with EtOAc several times. The combined organic layers were washed brine, dried (MgSO4), filtered, and concentrated. The residue was diluted with CH2Cl2, treated with PCC (1.33 g, 6.4 mmol) for 2 hours. The reaction mixture was filtered through a pack of silica gel to give 0.42 g of the title compound. MS (DCI) m/e 199 (M+H)+.
Reaction SMILES: C([NH:3][C@@H:4]1[C:53](=[O:54])[N:6]2[C:7]([C:37]([O:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])=[C:8]([S:11][CH2:12][C:13]3[CH:14]=[N:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)[CH2:9][S:10][C@H:5]12)=O.Cl>CO>[NH2:3][C@@H:4]1[C:53](=[O:54])[N:6]2[C:7]([C:37]([O:39][CH:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:38])=[C:8]([S:11][CH2:12][C:13]3[CH:17]=[N:16][NH:15][CH:14]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)CS[C@H]12
Agent: Cl
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
Diphenylmethyl 7β-formamido-3-[(1-tritylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (121.7 g) was suspended in methanol (1.46 l), concentrated hydrochloric acid (94.8 ml) was added thereto below 25° C. The reaction mixture was stirred at the room temperature for 3 hours, and then concentrated hydrochloric acid (4.0 ml) was added. After the reaction mixture was stirred at the same temperature for one hour, insoluble precipitate was filtered off below 10° C. The filtrate was poured into a mixture of ethyl acetate (4.5 l) and water (4 l). The aqueous layer was adjusted at pH 4.0 with 30% aqueous sodium hydroxide solution and then was adjusted at pH 6.9 with 2N-potassium hydroxide. The organic layer was separated, washed with brine (4 l), dried over magnesium sulfate, and evaporated until the volume amounted to 700 ml. IPE (100 ml) was added to the suspension gradually below 10° C., and was left below 10° C. for 12 hours. The precipitate was filtered and dried under reduced pressure to give diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (62.4 g) as powder.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[C:27]12([O:37][CH2:38][CH2:39]O)[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>CN(C)C=O>[O:12]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:39][CH2:38][O:37][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[CH:7][CH:6]=1)[C:3]([OH:2])=[O:13]
Reactant: OCCOC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(=O)c1ccc(OCCOC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the tosylate prepared from 2-(1-adamantyloxy) ethanol (1.5 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane-ethyl acetate; 80:20:2) and crystallized from diethyl ether-hexane to provide 0.77 g of alpha-oxo-4-[[2-[tricyclo(3.3.1.1-3,7)dec-1-yloxy]ethyl]oxy]benzeneacetic acid, mp 107°-109° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25](C=O)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25]1[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNC1CCCc2cccnc21
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N(CCCNC(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B, reaction of [3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-carbamic acid tert-butyl ester, 3,5-dimethylpyridine-2-carboxaldehyde and NaBH(OAc)3 in CH2Cl2 gave {3-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-carbamic acid tert-butyl ester as a pale beige sticky solid. 1H NMR (CDCl3) δ 1.75 (m, 4H), 2.18 (br t, 1H), 2.27 (s, 3H), 2.30 (s, 3H), 2.37 (br, 1H), 2.56 (t, 1H, J=10.5 Hz), 2.83 (m, 4H), 3.38 (br, 1H), 3.68 (d, 1H, J=15.0 Hz), 3.84 (br, 1H), 4.04 (d, 1H, J=15.0 Hz), 7.13 (m, 1H), 7.26 (s, 1H), 7.41 (d, 1H, J=7.0 Hz), 8.33 (s, 1H), 8.53 (d, 1H, J=4.5 Hz). Deprotection with TFA using General Procedure F gave N-(3,5-dimethyl-pyridin-2-yl)-N]-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(OCC)c1c(F)cc(Oc2ccc(OC)cc2)cc1F
Yield: 64.6 %

Procedure:
(RS)-(2,6-Difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (500 mg) was dissolved in CH2Cl2 (20 ml). Cu(OAc)2 (349 mg), 4-methoxyphenylboronic acid (876 mg) and MS4 Å were added followed by pyridine (760 mg). The mixture was stirred over night before filtration and evaporation of the solvent. CC (Hept/CH2Cl2 1:4) afforded 455 mg (65%) of (RS)-[2,6-difluoro-4-(4-methoxy-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester. Yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.O=[C:14]1[CH2:19][CH2:18][CH2:17][S:16][CH:15]1[C:20](OCC)=[O:21]>C(O)(=O)C.O>[N:7]1([C:4]2[N:3]=[C:2]3[NH:1][C:14]4[CH2:19][CH2:18][CH2:17][S:16][C:15]=4[C:20](=[O:21])[N:6]3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nc(N2CCCCC2)n[nH]1
Reactant: CCOC(=O)C1SCCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c([nH]c3nc(N4CCCCC4)nn13)CCCS2
Reaction time: 0.17 h
Yield: 80 %

Procedure:
16.7 g (0.1 mole) of 5-amino-3-piperidino-1H-1,2,4-triazole are dissolved in 10 ml of acetic acid and 18.8 g (0.1 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added, then the reaction mixture is boiled for 10 minutes. The thick crystal mass thus obtained is diluted with 100 ml of water, the precipitated product is filtered off, washed with i-propanol and recrystallized from dimethylformamide. Thus 23.3 g (82.2%) of 2-piperidino-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained with a melting point above 350° C.