Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][NH:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][OH:19])[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.Cl[C:23]1[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35]([C:23]2[N:28]=[CH:27][C:26]([O:19][CH2:18][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[O:20])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH3:17])=[CH:25][CH:24]=2)=[CH:34][CH:33]=1
Reactant: CCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: Oc1ccc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Example 21, using 3-[4-(1-hydroxymethyl-butyl)-benzoylamino]-propionic acid methyl ester and 6-chloro-pyridin-3-ol as starting materials in Step A, followed by 4-trifluoromethyl phenyl boronic acid in Step B. MS (ES): 499.2 [M+H]−.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[N:20]3[CH:21]=[C:22]([O:25][C@@H:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C@H:29]([NH:36][C:37]([NH:39][C:40]5[N:41]([C:49]6[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=6)[N:42]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:44]=5)=[O:38])[CH2:28][CH2:27]4)[CH:23]=[CH:24][C:19]3=[N:18][N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[C:45]([C:43]1[CH:44]=[C:40]([NH:39][C:37]([NH:36][C@@H:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]4[N:20]([C:16]([CH2:15][N:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)=[N:17][N:18]=4)[CH:21]=3)[CH2:27][CH2:28]2)=[O:38])[N:41]([C:49]2[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=2)[N:42]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@@H]2CC[C@H](Oc3ccc4nnc(CN5CCN(C(=O)OC(C)(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCNCC5)n4c3)c3ccccc32)cc1
Reaction time: 4.5 h

Procedure:
HCl (4M in dioxane; 1 mL) was added to a solution of Intermediate 7d (92 mg, 0.12 mmol) in MeOH (1 mL) at Rt and stirred for 4.5 h. The solution was loaded on to a SCX-2 cartridge, eluting with MeOH followed by 2M NH3 in MeOH, to give a pale yellow foam. Further purification by HPLC (40-80% MeCN in H2O (0.1% NH3)) gave the title compound as an off-white powder after freeze drying (28 mg, 35%). LCMS (Method 5): Rt 3.59 min, m/z 634 [MH+]. 1H NMR (400 MHz, CDCl3): 1.33 (9H, s), 1.89-1.98 (1H, m), 2.06-2.14 (2H, m), 2.25-2.32 (1H, m), 2.38 (3H, s), 2.38-2.48 (4H, m), 2.80-2.83 (4H, m), 4.03 (2H, s), 5.06-5.12 (1H, m), 5.20-5.24 (2H, m), 6.28 (1H, s), 6.34 (1H, br s), 7.08 (1H, dd, J 9.8, 2.0), 7.23-7.36 (6H, m), 7.40 (2H, d, J 7.7), 7.63 (1H, d, J 9.5), 8.14 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][C@@H:17]([F:20])[CH2:16]2)[N:11]([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][C@@H:17]([F:20])[CH2:16]2)[N:11]([CH2:21][C:22]([OH:24])=[O:23])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CN2CC[C@@H](F)C2)CN1C(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)O)[C@@H](CN2CC[C@@H](F)C2)CN1C(=O)OC(C)(C)C

Procedure:
Prepared from (2R,5S)-4-benzyloxycarbonylmethyl-5-((R)-3-fluoro-pyrrolidin-1-ylmethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester using a similar method to that described in Preparation 272 (EtOH used as solvent). 1H NMR (CDCl3): 10.12-9.12 (1H, brs), 5.27 (1H, d), 4.17-3.89 (1H, m), 3.81-3.45 (3H, m), 3.45-2.78 (8H, m), 2.78-2.43 (2H, m), 2.42-1.99 (2H, m), 1.47 (9H, s), 1.23 (3H, d).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:40])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:40])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][C:36]([F:38])([F:39])[F:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCC(F)(F)F)c1
Yield: 74 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 4.8 eq) of sodium hydroxide and methyl 3-[3′-(3-heptyl-1-methylureido)-2-(4,4,4-trifluorobutoxy)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 252 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(4,4,4-trifluorobutoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=78° C.). Yield=74% over the two steps
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:30][C:31]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([OH:40])[CH:34]=[CH:33][C:32]=1[C:41](=[O:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:40][C:35]3[CH:34]=[CH:33][C:32]([C:41](=[O:43])[CH3:42])=[C:31]([OH:30])[C:36]=3[CH2:37][CH2:38][CH3:39])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCBr)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 72.5 %

Procedure:
A mixture of 2 g of [[8-acetyl-7-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.9 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 14 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. The solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil which was purified by high pressure liquid chromatography (60% ethyl acetate-hexane) to yield 1.8 g (73%) of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32](Cl)[C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=1)[CH3:21]>CN(C)C=O.O>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]([CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH:32]([S:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=1)[CH3:21]
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(C)cc1
Temperature: 25 °C

Procedure:
ρ-Thiocresol (0.43 g) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.14 g) in dry N, N-dimethylformamide (23 mL,) under N2. The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate (1.31 g) in dry N,N-dimethylformamide (16 mL) and the mixture was then left stirring at room temperature for a further 12 hrs. The reaction mixture was diluted with water (375 mL) before extracting with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with water (3×100 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using 60% hexane in ethyl acetate as eluent to afford the title compound which solidified on standing, mp 88.6°-90.1° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)O1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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>[CH:14]([N:12]1[CH:13]=[C:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:29][CH:30]=3)[CH:3]=2)[N:10]=[N:11]1)([CH3:16])[CH3:15]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(N4CCOCC4)cc3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (100 mg, 0.35 mmol) and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-morpholine (88 mg, 0.42 mmol) in 1,4-dioxane (7.0 mL)/water (3.0 mL) was added Cs2CO3 (227 mg, 0.70 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(PPh3)4 (20.2 mg, 0.017 mmol) was added and allowed to stir at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 3-97% MeOH in DCM to afford the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11].[Cl:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH3:14])[C:10]#[N:11]
Reactant: CON=C(C#N)c1ccccc1CBr
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1COc1cccc(Cl)c1
Yield: 61.5 %

Procedure:
2-Bromomethyl-α-methoxyiminophenylacetonitrile (5.0 g, 20 mmol) and 3-chlorophenol (3.0 g, 23 mmol) were dissolved in dimethylformamide (25 ml), and the mixture was stirred at room temperature for 2 hours in the presence of potassium carbonate (3.3 g, 24 mmol). After completion of the reaction, diethyl ether (ca. 100 ml) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and crystallized from diethyl ether/n-hexane to give 2-(3-chlorophenoxymethyl)-α-methoxyiminophenylacetonitrile (3.7 g, 62%) as colorless crystals.
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=1[CH3:29]>C1(C)C=CC=CC=1>[CH3:29][C:19]1[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:27]=[CH:28][C:18]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Into 150 ml of water were suspended 55.9 g of sodium carbonate and 38.6 g of phenylboronic acid. Thereto was added 51.4 g of ethyl 4-bromo-3-methylbenzoate dissolved in 400 ml of toluene and then was added 4.0 g of tetrakistriphenylphosphine palladium, followed by 2 hours of reflux with heating. After the reaction solution was cooled to room temperature, filtration was conducted using celite, water was added to the filtrate and the organic layer was extracted with toluene. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 50.4 g of ethyl 2-methylbiphenyl-4-carboxylate as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58](ON2C3C=CC=CC=3N=N2)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O>[C:32]([NH:51][C:52]1[S:53][CH:54]=[C:55](/[C:57](=[N:70]/[O:71][CH3:72])/[C:58]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:15]([NH:16][CH:17]([CH3:18])[CH3:19])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:59])[N:56]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 84.7 %

Procedure:
To a solution of 7β-amino-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.35 g, 3.63 mmol) and triethylamine (0.735 mg, 7.26 mmol) in dimethylacetamide (17 ml) was added 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (3.05 g, 5.44 mmol). The mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-isopropylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.45 g, 84.8%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.[OH-].[K+]>O.O1CCOCC1>[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)n1
Reactant: COCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1ccccc1-c1ccc(OCc2cccc(C(=O)O)n2)cc1
Reaction time: 1 h

Procedure:
A first stock solution was prepared consisting of 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (of intermediate 5; 1.77 g, 4.8 mmol), bis(tri -cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 168 mg, 0.25 mmol), and dioxane (approximately 100 mL). A second stock solution was prepared consisting of potassium carbonate (1.99 g, 14.4 mmol) and water (approximately 10 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction tube containing 2-methoxymethyl-phenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK; 100 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min, and then 1 M KOH solution (1 equivalent) was added and the reaction mixture was heated in the microwave for 10 minutes at 120 degrees, for 10 minutes at 130 degrees, and at 170 degrees for one hour. The reaction mixture was then filtered through a silica column (1 g) and washed with dimethylacetamide (2×1 mL). The solvent was evaporated to give 6-(2′-methoxymethyl-biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid. Mass spectrum MH+=350.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:25]=1)[C:22]1[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([Cl:24])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:25]=1)[C:10]1[CH:11]=[C:12]([Cl:24])[CH:13]=[CH:14][C:15]=1[O:16][C:17]1[C:22]2=[CH:21][C:20]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Cl)ccc1Oc1ccc(Br)cc12
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: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC1=NC2(CS1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 100 °C

Procedure:
A 10-20 mL microwave vial was charged with racemic-N-tert-butyl-2′-bromo-7′-chloro-spiro[1,3-thiazole-4,9′-xanthen]-2-amine (363 mg, 829 μmol), pyrimidin-5-ylboronic acid (257 mg, 2073 μmol), tetrakis(triphenylphosphine)palladium(0) (95.8 mg, 82.9 μmol), THF (8292 μl, 829 μmol), and potassium carbonate (3455 μl of a 1.2 M aqueous solution, 4146 μmol). The vial was covered with a blanket of Ar (g), capped, and heated in a Biotage Initiator microwave reactor for 1 h at 100° C. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on an 80-g Redi-Sep column, eluting with 0-50% EtOAc/Hexane to give rac-N-tert-butyl-2′-chloro-7′-(5-pyrimidinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine as an orange-yellow solid. MS m/z=437.2 [M+H]+. Calc'd for C23H22ClN4OSS: 437.1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][NH:3]1.[O:13]1[CH:17]=[CH:16][CH2:15][CH2:14]1>N1C=CC=CC=1>[O:13]1[CH2:14][CH2:15][CH2:16][CH:17]1[N:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:8])[N:7]([CH:14]2[CH2:15][CH2:16][CH2:17][O:13]2)[C:2]1=[O:1]
Reactant: C1=COCC1
Reactant: COC(=O)c1c[nH]c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: COC(=O)c1cn(C2CCCO2)c(=O)n(C2CCCO2)c1=O
Yield: 12.9 %

Procedure:
In 14 ml. of pyridine are dissolved 3.4 g. (20.0 mmoles) of methyl 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate and 4.9 g. (70.0 mmoles) of 2,3-dihydrofuran and the solution is heated in a closed reaction vessel at 140° C. for 6 hours. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is dissolved in 30 ml. of chloroform and applied to a column of 68 g. of silica gel. Elution is carried out with 250 ml. of chloroform and the eluate is concentrated to dryness under reduced pressure to give 0.8 g. (yield 12.9%) of methyl 1,3-bis(2-tetrahydrofuryl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35]([O:37][CH2:38][CH2:39]Cl)=[O:36])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:43])[C:5]2=[N:4][C:3]=1[CH3:44].C[O-].[Na+].O>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:42])[CH2:23][NH:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][O:37][C:35]5=[O:36])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:43])[C:5]2=[N:4][C:3]=1[CH3:44]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)OCCCl)cc4)c3Cl)cccn2c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5CCOC5=O)cc4)c3Cl)cccn2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-[4-(2-chloroethoxycarbonylamino)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (128 mg) in methanol was added dropwise sodium methanolate (28% in methanol, 37 mg) under nitrogen in ice-water bath and the mixture was stirred for 1 hour at same temperature and then at ambient temperature for 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography(ethyl acetate) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(2-oxo-3-oxazolidinyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (77 mg) as an amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([C@H:16]([CH2:20][O:21][CH3:22])[CH2:17][CH:18]=O)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([C@H:16]([CH2:20][O:21][CH3:22])[CH2:17][CH2:18][N:30]2[CH2:31][CH2:32][C:27]3([CH2:25][CH2:26]3)[C@H:28]([OH:33])[CH2:29]2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC[C@H](CC=O)N1C[C@@H](C)N(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)OC(C)(C)C)CCC1=O
Yield: 94 %

Procedure:
In analogy to the procedure described for example 58D, (R)-4-((S)-1-methoxymethyl-3-oxo-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 94% yield as yellow viscous oil. MS: 440.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:13][C:10]1[O:9][C:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([N:37]4[C:38]5[CH:39]=[C:40]6[C:27]7([CH2:30][O:31][C:32]6=[CH:33][C:34]=5[CH2:35][CH2:36]4)[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]7)=[O:22])=[CH:18][CH:19]=3)=[C:2]([CH3:1])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Product: Cc1ccc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
2'-Methyl-4'-(5-methylfuran-2-yl)biphenyl-4-carboxylic acid (D119) (160 mg, 0.55 mmol) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 134 mg, 0.55 mmol) were converted to the title compound using the method outlined in Example 29, as an off-white foam (176 mg, 62%).